A stereoselective total synthesis of xyolide, a natural bioactive nonenolide

Article abstract of DOI:10.1002/hlca.201400291

A stereoselective total synthesis of xyolide, a naturally occurring bioactive nonenolide, has been accomplished. The acid fragment of the molecule has been prepared from D-mannitol and the alcohol fragment from (2Z)-but-2-ene-1,4-diol. The synthesis invol

Full text of DOI:10.1002/hlca.201400291

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A Stereoselective Total Synthesis of Xyolide, a Natural Bioactive
Nonenolide1)
by Lingaiah Maram and Biswanath Das*
Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Hyderabad-
500007, India (phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
A stereoselective total synthesis of xyolide, a naturally occurring bioactive nonenolide, has been
accomplished. The acid fragment of the molecule has been prepared from d-mannitol and the alcohol
fragment from (2Z)-but-2-ene-1,4-diol. The synthesis involves the coupling of these two fragments
using the Yamaguchi esterification protocol, followed by intramolecular ring-closing methathesis. The
diastereoisomeric alcohol fragment has also been utilized in this synthesis by employing the Mitsunobu
esterification.
Introduction. – Naturally occurring nonanolides and nonenolides (ten-membered
lactones) possess interesting structural patterns and impressive biological properties
[1]. They contain various functionalities with different configurations. They also bear
alkyl side chains of various lengths. Some of the natural nonenolides, such as
herbarumins I, II, and III [2], stagonolides A and B [3], and seimatopolides A and B [4]
(Fig.), have been found to exhibit diverse bioactivities including phytotoxic, herbicidal,
and anticancer properties.
Xyolide (1; Fig.), a ten-membered lactone, has recently been isolated from an
Amazonian endophyte Xylaria ferieensis [5]. The structure of the compound was
established by 1D- and 2D-NMR spectral analysis, and its absolute configuration
(4S,7S,8S,9R) by exciton-coupled circular dichroism spectroscopy. The molecule
contains a long-chain alkyl group at C(9), along with cis-vicinal OH groups at C(7)
and C(8) with a-configuration. The third OH group at C(4) (also with a-configuration)
of 1 is esterified with succinic acid. The compound was found to inhibit the plant
pathogen, Pythium utimum with a MIC value of 425 mm. The structure and bioactivity
of xyolide (1) have attracted the attention of organic chemists to perform its synthesis
[6]. Here, we report our approach for a stereoselective total synthesis of 1.
Results and Discussion. – In continuation of our work [7] on the stereoselective
construction of natural bioactive molecules, we have realized that xyolide (1) might be
synthesized from the diene 2, which can be prepared from the alcohol fragment 3 and
acid fragment 4 (Scheme 1). A similar strategy has been applied in a previous synthesis
of xyolide [6c]. However, the stereoselective preparation of the two fragments, 3 and 4,
are different here, and they were obtained from (2Z)-but-2-ene-1,4-diol (5) and d-
mannitol (6), respectively.
1
)
Part 82 in the series ꢁSynthetic Studies on Natural Productsꢂ.
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 98 (2015)
675
Figure. Structures of some nonenolides
Scheme 1. Retrosynthetic Analysis of 1 (see also [6c])
Synthesis of the Alcohol Fragment 3. For the synthesis of 3, (2Z)-but-2-ene-1,4-diol
(5) was converted to the known chiral epoxy alcohol 7 [8], which was oxidized with
SO3 · Py [9] in CH2Cl2, and the corresponding aldehyde was subjected to C1-Wittig
olefination [10a] with Ph3PCH3Br using NaHMDS in THF to form the epoxy alkene 8
(Scheme 2). The analogous transformation of 7 into 8 has been already described in
[10b]. The epoxy ring of 8 was opened with Sc(OTf)3 in THF/H2O 10 :1 to furnish the
diol 9 [11]. The two OH groups of 9 were protected as acetonide (!10) by treatment

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Scheme 2. Synthesis of the Alcohol Fragment 3
a) See [8]. b) i) SO3 · Py, CH2Cl2/DMSO 3 :1, Et3N, 08, 2 h; ii) Ph3PCH3Br, sodium bis(trimethylsilyl)-
amide (NaHMDS), THF, 08 – r.t., 8 h; 84% (for two steps). c) Scandium(III) trifluoromethanesulfonate
(Sc(OTf)3), THF/H2O (10 :1), 3 h; 94%. d) 2,2-Dimethoxypropane(2,2-DMP), CH2Cl2, pyrodonium p-
toluenesulfonate (PPTS), 08 – r.t., 4 h; 98%. e) Li Metal, naphthalene, dry THF, À 258, 2 h; 96%. f) i)
SO3 · Py, CH2Cl2/DMSO 3 :1, Et3N, 08, 1 h; ii) Me(CH2)6MgBr (1.2m in THF), THF, 08 – r.t., 6 h; 96%
(for two steps).
with 2,2-dimethoxypropane (2,2-DMP) and PPTS. The Bn group of 10 was removed
with Li and naphthalene to afford the alcohol 11 in high yield. The latter was oxidized
with SO3 · Py in CH2Cl2, and the aldehyde obtained was treated with the Grignard
reagent Me(CH2)6MgBr to afford the diastereoisomeric alcohols 3 (major) and 3a
(minor) in a ratio of 3 :2. The alcohols 3 and 3a were separated and used for the next
steps. Comparison of the data of the newly introduced stereogenic center C(9) of the
target molecule, or C(5) of the diastereoisomers 3 and 3a with those reported
previously confirmed the presence of 3 [6c] as (9R) and 3a as (9S)-isomer. Both
diastereoisomers were utilized for the synthesis of the target molecule and reconfirmed
the absolute configuration of the diastereoisomers at C(5) of the alcohol fragment.
Synthesis of the Acid Fragment 4. For the synthesis of the acid fragment 4, d-
mannitol (6) was initially converted to the known alcohol 13 via the alkene 12, as
described in [12] (Scheme 3). The free OH group of 13 was protected by treatment with
PivÀCl and Et3N to afford ester 14, which was treated with 90% CF3COOH in H2O to
afford the diol 15. The latter was reacted with I2, Ph3P, and 1H-imidazole under reflux
to furnish the alkene ester 16 [13]. The ester group in 16 was deprotected by using
methanolic K2CO3 under reflux, and the alcohol obtained was oxidized with
[bis(acetoxy)iodo]benzene (BIAB) and TEMPO in MeCN and H2O to give the
desired acid fragment 4.
Synthesis of Xyolide (1). The alcohol fragment 3 was coupled with the acid 4 under
Yamaguchi esterification conditions [14] using 2,4,6-trichlorobenzoyl chloride in Et3N
and DMAP to furnish the ester 17 (Scheme 4). The same ester 17 was also produced
when the alcohol 3a was esterified with the acid 4 under Mitsunobu esterification
conditions [15] using Ph3P and DIAD. Thus, both the major and minor diastereoiso-
meric alcohols 3 and 3a (in Scheme 3) were employed to obtain the required ester 17.
The Bn-ether group of 17 was cleaved with Li and naphthalene to generate the diene
ester 2, which underwent intramolecular ring-closing methathesis (RCM) [16] in the

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Scheme 3. Synthesis of the Acid Fragment 4
677
a) See [12]. b) See [12]. c) Pivaloyl chloride (2,2-dimethylpropanoyl chloride; PivÀCl), Et3N, CH2Cl2,
08 – r.t., 2 h; 98%. d) 90% CF3CO2H in H2O, 08, 2 h; 86%. e) Ph3P, I2 , 1H-imidazole, toluene, reflux, 4 h,
92%. f) i) K2CO3, MeOH, reflux, 3 h; ii) (Diacetoxyiodo)benzene, (2,2,6,6,-tetramethylpiperidin-1-
yl)oxyl (TEMPO), MeCN/H2O 10 :1, 08, 3 h; 90% (for two steps).
Scheme 4. Synthesis of Xyolide (1)
a) For 3: 2,4,6-Trichlorobenzoyl chloride, Et3N, 4-(dimethylamino)pyridine (DMAP), toluene, 08 to r.t.,
6 h; 98%. b) for 3a: Ph3P, diisopropyl azodicarboxylate (DIAD), THF, 08 – r.t., 10 h, 80%. c) Li Metal,
naphthalene, dry THF, À 258, 4 h, 96%. d) Grubbsꢂ II (cat.), CH2Cl2, reflux, 12 h; 82%. g) i) Succinic
anhydride, DMAP, CH2Cl2, 08 to r.t., 1 h; ii) MeCN, 4n HCl, 08 to r.t., 4 h; 90% (for two steps).
presence of Grubbsꢂ second-generation catalyst to yield the nonanolide 18. The
esterification of the free OH group of 18 with succinic anhydride and DMAP, followed
by treatment of the product with 4n HCl afforded the xyolide (1). The physical (optical

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rotation) and spectral (1H-NMR, 13C-NMR, and MS) properties of the synthetic
compound 1 were in agreement with those reported for the natural product [5]. It
should be mentioned that the reaction steps shown in Scheme 4 were also used in the
earlier synthesis of xyolide, however, the protecting group was different [6c]. The new
input is that, in the present synthesis, both diastereoisomers 3 and 3a have been utilized
for the preparation of 17 and 2.
In conclusion, we have described a simple and straightforward stereoselective
synthesis of xyolide, a naturally occurring bioactive nonenolide. The synthesis involves
d-mannitol and (2Z)-but-2-ene-1,4-diol as the starting materials. The key steps of the
synthesis are Yamaguchi and Mitsunobu esterification and intramolecular ring-closing
metathesis. The present synthesis is an access to various analogs of xyolide, required for
advanced biological screening.
The authors thank CSIR and UGC, New Delhi, for financial support.
Experimental Part
General. All reactions were monitored by TLC (silica gel F254 pre-coated plates; visualization with
UV light or I2 stain). Column chromatography (CC): silica gel 60 – 120 mesh (Qingdao Marine Chemical,
P. R. China); solvents (AcOEt and hexane) were of technical grade. Optical rotations: JASCO DIP 360
digital polarimeter. IR: Perkin-Elmer RX FT-IR spectrophotometer. 1H- and 13C-NMR: Bruker
(Avance) 300 (1H) and 75 MHz (13C), and Varian Unity (Innova) 500 (1H) and 125 MHz (13C)
spectrometers at r.t. ESI-MS: VG-Autospec micromass spectrometer; in m/z.
(2R,3R)-2-((Benzyloxy)methyl)-3-vinyloxirane (¼ 3,4-Anhydro-5-O-benzyl-1,2-dideoxy-d-threo-
pent-1-enitol; 8). To a stirred soln. of {(2R,3R)-3-[(benzyloxy)methyl]oxiran-2-yl}methanol (7 [8];
1.5 g, 7.73 mmol) in a mixture of CH2Cl2/DMSO 3 :1 (15 ml) at 08, Et3N (5.43 ml, 38.65 mmol) and SO3 ·
Py (6.2 g, 38.65 mmol) were added subsequently under N2. The resulting mixture was stirred at the same
temp. for 1 h. After completion of the reaction (TLC), the mixture was diluted with cold H2O (5 ml), and
the org. layer was extracted with Et2O (3 Â 15 ml). The combined org. layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The crude aldehyde (1.4 g, 96%) was used directly after flash
chromatography (FC) for the next reaction.
Methyl(triphenyl)phosphonium bromide (5.12 g, 14.34 mmol) was thoroughly flame-dried, and anh.
THF (25 ml) was added, and the resulting suspension was cooled to 08 prior to the dropwise addition of
NaHMDS in THF (14.34 ml, 14.34 mmol). The resulting cold suspension was warmed to 258 for 30 min
and recooled to À 108 prior to the addition of the above aldehyde (1.40 g, 7.29 mmol) soln. in anh. THF
(5 ml). The mixture was stirred at r.t. for 10 h, and the reaction was quenched by the addition of sat. aq.
NH4Cl (20 ml). The mixture was then extracted with Et2O (4 Â 10 ml), washed sequentially with H2O
(15 ml) and sat. NaCl (3 Â 10 ml), and dried (Na2SO4). Removal of solvents under reduced pressure,
followed by FC (SiO2; AcOEt/hexane, 3 :7) gave compound 8 (1.2 g, 84%). Colorless oil. [a]2D5 ¼ þ10.00
1
(c ¼ 1.0, CHCl3). IR (KBr): 2988, 2859, 1643, 1454, 1360, 1103, 927, 877, 739, 698. H-NMR (500 MHz,
CDCl3): 7.38 – 7.27 (m, 5 H); 5.61 – 5.53 (m, 1 H); 5.49 (d, J ¼ 16.0, 1 H); 5.29 (d, J ¼ 9.0, 1 H); 4.60 (d, J ¼
12.0, 1 H); 4.53 (d, J ¼ 12.0, 1 H); 3.75 (dd, J ¼ 12.0, 4.0, 1 H); 3.51 (dd, J ¼ 12.0, 6.0, 1 H); 3.28 (dd, J ¼
7.0, 2.0, 1 H); 3.11 – 3.08 (m, 1 H). 13C-NMR (125 MHz, CDCl3): 137.7; 134.9; 128.3; 127.6 (2C); 119.6;
73.2; 69.7; 58.5; 55.8. ESI-MS: 191 ([M þ H]þ). Anal. calc. for C12H14O2 (190.24): C 75.76, H 7.42; found:
C 75.61, H 7.38.
(2R,3S)-1-(Benzyloxy)pent-4-ene-2,3-diol (¼ 5-O-Benzyl-1,2-dideoxy-d-erythro-pent-1-enitol; 9).
To a stirred soln. of 8 ([10]; 1.0 g, 5.26 mmol) in THF/H2O 10 :1 (10 ml) was added Sc(OTf)3 (0.52 g,
0.45 mmol), and the mixture was stirred at r.t. for 3 h. The resulting diol was extracted with AcOEt (4 Â
10 ml) and washed sequentially with sat. aq. NH4Cl and brine, dried (Na2SO4), and concentrated under
reduced pressure. The crude mixture was purified by CC (SiO2 ; AcOEt/hexane 4 :6) to provide 9 (1.02 g,
94%). Colorless oil. [a]2D5 ¼ À4.64 (c ¼ 1.0, CHCl3). IR (KBr): 3420, 2921, 2867, 1454, 1098, 994, 928, 698.

Helvetica Chimica Acta – Vol. 98 (2015)
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1H-NMR (500 MHz, CDCl3): 7.39 – 7.30 (m, 5 H); 5.93 – 5.84 (m, 1 H); 5.35 (d, J ¼ 16.0, 1 H); 5.22 (d, J ¼
9.0, 1 H); 4.56 (d, J ¼ 12.0, 1 H); 4.52 (d, J ¼ 12.0, 1 H); 4.29 – 4.23 (m, 1 H); 3.81 (q, J ¼ 7.0, 1 H); 3.64 –
3.59 (m, 2 H); 2.74 (br. s, 1 H); 2.61 (br. s, 1 H). 13C-NMR (125 MHz, CDCl3): 137.5; 136.4; 128.5; 127.8;
127.9; 116.8; 74.2; 73.6; 72.3; 71.0. ESI-MS: 209 ([M þ H]þ). Anal. calc. for C12H16O3 (208.25): C 69.21, H
7.74; found: C 69.32, H 7.69.
(4R,5S)-4-((Benzyloxy)methyl)-5-ethenyl-2,2-dimethyl-1,3-dioxolane (¼ 5-O-Benzyl-1,2-dideoxy-
3,4-O-(1-methylethylidene)-d-erythro-pent-1-enitol; 10). To a stirred soln. of 9 (1.0 g, 4.80 mmol) in
15 ml of dry CH2Cl2 was added a cat. amount of PPTS and 2,2-DMP (1.18 ml, 9.61 mmol) at 08. The
mixture was stirred at 08 to r.t. for 6 h. After completion (TLC), the reaction was quenched with cold
H2O (5 ml), and then the mixture was extracted with CH2Cl2 (3 Â 10 ml). The combined org. layers were
dried (Na2SO4) and concentrated in vacuo. The residue was purified by CC (SiO2; AcOEt/hexane 2 :98)
to afford 10 (1.168 g, 98%). Colorless liquid. [a]2D5 ¼ À5.41 (c ¼ 1.0, CHCl3). IR (KBr): 2867, 1453, 1218,
1
1094, 928, 771, 698. H-NMR (500 MHz, CDCl3): 7.38 – 7.27 (m, 5 H); 5.84 – 5.76 (m, 1 H); 5.35 (d, J ¼
16.0, 1 H); 5.21 (d, J ¼ 9.0, 1 H); 4.62 – 4.56 (m, 2 H); 4.51 (d, J ¼ 12.0, 1 H); 4.39 (q, J ¼ 7.0, 1 H);
3.48 – 3.42 (m, 2 H); 1.50 (s, 3 H); 1.39 (s, 3 H). 13C-NMR (125 MHz, CDCl3): 138.1; 133.6; 128.5; 127.8;
127.7; 118.1; 109.0; 78.6; 77.0; 73.6; 69.5; 27.9; 25.3. ESI-MS: 249 ([M þ H]þ). Anal. calc. for C15H20O3
(248.32): C 72.55, H 8.12; found: C 72.68, H 8.06.
[(4R,5S)-5-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (¼1,2-Dideoxy-3,4-O-(1-methylethyli-
dene)-d-erythro-pent-1-enitol; 11). To soln. of naphthalene (2.0 g, 16.13 mmol) in dry THF (15 ml)
was added Li metal (112 mg, 16.13 mmol). After 30 min, a dark-green color developed which turned
darker after 1.5 h. This soln. was cooled to À 258, and a soln. of 10 (1.0 g, 4.0 mmol) in dry THF (3 ml)
was added by cannula. The resulting mixture was stirred at À 258 for 3 h. After completion of reaction
(TLC), sat. aq. NH4Cl (5 ml) and H2O (15 ml) were added. The resulting mixture was extracted with
Et2O (3 Â 10 ml), the org. phase was washed with brine and dried (anh. Na2SO4). The solvent was
removed under reduced pressure to a yield a crude compound, which was purified by CC (AcOEt/hexane
15 :85) to afford 11 (0.6 g, 96%). [a]2D5 ¼ À2.22 (c ¼ 1.0, CHCl3). IR (KBr): 3420, 2927, 1646, 1039, 770.
1H-NMR (500 MHz, CDCl3): 5.91 – 5.82 (m, 1 H); 5.41 (d, J ¼ 16.0, 1 H); 5.29 (d, J ¼ 9.0, 1 H); 4.64 (t,
J ¼ 7.0, 1 H); 4.28 (d, J ¼ 7.0, 1 H); 3.59 (d, J ¼ 7.0, 2 H); 2.21 (br. s, 1 H); 1.51 (s, 3 H); 1.40 (s, 3 H).
13C-NMR (125 MHz, CDCl3): 133.1; 118.8; 108.8; 78.2; 78.1; 61.8; 27.8; 25.1. ESI-MS: 181 ([M þ Na]þ).
Anal. calc. for C8H14O3 (158.19): C 60.74, H 8.92; found: C 60.63, H 8.88.
(1R)-1-[(4R,5S)-5-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl]octan-1-ol (3). To a stirred soln. of 11
(0.5 g, 3.164 mmol) in CH2Cl2/DMSO 3 :1 (15 ml) at 08, Et3N (2.22 ml, 15.82 mmol) and SO3 · Py (2.53 g,
15.82 mmol) were added subsequently under N2. The resulting soln. was stirred at same temp. for 1 h.
After completion of the reaction (TLC), the mixture was diluted with cold H2O (5 ml), and the org. layer
was extracted with Et2O (3 Â 15 ml). The combined org. layers were dried (Na2SO4), filtered, and
concentrated in vacuo. The crude aldehyde was used directly after FC for the next reaction.
To a stirred soln. of the aldehyde (0.45 g, 2.88 mmol) in dry THF (10 ml) was added
heptylmagnesium bromide (1.2m soln. in THF) at 08, and the mixture was stirred for 4 h at the same
temp. After completion of the reaction (TLC), sat. aq. NH4Cl (10 ml) was added at 08. The mixture was
extracted with AcOEt (3 Â 10 ml), the org. phase was washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was purified by CC (hexane/AcOEt 97:3) to
obtain pure 3 (0.42 g, 1.64 mmol) and 3a (0.28 g, 1.093 mmol) as colorless liquid (0.70 g, 2.73 mmol, dr
3 :2, 96% (for two steps)).
Data of 3. [a]2D5 ¼ þ11.2 (c ¼ 1.0, CHCl3). IR (KBr): 3444, 2926, 2856, 1664, 1379, 1217, 1055, 925,
874, 770, 723. 1H-NMR (500 MHz, CDCl3): 6.08 – 6.01 (m, 1 H); 5.43 (d, J ¼ 16.0, 1 H); 5.31 (d, J ¼ 9.0,
1 H); 4.65 (t, J ¼ 7.0, 1 H); 3.98 (t, J ¼ 7.0, 1 H); 3.69 – 3.62 (m, 1 H); 1.75 – 1.68 (m, 2 H); 1.49 (s, 3 H);
1.38 (s, 3 H); 1.34 – 1.22 (m, 10 H); 0.89 (t, J ¼ 7.0, 3 H). 13C-NMR (125 MHz, CDCl3): 134.9; 118.5; 108.9;
80.9; 79.0; 70.1; 33.9; 31.8; 29.8; 29.2; 28.0; 25.2; 25.1; 22.5; 14.0. ESI-MS: 257 ([M þ H]þ). Anal. calc. for
C15H28O3 (256.38): C 70.27, H 11.01; found: C 70.40, H 11.05.
Data of (1S)-1-[(4R,5S)-5-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl]octan-1-ol (3a). [a]2D5 ¼ þ7.66
1
(c ¼ 1.0, CHCl3). IR (KBr): 3445, 2928, 2857, 1717, 1446, 1216, 1067, 765. H-NMR (500 MHz, CDCl3):
6.02 – 5.93 (m, 1 H); 5.35 (d, J ¼ 16.0, 1 H); 5.29 (d, J ¼ 9.0, 1 H); 4.58 (t, J ¼ 7.0, 1 H); 4.02 (t, J ¼ 7.0,
1 H); 3.60 – 3.53 (m, 1 H); 1.52 (s, 3 H); 1.48 – 1.41 (m, 4 H); 1.39 (s, 3 H); 1.35 – 1.24 (m, 8 H); 0.89

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(t, J ¼ 7.0, 3 H). 13C-NMR (125 MHz, CDCl3): 134.1; 119.2; 108.7; 81.0; 79.1; 71.1; 33.8; 31.9; 30.2; 27.5;
25.6; 25.1; 24.4; 22.6; 14.0. ESI-MS: 257 ([M þ H]þ). Anal. calc. for C15H28O3 (256.38): C 70.27, H 11.01;
found: C 70.16, H 10.94.
4-O-Benzyl-5,6-O-cyclohexane-1,1-diyl-2,3-dideoxy-1-O-(2,2-dimethylpropanoyl)-d-erythro-hexitol
(14). To a stirred soln. of 13 ([12]; 3.0 g, 9.375 mmol) in dry CH2Cl2 (15 ml) were added Et3N (3.16 ml,
22.5 mmol) and PivÀCl (1.38 ml, 11.25 mmol) subsequently at 08 under N2. The mixture was stirred for
4 h at r.t. After completion of the reaction (TLC), the mixture was diluted with cold H2O (10 ml),
extracted with CH2Cl2 (3 Â 10 ml), and the org. layer was washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was purified by CC (hexane/AcOEt 95 :5) to
furnish 14 (3.70 g, 9.16 mmol, 98%). [a]2D5 ¼ þ5.4 (c ¼ 1.0, CHCl3). IR (KBr): 2935, 1726, 1282, 1161, 935,
712. 1H-NMR (500 MHz, CDCl3): 7.37 – 7.28 (m, 5 H); 4.61 (q, J ¼ 11.4, 2 H); 4.10 – 4.02 (m, 4 H); 3.91 –
3.86 (m, 1 H); 3.56 – 3.52 (m, 1 H); 1.65 – 1.51 (m, 12 H); 1.44 – 1.34 (m, 2 H); 1.20 (s, 6 H); 1.18 (s, 3 H).
13C-NMR (125 MHz, CDCl3): 178.5; 138.3; 128.3 (2C); 127.8; 127.7; 109.6; 78.7; 72.5; 66.2; 64.2; 36.3;
34.8; 27.3; 25.1; 24.1; 24.0; 23.8. ESI-MS: 427 ([M þ H]þ). Anal. calc. for C24H36O5 (404.54): C 71.27, H
8.97; found: C 71.14, H 8.89.
(4S,5R)-4-(Benzyloxy)-5,6-dihydroxyhexyl Pivalate (¼4-O-Benzyl-2,3-dideoxy-1-O-(2,2-dimethyl-
propanoyl)-d-erythro-hexitol; 15). Compound 14 (3.5 g, 9.5 mmol) was dissolved in 90% aq. CF3CO2H
(10 ml) at 08, and the mixture was stirred at the same temp. for 2 h. The mixture was then extracted with
CH2Cl2 (3 Â 30 ml). The collected org. layers were combined, washed with 10% NaHCO3 (3 Â 50 ml),
H2O, and brine, and dried (Na2SO4), and concentrated in vacuo. The residue was purified by CC (AcOEt/
hexane 3 :7) to afford 15 (2.63 g, 86%). Syrup. [a]2D5 ¼ À6.2 (c ¼ 1.0, CHCl3). IR (KBr): 3442, 2960, 1723,
1283, 1163, 714. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.31 (m, 5 H); 4.62 (d, J ¼ 12.0, 1 H); 4.58 (d, J ¼ 12.0,
1 H); 4.17 – 4.03 (m, 2 H); 3.80 – 3.70 (m, 3 H); 3.66 – 3.54 (m, 1 H); 1.85 – 1.80 (m, 4 H); 1.20 (s, 9 H).
13C-NMR (75 MHz, CDCl3): 178.7; 137.9; 129.7; 128.4; 127.8; 79.6; 72.1; 72.0; 63.9; 63.0; 38.5; 27.0; 26.3;
24.2. ESI-MS: 325 ([M þ H]þ). Anal. calc. for C18H28O5 (324.41): C 66.64, H 8.70; found: C 66.78, H 8.74.
(S)-4-(Benzyloxy)hex-5-en-1-yl Pivalate (¼(4S)-4-(Benzyloxy)hex-5-en-1-yl 2,2-Dimethylpropan-
oate; 16). To a soln. of 15 (2.5 g, 7.71 mmol) in dry toluene (20 ml) was added Ph3P (8.0 g, 30.54 mmol),
followed by 1H-imidazole (2.1 g, 30.88 mmol), and stirred vigorously. To the resulting soln. was added I2
(5.87 g, 23.14 mmol), and the mixture was heated under reflux at 1108 for 3 h. The mixture was cooled to
r.t., and decanted into excess sat. aq. Na2S2O3 (20 ml) and sat. aq. NaHCO3 (30 ml) in a separating funnel.
The residue in the reaction flask was extracted with AcOEt (3 Â 10 ml). This org. layers were combined
with the material in the separating funnel and shaken until the I2 was consumed. The org. phase was
washed with H2O (2 Â 10 ml), and dried and concentrated. The crude residue was purified by CC
(hexanes/AcOEt 95 :5) to give 16 (2.0 g, 6.89 mmol, 92%). Viscous liquid. [a]2D5 ¼ þ5.2 (c ¼ 1.0, CHCl3).
IR (KBr): 2935, 1736, 1282, 1161, 935, 712. 1H-NMR (300 MHz, CDCl3): 7.37 – 7.24 (m, 5 H); 5.81 – 5.66
(m, 1 H); 5.29 – 5.19 (m, 2 H); 4.60 (d, J ¼ 12.0, 1 H); 4.35 (d, J ¼ 12.0, 1 H); 4.03 (t, J ¼ 7.0, 2 H); 3.75 (q,
J ¼ 7.0, 1 H); 1.78 – 1.58 (m, 4 H); 1.19 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 178.6; 138.6; 138.5; 128.2;
127.6; 127.4; 117.5; 79.9; 70.0; 64.2. 38.6; 31.7; 27.1; 24.5. ESI-MS: 291 ([M þ H]þ). Anal. calc. for
C18H26O3 (290.40): C 74.45, H 9.02; found: C 74.34, H 8.96.
(S)-4-(Benzyloxy)hex-5-enoic Acid (4). To a stirred soln. of 16 (1.8 g, 6.20 mmol) in MeOH (15 ml)
was added K2CO3 (4.28 g, 31.0 mmol) at r.t., and the mixture was heated at reflux for 2 h. After
completion of the reaction (TLC), MeOH was removed under vacuum. Then, the residue was diluted
with AcOEt (20 ml), and the mixture was filtered through Celite pad. The org. layer was dried (Na2SO4)
and concentrated under reduced pressure to yield the corresponding alcohol. The crude alcohol was used
directly after FC for the next reaction.
To a soln. of the alcohol (1.2 g, 5.82 mmol) in MeCN/H2O 2 :1 (20 ml) were added [bis(acetoxy)-
iodo]benzene (BAIB; 4.126 g, 12.81 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO;
182 mg, 1.164 mmol) at 08. The mixture was stirred at r.t. for 3 h. After completion of the reaction
(TLC), the mixture was filtered and extracted with AcOEt (3 Â 10 ml). The combined org. phases were
dried and concentrated under reduced pressure. The crude residue was purified by CC (hexanes/AcOEt
95 :5) to give the acid fragment 4 (1.15 g, 90% yield). Pale-yellow liquid. [a]2D5 ¼ À25.49 (c ¼ 1.0, CHCl3).
IR (neat): 3421, 2925, 1708, 1423, 1070, 929, 698. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.25 (m, 5 H); 5.79 –
5.69 (m, 1 H); 5.30 – 5.22 (m, 2 H); 4.60 (d, J ¼ 12.0, 1 H); 4.33 (d, J ¼ 12.0, 1 H); 3.81 (q, J ¼ 7.0, 1 H);

Helvetica Chimica Acta – Vol. 98 (2015)
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2.50 – 2.43 (m, 2 H); 1.99 – 1.82 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 179.5; 138.2; 138.0; 128.2; 127.7;
127.4; 117.8; 79.1; 70.1; 30.1; 29.6. ESI-MS: 221 ([M þ H]þ). Anal. calc. for C13H16O3 (220.26): C 70.89; H
7.32; found: C 70.74; H 7.25.
(1R)-1-[(4R,5S)-5-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl]octyl (4S)-4-(Benzyloxy)hex-5-enoate
(17). a) To a stirred soln. of 4 (0.2 g, 0.90 mmol) in toluene (5 ml) were added Et3N (0.16 ml,
1.163 mmol) and 2,4,6-Cl3C6H2COCl (0.18 ml, 1.172 mmol) at 08. The mixture was stirred for 1 h at 08,
and a soln. of 3 (0.2 g, 0.78 mmol) and DMAP (190 mg, 1.56 mmol) in toluene (5.0 ml) were then added
at 08. The resulting mixture was stirred at r.t. for 6 h. After completion of the reaction (TLC), the
reaction was quenched with sat. NaHCO3 at 08, and the mixture was extracted with AcOEt (3 Â 10 ml),
washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was
purified by FC (AcOEt/hexane 1:9) to give 17 (0.35 g, 0.76 mmol, 98%). Colorless oil. [a]2D5 ¼ þ3.88 (c ¼
1.0, CHCl3). IR (neat): 2927, 2856, 1738, 1380, 1248, 1168, 1069, 927, 874, 698. 1H-NMR (500 MHz,
CDCl3): 7.38 – 7.27 (m, 5 H); 5.82 – 5.69 (m, 2 H); 5.32 – 5.18 (m, 4 H); 4.90 (t, J ¼ 7.0, 1 H); 4.60 – 4.56 (m,
2 H); 4.32 (d, J ¼ 12.0, 1 H); 4.16 (t, J ¼ 7.0, 1 H); 3.79 (q, J ¼ 7.0, 1 H); 2.44 – 2.37 (m, 1 H); 2.34 – 2.27 (m,
1 H); 1.97 – 1.88 (m, 1 H); 1.86 – 1.79 (m, 1 H); 1.72 – 1.64 (m, 1 H); 1.63 – 1.56 (m, 2 H); 1.48 (s, 3 H);
1.47 – 1.44 (m, 1 H); 1.33 (s, 3 H); 1.32 – 1.22 (m, 8 H); 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR (125 MHz, CDCl3):
172.7; 138.5; 138.2; 133.3; 128.3; 127.7; 127.4; 118.2; 118.0; 108.9; 79.6; 79.1; 78.7; 72.0; 70.1; 32.0; 31.1;
30.2; 30.1; 29.8; 29.2; 27.2; 25.1; 24.8; 22.8; 14.0. ESI-MS: 459 ([M þ H]þ). Anal. calc. for C28H42O5
(458.63): C 73.33, H 9.23; found: C 73.19, H 9.18.
b) To a soln. of 3a (0.2 g, 0.78 mmol), 4 (0.2 g, 0.94 mmol), and PPh3 (0.29 g, 1.1 mmol) in THF
(15 ml) at 08 was added DIAD (0.21 ml, 1.1 mmol). Stirring was continued at 08 for 1 h and then at r.t. for
10 h, then the soln. was concentrated and the crude residue was purified by CC (AcOEt/hexane 5 :95) to
afford 17 (0.29 g, 0.62 mmol, 80%). Colorless oil.
(1R)-1-[(4R,5S)-5-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl]octyl (4S)-4-Hydroxyhex-5-enoate (2).
To soln. of naphthalene (0.67 g, 5.24 mmol) in dry THF (15 ml) was added Li metal (0.037 g, 5.24 mmol).
After 30 min, a dark-green color developed which turned darker after 1 h. This soln. was cooled to À 258,
and to this a soln. of 17 (0.6 g, 1.31 mmol) in dry THF (3 ml) was added by cannula. The resulting mixture
was stirred at À 258 for 3 h. After completion of reaction (TLC), the reaction was quenched with sat. aq.
NH4Cl (5 ml) and H2O (15 ml). The resulting soln. was extracted into Et2O (4 Â 10 ml) and washed with
brine, dried (Na2SO4). The solvent was removed under reduced pressure to yield crude compound, which
was purified by CC (AcOEt/hexane 1:9) to afford 2 (0.46 g, 96%). [a]2D5 ¼ þ28.6 (c ¼ 1.0, CHCl3). IR
(neat): 3446, 2928, 1734, 1646, 1217, 771. 1H-NMR (500 MHz, CDCl3): 5.89 – 5.76 (m, 2 H); 5.32 (d, J ¼
16.0, 1 H); 5.27 (d, J ¼ 16.0, 1 H); 5.22 (d, J ¼ 9.0, 1 H); 5.15 (d, J ¼ 9.0, 1 H); 4.92 (t, J ¼ 7.0, 1 H); 4.80 (t,
J ¼ 7.0, 1 H); 4.20 – 4.14 (m, 2 H); 2.41 – 2.35 (m, 2 H); 1.90 – 1.81 (m, 2 H); 1.75 – 1.66 (m, 1 H); 1.64 –
1.58 (m, 3 H); 1.48 (s, 3 H); 1.36 (s, 3 H); 1.32 – 1.22 (m, 8 H); 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR
(125 MHz, CDCl3): 173.0; 140.3; 133.2; 118.6; 115.1; 109.0; 79.0; 78.4; 72.1; 72.0; 31.9; 31.6; 31.1; 30.3;
29.5; 29.1; 27.8; 25.1; 24.7; 22.3; 14.0. ESI-MS: 391 ([M þ Na]þ). Anal. calc. for C21H36O5 (368.51): C
68.48, H 9.85; found: C 68.36, H 9.78.
(3aR,4R,9S,10E,11aS)-4-Heptyl-3a,4,7,8,9,11a-hexahydro-9-hydroxy-2,2-dimethyl-6H-[1,3]dioxo-
lo[4,5-c]oxecin-6-one (18). Grubbsꢂ second-generation catalyst (45 mg, 0.05 mmol) was dissolved in dry,
deoxygenated CH2Cl2 (120 ml). After heating the soln. to reflux, 2 (0.05 g, 0.14 mmol) dissolved in
deoxygenated dry CH2Cl2 (80 ml) was added dropwise over 30 min. The mixture was heated at reflux for
12 h at 508. After completion of the reaction (TLC), the mixture was concentrated in vacuo, and the
residue was purified by CC (AcOEt/hexane 3 :7) to afford 18 (0.037 g, 0.11 mmol, 82%). Light-yellow
1
oil. [a]2D5 ¼ þ47.5 (c ¼ 1.0, CHCl3). IR (neat): 3444, 2928, 2858, 1731, 1379, 1217, 1073, 770. H-NMR
(500 MHz, CDCl3): 5.82 (dd, J ¼ 16.0, 3.0, 1 H); 5.68 (ddd, J ¼ 16.0, 10.0, 2.0, 1 H); 4.92 (td, J ¼ 7.0, 3.0,
1 H); 4.71 – 4.66 (m, 1 H); 4.21 – 4.13 (m, 1 H); 3.97 (dd, J ¼ 10.0, 5.0, 1 H); 2.37 – 2.31 (m, 1 H); 2.09 –
2.00 (m, 2 H); 1.83 – 1.74 (m, 1 H); 1.71 – 1.54 (m, 1 H); 1.54 (s, 3 H); 1.52 – 1.41 (m, 1 H); 1.38 (s, 3 H);
1.32 – 1.22 (m, 10 H); 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR (125 MHz, CDCl3): 175.1; 128.4; 126.2; 109.4; 78.8;
75.9; 75.8; 71.1; 33.8; 32.0; 31.9; 31.1; 29.1; 29.0; 28.5; 26.2; 24.4; 22.6; 14.0. ESI-MS: 341 ([M þ H]þ).
Anal. calc. for C19H32O5 (340.45): C 67.03, H 9.47; found: C 67.14, H 9.41.
Xyolide (¼4-{[(5S,6E,8S,9S,10R)-10-Heptyl-3,4,5,8,9,10-hexahydro-8,9-dihydroxy-2-oxo-2H-oxe-
cin-5-yl]oxy}-4-oxobutanoic Acid; 1). To a stirred soln. of 2 (0.02 g, 0.058 mmol) and DMAP (0.010 g,

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Helvetica Chimica Acta – Vol. 98 (2015)
0.09 mmol) in CH2Cl2 under N2 at 08, succinic anhydride (0.009 g, 0.09 mmol) in CH2Cl2 was added
dropwise, and the mixture was stirred at r.t. for 1 h. After completion of the reaction (TLC), the mixture
was concentrated. The crude mixture was dissolved in MeCN (10 ml), then 4n HCl was added until the
mixture became acidic. The mixture was stirred at r.t. for 4 h. After completion of the reaction, the
mixture was carefully extracted with AcOEt (3 Â 5 ml). The org. extract was dried (Na2SO4) and
concentrated. The crude mixture was purified by CC (AcOEt/hexane 9 :1 to AcOEt) to provide 1
(0.021 g, 0.052 mmol, 90%). Yellow solid. [a]2D5 ¼ þ2.8 (c ¼ 1.0, CHCl3). IR (neat): 3615, 3494, 3044,
1742, 1698, 1375, 1059, 968, 770. 1H-NMR (500 MHz, CDCl3): 5.87 (dd, J ¼ 15.5, 2.0, 1 H); 5.49 (ddd, J ¼
15.5, 10.0, 1.5, 1 H); 5.19 – 5.11 (m, 1 H); 5.00 (td, J ¼ 10.0, 2.0, 1 H); 4.51 (br. s, 1 H); 3.59 (dd, J ¼ 10.0,
2.0, 1 H); 2.65 (t, J ¼ 6.0, 1 H); 2.60 (t, J ¼ 5.5, 1 H); 2.39 – 2.28 (m, 1 H); 2.08 – 1.98 (m, 3 H); 1.91 – 1.82
(m, 1 H), 1.66 – 1.48 (m, 1 H); 1.35 – 1.20 (m, 3 H); 0.88 (t, J ¼ 7.0, 3 H). 13C-NMR (125 MHz, CDCl3):
176.2; 174.9; 171.9; 132.9; 123.7; 76.8; 73.5; 72.8; 71.0; 31.8; 31.6; 31.3; 29.6; 29.4; 29.3; 29.2; 28.9; 24.5;
22.7; 14.1. ESI-MS: 423 ([M þ Na]þ). Anal. calc. for C20H32O8 (400.46): C 59.98, H 8.05; found: C 59.86,
H 8.03.
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Received September 12, 2014