Synthesis of the structures proposed for natural butanolides piliferolides A and C

Article abstract of DOI:10.1016/j.tet.2010.12.037

The structures proposed for natural butanolides piliferolides A and C have been synthesized. The allylic and lactone stereogenic centers in the target structures were derived from d-mannitol, while that near the side-chain terminal was taken from (R)-prop

Full text of DOI:10.1016/j.tet.2010.12.037

Tetrahedron 67 (2011) 860e865
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the structures proposed for natural butanolides piliferolides A and C
,
,
,
,
Jing Guan a b, Zhi-Bin Zhen a, Yang Zou a, Zheng-Yu Yue b y, Ping Jiang a c, Yan Li c, Yikang Wu a
*
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
b School of Chemistry and Materials, Heilongjiang University, Harbin 150080, China
c Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules and School of Chemistry and Chemical Engineering,
Hubei University, Wuhan 430062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The structures proposed for natural butanolides piliferolides A and C have been synthesized. The allylic
and lactone stereogenic centers in the target structures were derived from -mannitol, while that near
the side-chain terminal was taken from (R)-propylene oxide. The synthetic samples helped to reveal that
a signal at around
2.0 ppm was missing in the 1H NMR data listing for the structures proposed for
natural piliferolides, whereas the
29.7 ppm signal in the 13C NMR reported for the structure proposed
Received 9 September 2010
Received in revised form 8 December 2010
Accepted 14 December 2010
Available online 17 December 2010
D
d
d
for natural piliferolide C most likely stemmed from the impurities in the chromatography solvent.
Keywords:
Butanolides
Ó 2011 Elsevier Ltd. All rights reserved.
Natural products
Structure elucidation
Epoxides
Metathesis
1. Introduction
determined mainly by spectroscopic means, with the absolute
configurations of the lactone and allylic stereogenic centers
The butanolides piliferolides AeC (1aec, Fig. 1) were isolated1 in
1994 by Ayer and Khan from Ophiostoma piliferum (Fr) H.P. Sydow
(¼Ceratocystis pilifera), a blue strain fungus known to cause staining
of aspen logs and chips. The structures of these compounds were
assigned on the basis of circular dichroism (CD) analysis.1
In continuation of our work on enantioselective synthesis of
biologically active butanolides performed in recent years,2 we
conducted a total synthesis of piliferolides A and C, which have not
been synthesized to date. Although because of the unexpected
partial discrepancy of the spectroscopic data between those repor-
ted for the natural samples and their synthetic counterparts made in
this work the genuine structures of the ‘natural piliferolides’ are still
to be further investigated, additions and corrections have been
reliably made tothe data for the structures proposed for piliferolides
A and C. Herein we wish to present the results of this study.
1
4
O
O
O
O
1a
(Piliferolide A)
23 (c 0.1, CHCl3)
1b
11
(Piliferolide B)
OH
OH
20
21
[
α]D
18.2 (c 0.17, CHCl3)
[α]D
2. Results and discussion
1
4
17
1c (Piliferolide C)
10.8 (c 0.13, CHCl3)
O
O
The general features of our synthetic plan are outlined in Fig. 2.
Close inspection of the molecular architecture suggested that the
C-4 and C-11 stereogenic centers of desired absolute configurations
in 1c could be built up from a bis-epoxide (5) and the C-17
stereogenic center might be taken from (R)-propylene oxide (8).
Accordingly, the framework of 1c could be disconnected at the
carbonecarbon double bond, leading to fragments 2 and 3b.
Using a simpler alkene 3a inplace of 3b would allow for synthesis
of target structure 1a. The fragment common to both targets (the
larger fragment 2) in turn could be disconnected into a one-carbon
11
OH
21
[α]D
OH
Fig. 1. The structures proposed for natural piliferolides AeC (1aec) and the corre-
sponding optical rotation data measured on the natural samples.
* Corresponding author. E-mail address: yikangwu@sioc.ac.cn (Y. Wu).
Deceased on August 9, 2009.
y
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.037

J. Guan et al. / Tetrahedron 67 (2011) 860e865
861
Introduction of the vinyl group, which was required in the
coupling with alkenes either 3a or 3b by a cross metathesis at
a later stage, was effected through a selective ring-opening7 re-
action (Scheme 2) of only one epoxy ring in 5 with Me2S]CH2
(generated in situ from Me3SI and n-BuLi). The remaining epoxy
OH
11
CM
CM
1a
1c
+
3a
2
4
17
ring was then transformed into the g-lactone unit by reaction with
O
+
(CM = Cross metathesis)
dimethyl malonate in the presence of NaOMe. Finally, removal of
the superfluous ester group in the lactone ring by heating the
resultant 1:1 epimers of 17 at 160 ꢀC (bath temperature) in DMSO
containing NaCl delivered the common fragment 2 in 81% yield.
OH
3b
O
H2C
S
H
4
O
11
(ref. 9)
4
O
O
OR
H
5
H
H
O
O
6
O
Wittig
CH2
CO2Me
CO2Me
n
-BuLi
1:1
BrMg
O
O
16
Me3SI/THF
0 °C/6 h
7
CO2Me
O
+
Ph3P
O
NaOMe
MeOH
H
67%
O
+
+
H
rt/12 h
85%
O
O
OH
17
9
PPh3
H
8
5
9
10
O
15
O
H
OH
NaCl/DMSO
160 °C/3 h
81%
O
Fig. 2. The retrosynthetic analysis of this work.
O
O
unit (sulfur ylid 4), a known bis-epoxide 5,3 and a propertwo-carbon
carbanion species (6). The smaller fragment (3a) needed for
synthesis of 1a was commercially available reagent, while that for 1c
(3b) was planned to be built up via a ring-opening reaction of ep-
oxide 8 with Grignard reagent 7. The bis-epoxide 5 could be derived
from aldehyde 9 and the Wittig reagent 10.
1
O
3a
4
18/CH2Cl2/rt/17 h
59% (for trans 1a
11
14
)
OH
2
OH
1a
18/CH2Cl2
The detailed synthesis is shown in Scheme 1. Following the lit-
erature4 procedure, aldehyde 9 ([
a]
D
28 þ59.7 (c 4.1, CHCl3)) was readily
rt/17 h
Zhan's catalyst 1B
OH
O
3b
57%
prepared from D-mannitol in two steps. Subsequent treatment of this
(for trans 1c)
N
N
aldehyde with the known5 Wittig reagent 10 (derived in situ from its
precursor 100) gave diene species 11 as a mixture of the (E)- and
(Z)-isomers of the CeC double bonds, which on hydrogenation over
Pd/C afforded the bis-acetonide 12 in an enantiopure form.
18
Mes
Mes
O
1
Cl Ru
1c
O
S
Cl
O
Piliferolide C
O
4
14
17
NMe2
11
Mes = 2,4,6-Trimethylphenyl
Scheme 2.
CHO
HO
HO
HO
OH
OH
n
-BuLi
H
Ref. 4
O
rt/1 h
55%
O
O
O
O
9
OH
OH
OH
11
The cross coupling reaction between the common fragment 2
and the linear alkene 3a was achieved in CH2Cl2 with the aid of the
Zhan’s catalyst 1B8 (18). After stirring at ambient temperature for
17 h, 1a was formed in 59% yield. Similarly, the reaction of 2 with
3b9 instead of 3a under otherwise the same conditions delivered 1c
in 57% yield. In both cases the newly formed CeC double bonds
isomers could be cleanly separated from each other and the double
bond geometry was reliably established on the basis of the coupling
constant in the 1H NMR.
With both 1a and 1c in hand, our endeavor seemed to approach
to an end. The only remaining thing to do was to compare the
spectroscopic data with those reported for the natural ones.
Because both piliferolides A and C are rather simple compounds, we
did not expect any discrepancies between the two sets of data. The
13C data for synthetic 1a did agree very well with those reported for
the natural piliferolide A. However, among all those signal lines in
O
H
PPh3
PPh3
Br
10'
D-Mannitol
H2/Pd-C
EtOAc 100%
rt/2 d
Br
O
2N HCl/THF
80 °C/3 h
OH
OH
O
O
OH
13
94% (crude)
HO
12
O
n
-Bu2SnO CH2Cl2/2 h
p
-TsCl/Et3N
75%
H
K2CO3/MeOH
rt/12 h
O
O
4
OH
4
11
11
14
OTs
65%
HO
OTs
5
H
the
the only one that is much higher than the remainder (of more or
less the same height) occurred at 28.9 ppm, rather than 29.3 ppm.
d 37.3e14.0 ppm region (those methylene groups in the chain),
Scheme 1.
The acetonide protecting groups in bis-acetonide 12 were
removed by treatment of 12 with 2 N HCl in THF at 80 ꢀC for 3 h to
afford tetraol 13. Because of its highly polar/water soluble nature,
the crude tetraol, after removal of all volatiles by repeated co-
evaporation first with toluene and with EtOH was directly treated
with n-Bu2SnO/p-TsCl/Et3N6 in CH2Cl2 at ambient temperature to
deliver bis-tosylate 14, which on subsequent exposure to K2CO3/
MeOH resulted in the desired bis-epoxide 5.
d
Because those methylene groups have very similar surroundings
and consequently more or less the same relaxation time, they
should give lines of similar heights in 13C NMR. The one that is
much higher than the remainder must stem from two different
carbons. On the basis of this line of reasoning, the two carbons
overlapped in 13C NMR should be at
29.3 ppm as suggested1 in the literature.
d 28.9 ppm, rather than

862
J. Guan et al. / Tetrahedron 67 (2011) 860e865
More distinct differences were then observed between the 1H
To exclude the any unexpected effects (causing an upfield shift
NMR for 1a and piliferolide Ada quartet at
d
2.02 ppm (J¼7.3 Hz,
of the allylic methylene group) associated with different relative
configurations of the two stereogenic centers in 1a, we also syn-
thesized a diastereomer of 1a as shown in Scheme 3. The alcohol 2
was first oxidized into ketone 19 with DesseMartin periodinane.
The carbonyl group was then stereo-selectively reduced under the
CBS11 (CoreyeBakshieShibata) conditions. Finally, the resulting 20
was coupled with alkene 3a in the presence of the Zhan catalyst 1B8
(18) to deliver the C-14 epimer of 1a (1a0).
2H) in the 1H NMR of synthetic 1a was missing in the data listing for
the natural piliferolide A, while two more protons were reported
for the latter in the
d 1.7e1.2 ppm region (Table 1).
Table 1
Comparison of the 1H NMR (in CDCl3) data for natural piliferolide A and 1a as well as
1a0 synthesized in this work
Natural1 (360 MHz)
1a (500 MHz)
1a0 (300 MHz)
O
5.65 (dt, J¼16.0,
5.63 (dt, J¼15.5,
6.9 Hz, 1H)
5.62 (dt, J¼15.3,
6.3 Hz, 1H)
O
7.0 Hz, 1H, H-13)
5.45 (ddt, J¼16.0, 7.0,
2.0 Hz, 1H, H-12)
4.48 (m, 1H, H-4)
O
O
Dess-Martin
periodinane
5.45 (dd, J¼15.2,
5.44 (dd, J¼15.0,
4
6.9 Hz, 1H)
7.1 Hz, 1H)
NaHCO3/CH2Cl2
100%
4.48 (br quint,
J¼7.0 Hz, 1H)
4.48 (br quint,
J¼6.8 Hz, 1H)
11
19
O
OH
4.08 (q, J¼7.0 Hz,
1H, H-11)
4.03 (q, J¼6.3 Hz, 1H)
4.02 (q, J¼6.5 Hz, 1H)
2
BH3-SMe2
THF/ 42 °C
(R)-2-Methyl-CBS
oxazoborolidine
2.52 (dd, J¼6.8, 9.0 Hz,
2.53 (dd, J¼8.3,
7.8 Hz, 2H)
2.53 (dd, J¼9.4,
7.2 Hz, 2H)
2H, H-2)
96%
O
O
2.32 (ddt, J¼12.0, 6.8,
6.8 Hz, 1H, H-3a)
(No signal given here)
1.85 (m, 1H, H-3b)
2.31 (ddt, J¼12.8,
2.34 (ddt, J¼12.9,
1
O
O
6.4, 6.4 Hz, 1H)
6.5, 6.5 Hz, 1H)
2.03 (br q, J¼7.3 Hz, 2H) 2.02 (br q, J¼6.8 Hz, 2H)
3a
4
1.88e1.81 (m, 1H)
1.91e1.81 (m, 1H)
1.82e1.11 (m, 19H)
11
18/CH2Cl2/rt/17 h
1.2e1.7 (m, 21H, H-5 to 1.76e1.25 (m, 19H)
14
10 and H-14 to 17)
59% (for trans 1a')
OH
OH
20
1a'
0.88 (t, J¼6.2 Hz,
0.88 (t, J¼6.9 Hz, 3H)
0.86 (t, J¼7.1 Hz, 3H)
3H, H-18)
Scheme 3.
The protons for an allylic methylene group without any other
Similar data disagreements were also observed between the
synthetic and the natural 1c: in the 13C NMR of the synthetic 1c no
functional groups in close vicinity (similar to the C-14 in 1a and 1c)
normally10 appear at around
d
2.0 ppm and can never go down to
signal appeared at
(Tables 2 and 3). And the two-proton quartet at
d
29.7 ppm as reported for the natural one
d
2.07 ppm in the 1H
d
1.7 ppm. Therefore, the two-proton broadened quartet at d 2.03/
2.07 ppm in the 1H NMR for synthetic 1a/1c is quite normal, while
the absence of such a signal in the data listing for the natural pili-
ferolides is very unusual.
NMR of synthetic 1c was, as in the case of 1a, not in the data listing
for the natural 1c.
1
The H NMR of 1a0 was then recorded to see if the different
relative configuration might lead to the unusual appearance of
Table 2
Comparison of the 13C NMR (in CDCl3) data for natural piliferolide C and 1c syn-
the allylic methylene group (C-14) at
d 1.7 ppm as reported for the
thesized in this work
natural piliferolides. The results turned out to be negative; the
Natural1
(125 MHz)
Synthetic 1c
Natural1
Synthetic 1c
d
2.02 ppm quartet still remained unshifted. In fact, no significant
differences could be found between the 1H and 13C NMR for 1a and
1a0. These results unequivocally confirmed that in any case the
methylene group at the allylic position in a structure closely related
(100 MHz)
(125 MHz)
(100 MHz)
177.2 (C-1)
133.5 (C-12)
131.7 (C-13)
81.0 (C-4)
73.1 (C-11)
68.1 (C-17)
38.8 (C-16)
37.3 (C-10)
35.6 (C-5)
177.4
133.4
131.7
81.1
73.0
67.9
38.7
37.2
35.6
32.2 (C-14)
29.7 (C-15)
29.4 (C-8)
29.3 (C-7)
28.9 (C-2)
28.1 (C-3)
25.4 (C-9)
25.2 (C-6)
23.6 (C-18)
32.1
da
29.371
29.286
28.8b
28.0
25.3
25.2
to that of 1a and 1c should appear at around d 2.0 ppm (rather than
1.7 ppm) in 1H NMR.
As the synthetic 1a and 1c were constructed through an
unambiguous route with all stereogenic centers derived from
well-established enantiopure chiral building blocks and the spec-
troscopic analyses were performed with care to eliminate/reduce
the artifacts caused by solvent impurities and the errors associated
with low sample concentrations, the NMR as well as rotation data
collected on the synthetic samples should better represent the
structures 1a and 1c than those given in the previous paper.
As for the genuine structures for natural piliferolides A and C,
although at this stage no conclusion can be reached with absolute
confidence, judging from the otherwise excellent agreements be-
tween the NMR data for the synthetic and natural piliferolides, also
taking into account the reliability of the well-established meth-
odologies utilized for determination of the configurations in that
work along with the additional support from the IR and MS data,
the structures proposed for the natural piliferolides are likely to be
correct.
23.5
a
To our experience the high-boiling residue (which can be removed by re-dis-
tillation prior to use) in the chromatography solvent petroleum ether (consisting of
mainly n-hexane) normally gave a signal at
d
29.7 ppm in 13C NMR taken in CDCl3.
b
Two carbons here (C-2 and C-15, the same as observed with 1a and 1a0).
Table 3
Comparison of the 1H NMR (in CDCl3) data for the natural piliferolide C and 1c
synthesized in this work
Natural1 piliferolide C (360 MHz)
Synthetic 1c (400 MHz)
5.65 (dt, J¼16.0, 7.0 Hz, 1H, H-13)
5.45 (ddt, J¼16.0, 7.0, 2.0 Hz, 1H, H-12)
4.48 (m, 1H, H-4)
5.63 (dt, J¼15.3, 6.7 Hz, 1H)
5.46 (dd, J¼15.3, 7.1 Hz, 1H)
4.48 (br quint, J¼6.9 Hz, 1H)
4.03 (q, J¼6.4 Hz, 1H)
4.08 (q, J¼7.0 Hz, 1H, H-11)
3.78 (m, 1H, H-17)
3.81e3.78 (m, 1H)
2.52 (dd, J¼6.8, 9.0 Hz, 2H, H-2)
2.32 (ddt, J¼12.0, 6.8, 6.8 Hz, 1H, H-3a)
(No signal given here)
2.53 (dd, J¼9.1, 7.2 Hz, 2H)
2.33 (ddt, J¼12.8, 6.8, 6.8 Hz, 1H)
2.07 (br q, J¼7.2 Hz, 2H)
1.90e1.80 (m, 1H)
3. Conclusions
1.85 (m, 1H, H-3b)
In summary, the structures proposed for natural piliferolides
A and C have been synthesized for the first time through an efficient
and enantioselective route. The 1H and 13C NMR data for the
1.2e1.7 (m, 21H, H-5 to10 and H-14 to 17) 1.80e1.25 (m, 18H)
1.17 (d, J¼6.0 Hz, 3H, H-18) 1.21 (d, J¼5.9 Hz, 3H)

J. Guan et al. / Tetrahedron 67 (2011) 860e865
863
synthetic 1a and 1c are in excellent agreement with those reported
for their natural counterparts, except that a 2.03/2.07 ppm signal
was absent in the 1H NMR for both natural piliferolides and an extra
29.7 ppm signal in 13C NMR was reported for the natural pilifer-
olide C. Besides, the two overlapped carbons in the 13C NMR for 1a
are now re-assigned to 28.9 ppm. Although the natural pilifer-
(m, 4H), 3.44 (br t, J¼6.8 Hz, 2H), 1.68e1.35 (m, 12H), 1.30 (s, 12H);
13C NMR (75 MHz, CDCl3)
108.5, 76.0, 69.4, 33.5, 29.4, 26.9, 25.7,
25.6; FTIR (film) 2985, 2934, 2861, 1458, 1378, 1369, 1250, 1217,
1157, 1061, 857, 792, 513 cmꢂ1; EIMS m/z 271 (100) ([MꢂCH3]þ), 43
(96), 72 (70), 95 (34.96), 59 (31), 101 (29.4), 67 (27); EIHRMS calcd
for C16H30O4 ([M]þ) 286.2144, found 286.2141.
d
d
d
d
olides are not accessible to us and direct comparison is thus not
possible, judging from the available information the originally
assigned structures are likely to be correct though the accompa-
nying data listing contained some minor errors.
4.4. (2S,9S)-1,10-Di-tosyloxy-decan-2,9-diol (14)
A solution of bis-acetonide 12 (4.9 g, 17 mmol) in 6 N HCl
(10 mL) and EtOH (20 mL) was stirred at 80 ꢀC for 3 h. After being
cooled to ambient temperature, the mixture was transferred to
a large flask containing EtOH (100 mL) and toluene (50 mL) and
concentrated on a rotary evaporator to remove water. The residual
solution was dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation left the crude tetraol 13 (3.3 g, 16 mmol, 94%
from 12) as a white solid.
A mixture of crude tetraol 13 (382 mg, 1.87 mmol), Bu2SnO
(21 mg, 0.08 mmol), p-TsCl (715 mg, 3.75 mmol), and Et3N (379 mg,
3.75 mmol) in dry CH2Cl2 (8 mL) was stirred at ambient tempera-
ture for 2 h, when TLC showed completion of the reaction. Water
was added. The mixture was extracted with CH2Cl2 (3ꢁ50 mL). The
combined organic layers were washed with water and brine before
being dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation and column chromatography (2:1 PE/EtOAc) on
4. Experimental section
4.1. General
The 1H NMR and 13C NMR spectra were recorded at ambient
temperature using a Varian Mercury or a Bruker Avance instrument
operating at 300 or 400 MHz for proton as indicated in each
individual case. The FTIR spectra were scanned with a Nicolet
Avatar 360 FT-IR. EIMS and EIHRMS were recorded with an HP
5989A and a Finnigan MAT 8430 mass spectrometer, respectively.
The ESI-MS and ESI-HRMS were recorded with a PE Mariner
API-TOF and an APEX III (7.0 T) FTMS mass spectrometer, res-
pectively. Dry THF was distilled from Na/Ph2CO under N2. Unless
otherwise specified, all other solvents and reagents were com-
mercially available and used as received without any further puri-
fication. PE (chromatography solvent) stands for petroleum ether
(60e90 ꢀC). Optical rotations were recorded on a Jasco P-1030 Po-
larimeter. Melting points were taken on a micro melting point
apparatus equipped with a microscope and were uncorrected.
silica gel gave the bis-tosylate 14 (721 mg, 1.40 mmol, 75% from 13,
23
71% from 12) as a white solid. Mp 75e76 ꢀC. [
a
]
þ6.2 (c 2.50,
D
CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.79 (d, J¼8.0 Hz, 4H), 7.35 (d,
J¼8.0 Hz, 4H), 3.99 (dd, J¼10.0, 3.2 Hz, 2H), 3.88 (dd, J¼10.0, 7.2 Hz,
2H), 3.80e3.79 (m, 2H), 2.44 (s, 6H), 1.42e1.22 (m, 12H); 13C NMR
(100 MHz, CDCl3)
d 145.1, 132.6, 130.0, 127.9, 74.0, 69.2, 32.6, 29.13,
4.2. (E/Z)-1,6-Di-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-hex-
1,5-diene (11)
25.0, 21.6; FTIR (film) 3527, 2934, 2858,1598,1455,1356, 1308,1176,
1097, 968, 815, 667, 555 cmꢂ1; EIMS m/z 172 (p-TsOþ, 92), 155 (8),
107 (45), 91(100), 77 (20), 65 (31); EIHRMS calcd for C17H27O5S
([MꢂOTs]þ) 343.1579, found 343.1584.
n-BuLi (2.5 M, in hexanes, 24 mL, 60 mmol) was added to a so-
lution of phosphonium salt 100 (22.2 g, 30 mmol) in dry THF
(150 mL) stirred in an ice-water bath. After completion of the ad-
dition, stirring was continued at ambient temperature for 20 min.
The resulting red-brown mixture was cooled in an ice-water bath.
4.5. 1,6-Di-((S)-oxiran-2-yl)-hexane (5)
Finely powdered K2CO3 (129 mg, 0.94 mmol) was added to
a solution of bis-tosytlate 14 (241 mg, 0.47 mmol) in MeOH (15 mL)
stirred at ambient temperature. Stirring was continued at the same
temperature for 8 h. Water (2 mL) and Et2O (50 mL) were added.
The mixture was extracted with Et2O (3ꢁ40 mL). The combined
organic layers were washed with water and brine before being
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (10:1 PE/EtOAc) on silica
gel afforded the known bis-epoxide 5 (53 mg, 0.31 mmol, 66.6%) as
again. Freshly prepared aldehyde 9 ([
a
]
D
28 þ59.7 (c 4.1, CHCl3), neat,
7.7 g, 59 mmol) was added. The mixture was stirred at ambient
temperature for 1 h. Aq satd NH4Cl (200 mL) was added. The
mixture was extracted with Et2O (3ꢁ200 mL). The combined
organic layers were washed with water and brine before being
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (20:1 PE/EtOAc) on silica
gel gave 11 (a mixture of double bonds isomers, 4.8 g, 17 mmol,
23
27
56.4%) as a colorless oil. 1H NMR (300 MHz, CDCl3)
d
5.76e5.71 (m,
a colorless oil. [
a]
ꢂ17.0 (c 2.45, CHCl3) (lit.3
[
a]
ꢂ17.0 (c 0.79,
D
D
0.3H), 5.61e5.53 (m, 1.7H), 5.47e5.36 (m, 2H), 4.78 (dt, J¼8.1,
6.5 Hz, 1.7H), 4.42 (dt, J¼7.8, 6.4 Hz, 0.3H), 4.02 (dd, J¼6.2, 1.6 Hz,
2H), 3.55e3.45 (m, 2H), 2.29e2.06 (m, 4H), 1.39 (s, 6H), 1.36 (s, 6H);
CHCl3)). 1H NMR (400 MHz, CDCl3)
d 2.93 (m, 2H), 2.74 (br t,
J¼4.5 Hz, 2H), 2.47 (dd, J¼5.1, 2.8 Hz, 2H), 1.60e1.35 (m, 12H).
4.6. (S)-9-((S)-Oxiran-2-yl)-non-1-ene-3-ol (15)
13C NMR (75 MHz, CDCl3)
d 133.4, 128.1, 128.0, 127.7, 109.0, 71.8,
71.7, 69.3 (2C0s), 32.0, 27.5, 27.0, 26.7, 26.6, 25.9 (2C0s); FTIR (film)
2986, 2934, 2869, 1655, 1455, 1379, 1370, 1248, 1156, 1059, 861,
510 cmꢂ1; EIMS m/z 267 ([MꢂCH3]þ, 4.25), 72 (100), 43 (97), 59
(39), 101 (27), 55 (24), 83 (24), 105 (24), 41 (19); EIHRMS calcd for
C16H26O4 (Mþ) 282.1831, found 282.1825.
n-BuLi (2.5 M, in hexanes, 2.1 mL, 5.25 mmol) was added to
a solution of Me3SI (1.078 g, 5.28 mmol) in dry THF (10 mL) stirred
at ꢂ10 ꢀC under N2 (balloon). The mixture was stirred at the same
temperature for 1 h before being transferred dropwise to a solution
of bis-epoxide 5 (300 mg, 1.81 mmol) in dry THF (3 mL) stirred at
0 ꢀC under N2 (balloon). The mixture was stirred at 0 ꢀC for 6 h,
when TLC showed completion of the reaction. Aq satd NH4Cl
(15 mL) was added. The mixture was extracted with CH2Cl2
(3ꢁ20 mL). The combined organic layers were washed with water
and brine before being dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromatography (5:1
4.3. 1,6-Di-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-hexane (12)
A mixture of 11 (4.8 g, 17 mmol) and 10% Pd/C (480 mg) in EtOAc
(30 mL) was stirred at ambient temperature under atmospheric H2
for 48 h. The solids were filtered off. The filtrate was concentrated
on a rotary evaporator. The residue was chromatographed (10:1 PE/
EtOAc) on silica gel to afford 12 (4.9 g, 17 mmol, 100%) as a colorless
PE/EtOAc) on silica gel afforded alcohol 15 (217 mg, 1.17 mmol,
26
oil. [a
]
D
24 þ24.5 (c 2.1, CHCl3). 1H NMR (300 MHz, CDCl3)
d
4.06e3.95
64.6%) as a colorless oil. [
a]
ꢂ2.6 (c 0.35, CHCl3). 1H NMR
D

864
J. Guan et al. / Tetrahedron 67 (2011) 860e865
(300 MHz, CDCl3)
d
5.87 (ddd, J¼17.1, 10.5, 6.3 Hz, 1H), 5.22 (d,
chromatographed (3:1 PE/EtOAc) on silica gel to give 1a (15 mg,
26
J¼17.5 Hz, 1H), 5.11 (d, J¼10.4 Hz, 1H), 4.10 (q, J¼6.1 Hz, 1H), 2.91 (s,
0.05 mmol, 67.6% from 2) as a colorless oil. [
a]
ꢂ26.3 (c 0.53,
D
21
1H), 2.76 (t, J¼4.5 Hz, 1H), 2.47 (dd, J¼4.8, 2.7 Hz, 1H), 1.62e1.25 (m,
CHCl3) (lit.1 [
a
]
D
ꢂ23 (c 0.1, CHCl3)). For 1H NMR, see Table 1; 13C
14H); 13C NMR (100 MHz, CDCl3)
d
141.2, 114.5, 73.1, 52.4, 47.1, 36.9,
NMR (100 MHz, CDCl3) d 177.3, 133.0, 132.3, 81.0, 73.1, 37.3, 35.6,
32.4, 29.4, 29.3, 25.8, 25.2; FTIR (film) 3433, 2982, 2931, 2856, 1645,
1465, 1427, 1410, 1250, 992, 918, 832 cmꢂ1; ESI-MS m/z 207.2
([MþNa]þ). ESI-HRMS calcd for C11H20O2Na ([MþNa]þ) 207.1356,
found 207.1357.
32.1, 31.4, 29.4, 29.3, 28.9 (2C0s), 28.0, 25.4, 25.2, 22.5, 14.0; FTIR
(film) 3460, 2929, 2856, 1775, 1461, 1354, 1286, 1220, 1182, 1018,
971, 914, 726, 652 cmꢂ1; ESI-MS m/z 319.2 ([MþNa]þ). ESI-HRMS
calcd for C18H32O3Na ([MþNa]þ) 319.2248, found 319.2244.
4.7. (S)-9-((5S)-3-Methyloxycarbonyl-2-oxo-tetrahydrofuran-
4.10. (2R,8S,6E)-14-((5S)-2-Oxo-tetrahydrofuran-5-yl)-
5-yl)-non-1-en-3-ol (17)
tetradec-6-en-2,8-diol (1c)
A mixture of methanolic MeONa (1 M, 1.9 mL) and dimethyl
malonate (257 mg, 1.95 mmol) was stirred at ambient temperature
for 5 min being cooled in a 0 ꢀC bath. A solution of alcohol 15
(120 mg, 0.65 mmol) in THF (2 mL) was then added. The mixture
was stirred at ambient temperature overnight. The mixture was
acidified to pH 5 with 2 N HCl. Water (10 mL) was added, followed
by CH2Cl2 (10 mL). The mixture was extracted with CH2Cl2
(3ꢁ20 mL). The combined organic layers were washed with water
and brine before being dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromatography (6:1
CH2Cl2/EtOAc) on silica gel afforded a 1:1 mixture of diastereomers
of lactone 17 (157 mg, 0.55 mmol, 85%) as a colorless oil. 1H NMR
A mixture of 2 (21 mg, 0.095 mmol), alkene 3b (43 mg,
0.38 mmol), and Zhan’s catalyst 1B (9 mg, 0.012 mmol) in dry
CH2Cl2 (3 mL) was stirred at ambient temperature under N2 (bal-
loon) for 17 h before being concentrated on a rotary evaporator and
chromatographed (1:1 PE/EtOAc) on silica gel to give 1c (17 mg,
23
0.054 mmol, 56.8% from 2) as a colorless oil. [
a
]
ꢂ22.9 (c 0.35,
D
CHCl3) (lit.1 [
a
]
21 ꢂ10.8 (c 0.13, CHCl3)). FTIR (film) 3410, 2929, 2856,
D
1770, 1462, 1185, 1016, 969, 652 cmꢂ1
; ESI-MS m/z 335.2
([MþNa]þ); ESI-HRMS calcd for C18H32O4Na ([MþNa]þ): 335.2193;
found: 335.2200 (for NMR, see Tables 2 and 3).
4.11. (S)-9-((5S)-2-Oxo-tetrahydrofuran-5-yl)-non-1-en-
(400 MHz, CDCl3)
d
5.87 (ddd, J¼17.1, 10.4, 6.2 Hz, 1H), 5.23 (d,
3-one (19)
J¼17.5 Hz, 1H), 5.11 (d, J¼10.5 Hz, 1H), 4.67 (quint, J¼7.5, 6.7 Hz,
0.5H), 4.45 (quint, J¼7.8, 6.1 Hz, 0.5H), 4.13e4.05 (m, 1H), 3.82 and
3.81 (two singlets, 3H altogether), 3.69e3.60 (m,1H), 2.75e2.67 (m,
0.5H), 2.60e2.51 (m, 0.5H), 2.39e2.28 (m, 0.5H) 1.85e1.25 (m,
DesseMartin periodinane (135 mg, 0.32 mmol) and NaHCO3
(40 mg, 0.48 mmol) were added to a solution of alcohol 2 (37 mg,
0.17 mmol) in dry CH2Cl2 (3 mL) at ambient temperature. Stirring
was continued at the same temperature for 3 h. Et2O (8 mL) was
added. The solids precipitated were filtered off through Celite
(washing with Et2O). The filtrate and washings were combined and
concentrated on a rotary evaporator. The residue was chromato-
graphed (3:1 PE/EtOAc) on silica gel to give ketone 19 (37 mg,
12H); 13C NMR (100 MHz, CDCl3)
d
171.8 (2C0s), 168.4, 141.4, 114.4,
80.4, 79.6, 73.0, 53.1, 53.0, 47.2, 46.8, 36.9, 35.3, 35.2, 32.2, 31.9, 29.3,
29.3, 29.1, 25.1 (2C0s); FTIR (film) 3521, 2933, 2857, 1777, 1741, 1644,
1455, 1438, 1357, 1264, 1168, 992, 925, 726, 673 cmꢂ1; EIMS m/z 269
([MꢂCH3]þ), 110 (100), 55 (92). EIHRMS calcd for C15H24O5 (Mþ)
284.1624, found 284.1624.
0.17 mmol, 100%) as a colorless oil. [
NMR (400 MHz, CDCl3)
a
]
24 þ49.7 (c 0.450, CHCl3); 1H
D
d
6.35 (dd, J¼17.7, 10.5 Hz, 1H), 6.22 (dd,
4.8. (S)-9-((5S)-2-Oxo-tetrahydrofuran-5-yl)-non-
1-en-3-ol (2)
J¼17.6, 0.8 Hz, 1H), 5.83 (dd, J¼10.5, 0.9 Hz, 1H), 4.48 (quint,
J¼6.8 Hz, 1H), 2.59 (t, J¼7.3 Hz, 2H), 2.53 (dd, J¼9.5, 6.9 Hz, 2H),
2.32 (ddt, J¼13.2, 6.6, 6.6 Hz, 1H), 1.90e1.80 (m, 1H), 1.78e1.67 (m,
A solution of ester 17 (88 mg, 0.31 mmol), NaCl (36 mg,
0.62 mmol), and H2O (0.178 mL, 9.92 mmol) in DMSO (5 mL) was
heated in a 160 ꢀC bath with stirring for 3 h. After being cooled to
ambient temperature, water (10 mL) and Et2O (10 mL) were
added. The mixture was diluted with Et2O (3ꢁ30 mL). The com-
bined organic layers were washed with water and brine before
being dried over anhydrous MgSO4. Removal of the solvent by
rotary evaporation and column chromatography (3:1 PE/EtOAc)
1H) 1.67e1.27 (m, 9H); 13C NMR (100 MHz, CDCl3)
d 200.9, 177.2,
136.5, 128.0, 81.0, 39.5, 35.5, 29.1, 29.0, 28.8, 28.0, 25.1, 23.7; FTIR
(film) 2927, 2856, 1778, 1749, 1678, 1615, 1460, 1372, 1228, 1136,
1025, 960, 908, 778, 727, 652, 601 cmꢂ1; ESI-MS m/z 247.1
([MþNa]þ); ESI-HRMS calcd for C13H20O3Na ([MþNa]þ) 247.1305,
found 247.1303.
4.12. (R)-9-((5S)-2-Oxo-tetrahydrofuran-5-yl)-non-
on silica gel afforded lactone 2 (57 mg, 0.25 mmol, 81%) as a col-
1-en-3-ol (20)
23
orless oil. [
a
]
ꢂ21.2 (c 1.65, CHCl3). 1H NMR (300 MHz, CDCl3)
D
d
5.83 (ddd, J¼17.5, 10.0, 6.1 Hz, 1H), 5.18 (d, J¼17.4 Hz, 1H), 5.07 (d,
A
solution of (R)-2-methyl-CBS-oxazaborolidine (66 mg,
J¼10.2 Hz, 1H), 4.50e4.41 (m, 1H), 4.03 (q, J¼6.3 Hz, 1H), 2.50 (t,
J¼7.4 Hz, 2H), 2.29 (ddt, J¼13.2, 6.6, 6.2 Hz, 1H), 1.88e1.22 (m,
0.24 mmol) in dry THF (2 mL) was added to a solution of ketone 20
(27 mg, 0.12 mmol) in dry THF (2 mL) and stirred at ꢂ40 ꢀC under
argon. The mixture was stirred at the same temperature for
10 min. BH3$SMe2 (2 M, in THF, 0.3 mL, 0.6 mmol) was added.
Stirring was continued at ꢂ40 ꢀC for 1.5 h. EtOH (5 mL) was added.
The mixture was stirred at ambient temperature for 15 min. Water
(10 mL) was added, followed by Et2O (10 mL). The phases were
separated. The aq layer was extracted with Et2O (3ꢁ15 mL). The
combined organic layers were washed with water and brine be-
fore being dried over anhydrous MgSO4. Removal of the solvent by
rotary evaporation and column chromatography (3:1 PE/EtOAc) on
14H); 13C NMR (75 MHz, CDCl3)
d 177.3, 141.2, 114.5, 81.0, 73.1,
36.8, 35.5, 29.3, 29.2, 28.8, 27.9, 25.1 (2C0s); FTIR (film) 3449, 2932,
2857, 1774, 1460, 1422, 1350, 1283, 1184, 992, 917 cmꢂ1; EIMS m/z
85 ([MꢂCH2CHCH2OH]þ) 57 (100), 85 (71), 55 (61), 41 (38), 69
(34), 84 (33), 67 (29), 83 (28); EIHRMS calcd for C13H22O3 (Mþ)
226.1569, found 226.1564.
4.9. (8S,6E)-14-((5S)-2-Oxo-tetrahydrofuran-5-yl)-tetradec-6-
en-8-ol (1a)
silica gel afforded alcohol 20 (26 mg, 0.12 mmol, 96%) as a color-
23
A
mixture of
2
(17 mg, 0.075 mmol), alkene 3a (29 mg,
less oil. [
d
a
]
D
þ11.2 (c 0.95, CHCl3). 1H NMR (400 MHz, CDCl3)
0.30 mmol), and Zhan’s catalyst 1B (9 mg, 0.012 mmol) in dry
CH2Cl2 (3 mL) was stirred at ambient temperature under N2 (bal-
loon) for 17 h before being concentrated on a rotary evaporator and
5.87 (ddd, J¼16.9, 10.4, 6.2 Hz, 1H), 5.22 (d, J¼17.2 Hz, 1H), 5.10
(d, J¼10.4 Hz, 1H), 4.60e4.40 (m, 1H), 4.09 (q, J¼6.2 Hz, 1H), 2.53
(dd, J¼9.4, 7.4 Hz, 2H), 2.32 (ddt, J¼13.3, 6.6, 6.2 Hz, 1H), 1.88e1.20

J. Guan et al. / Tetrahedron 67 (2011) 860e865
865
(m, 14H); 13C NMR (100 MHz, CDCl3)
d
177.3, 141.3, 114.6, 81.0,
Supplementary data
73.2, 36.9, 35.6, 29.3, 29.3, 28.9, 28.0, 25.2 (2C0s); FTIR (film) 3463,
2930, 2857, 1774, 1645, 1461, 1422, 1182, 1015, 916, 704 cmꢂ1; ESI-
MS m/z 249.2 ([MþNa]þ); ESI-HRMS calcd for C13H22O3Na
([MþNa]þ) 249.1461, found 249.1465.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.12.037.
References and notes
4.13. (8R,6E)-14-((5S)-2-Oxo-tetrahydrofuran-5-yl)-tetradec-
6-en-8-ol (1a0)
1. Ayer, W. A.; Khan, A. Q. Heterocycles 1994, 39, 561e569.
2. For our previous work on synthesis of other natural butanolides, see: e.g.: (a)
Jian, Y.-J.; Wu, Y.-K. Org. Biomol. Chem. 2010, 8, 811e821; (b) Ren, G.-B.; Wu, Y.-
K. Tetrahedron 2008, 64, 4408e4415; (c) Tang, C.-J.; Wu, Y.- K. Tetrahedron 2007,
63, 4887e4906; (d) Yang, Y.-Q.; Wu, Y.-K. Chin. J. Chem. 2005, 23, 1519e1522;
(e) Jian, Y.-J.; Wu, Y.-K.; Li, L.; Lu, J. Tetrahedron: Asymmetry 2005, 16,
2649e2651; (f) Tang, C.-J.; Wu, Y.- K Helv. Chim. Acta 2004, 87, 667e673; (g)
Wu, Y.-K.; Shen, X.; Tang, C.-J.; Chen, Z.-L.; Hu, Q.; Shi, W. J. Org. Chem. 2002, 67,
3802e3810; (h) Wu, Y.-K.; Shen, X.; Tang, C.-J.; Chen, Z.-L. Helv. Chim. Acta 2001,
84, 3428e3432.
3. Tanano, S.; Murakami, T.; Samizu, K.; Ogasawa, K. Heterocycles 1994, 39, 67e72.
4. Earle, M. J.; Abdur-Rshid, A.; Priestley, N. D. J. Org. Chem. 1996, 61, 5697e5700.
5. Lemieux, V.; Branda, N. R. Org. Lett. 2005, 7, 2969e2972.
6. Martineli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Mohor, E. D.; Van Khau, V.; Kosmrlj, B. J. Am.
Chem. Soc. 2002, 124, 3578e3585.
A
mixture of 20 (34 mg, 0.15 mmol), alkene 3a (58 mg,
0.59 mmol), and Zhan’s catalyst 1B (18 mg, 0.024 mmol) in dry
CH2Cl2 (3 mL) was stirred at ambient temperature under N2
(balloon) for 22 h before being concentrated on a rotary evaporator
and chromatographed (1:1 PE/EtOAc) on silica gel to give 1a0
26
(20 mg, 0.05 mmol, 45% from 20) as a colorless oil. [
a
]
ꢂ13.1
D
(c 0.13, CHCl3). For 1H NMR, see Table 1; 13C NMR (100 MHz, CDCl3)
177.2, 133.0, 132.3, 81.0, 73.1, 37.2, 35.5, 32.1, 31.3, 29.3, 29.2, 28.8
d
(2C0s), 28.0, 25.3, 25.1, 22.5, 14.0; FTIR (film) 3469, 2927, 2856, 1775,
1462, 1346, 1278, 1182, 1018, 970, 912, 809, 710 cmꢂ1; EIMS m/z 252
([MꢂCO2]þ) 57 (100), 43 (92), 71 (84), 55 (71), 41 (64), 85 (61), 69
(55), 83 (40); EIHRMS calcd for C18H32O3 (Mþ) 296.2351, found
296.2354.
7. (a) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449e5452; (b) Baylon, C.; Heck, M.-P.;
Mioskowski, C. J. Org. Chem. 1999, 64, 3354e3360; (c) Crimmins, M. T.; Zhang,
Y.; Diaz, F. A. Org. Lett. 2006, 8, 2369e2372.
8. (a) Zhan, Z. -Y. PCT Int. Appl., 2007, 61 pp. CODEN: PIXXD2 WO 2007003135 A1
20070111. CAN 146, 142834. (b) Paquette, L. A.; Dong, S.; Parker, G. D. J. Org.
Chem. 2007, 72, 7135e7147.
Acknowledgements
9. Furstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett. 2001, 3, 449e451.
10. See, e.g.: Harusawa, S.; Osaki, H.; Fujii, H.; Yoneda, R.; Kurihara, T. Tetrahedron
1992, 48, 9433e9450.
11. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551e5553;
(b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925e7926; (c) For a review: Corey, E. J.; Helal, C. J. Angew. Chem., Int.
Ed. 1998, 36, 1986e2012.
This work was supported by the National Basic Research Program
of China (the 973 Program) (2010CB833200), the National Natural
Science Foundation of China (21032002, 20921091, 20672129,
20621062, 20772143), and the Chinese Academy of Sciences
(KJCX2.YW.H08).