Facile total synthesis of the (-)-Heliconol A

Article abstract of DOI:10.1016/j.tet.2007.07.053

The facile total synthesis of the (-)-Heliconol A (ent-1) as well as its diastereoisomer 18 is described, in which different reaction sequences lead to different results. The osmylation of 15 followed by hydrolysis afforded a single isomer 18, otherwise,

Full text of DOI:10.1016/j.tet.2007.07.053

Tetrahedron 63 (2007) 9991–9996
Facile total synthesis of the (L)-Heliconol A
a,
Weiguo Quan,a Binxun Yu,a Jiyong Zhang,a Qiren Liang,a Xuegong Shea,b, and Xinfu Pan
*
*
aDepartment of Chemistry, State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, PR China
Received 30 April 2007; revised 12 July 2007; accepted 17 July 2007
Available online 26 July 2007
Abstract—The facile total synthesis of the (ꢀ)-Heliconol A (ent-1) as well as its diastereoisomer 18 is described, in which different reaction
sequences lead to different results. The osmylation of 15 followed by hydrolysis afforded a single isomer 18, otherwise, a mixture of ent-1 and
18 resulted. Other important processes include the catalytic asymmetric CBS reduction and induced osmylation. The synthesis proceeded with
a sequence of 11 steps, affording ent-1 in 9.0% and 18 in 22% overall yield, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Heliconols A–C (1–3), three new polyketide-derived hemi-
ketals containing an unusual reduced furano-cyclopentane
unit, were isolated from the freshwater aquatic fungus
Helicodendron giganteum Glen-Bott (Helotiaceae) that
were collected from a sample of submerged wood in Alaska
by Gloer et al.1 Heliconols A–C (1–3) were tested against
Candida albicans (ATCC 14053), Staphylococcus aureus
(ATCC 29213), Bacillus subtilis (ATCC 6051), Escherichia
coli (ATCC 25922),2 Aspergillus flavus (NRRL 6541), and
Fusarium verticillioides (NRRL 25457).3 Heliconol A (1)
was found to inhibit the growth of F. verticillioides and
exhibited activity against C. albicans, S. aureus, and B. sub-
tilis.1 The absolute configuration of Heliconol A was as-
signed by single-crystal X-ray crystallographic analysis of
its dibromobenzoate derivative.1 To the best of our know-
ledge, no total synthesis of Heliconol A has been reported.
In order to study the relationship between the structure and
the bioactivity of the compound, we describe the first total
synthesis of (ꢀ)-Heliconol A (ent-1) and its diastereoisomer
18 in this paper (Fig. 1).
The synthesis began with the known enone 4 (Scheme 1),
which was readily available from cyclopentenone in three
steps according to the literature.4 Reduction of 4 with (S)-
nBu-CBS afforded alcohol 5 in 93% yield.5 The ee of 5
was determined as 87% by HPLC analysis, while its con-
figuration was anticipated to be R. This was confirmed by
converting 5 to compound ent-1 and comparing its optical
rotation to that reported for natural (+)-Heliconol A (1).
Acetylation of 5 provided acetate 6 in 98% yield. Dihydroxy-
lation of 6 using OsO4 generated an easily separable
OAc
O
OH
b
d
c
a
OBn
OBn
OBn
6
5
4
noe
OAc
OAc
H
OBn
H
OBn
OH
H
e
+
O
OAc
HO
HO
O
H
OH
BnO
OH
9
7
8
HO
HO
R
OAc
OAc
O
O
O
OH
f
OH
O
1 R=CH3
O
O
2 R=CH2OH
3 R=COOH
10
11
Figure 1.
Scheme 1. Reagents and conditions: (a) (S)-nBu-CBS, BMS, THF, ꢀ10 ꢁC,
93%; (b) Ac2O, pyridine, DMAP, rt, 98%; (c) OsO4, NMO, THF/H2O, rt,
90%; (d) DMP, CH2Cl2, p-TSA, rt, 99%; (e) 5% Pd/C, EtOH, H2, 98%;
(f) Swern oxidation, 90%.
* Corresponding authors. Fax: +86 (0)931 8912582; e-mail: shexg@lzu.
edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.053

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W. Quan et al. / Tetrahedron 63 (2007) 9991–9996
mixture of 7 and 8 in 90% yield and with 14:1 diastereo-
selectivity.6 The configurations of the newly formed C1 and
C5 stereocenters in 7 and 8 were confirmed by NOE dif-
ference experiment of compound 8. Protection of diol 7 with
2,2-dimethoxypropane in the presence of catalytic p-TSA
followed by Pd/C cleavage of benzyl ether provided the
acetonide-protected alcohol 10 in essentially quantitative
yield. Oxidation of 10 with standard Swern oxidation condi-
tion furnished aldehyde 11 in 92% yield.7
Treatment of 12 with 80% aqueous acetic acid afforded
diol 13 in 89% yield. In the process of the oxidation of com-
pound 13, three methods were tried. However, Dess–Martin
periodinane8 and IBX reagent9 gave an oxidative cleavage
product 14. Only Swern oxidation gave our desired ketone
15 in 80% yield.7
As shown in Scheme 3, osmium-mediated dihydroxylation
of b,g-unsaturated ketone 15 directly gave a single isomer
16. Basic hydrolysis of 16 led to compound 18, of which
the spectral data did not completely match the data of the
natural Heliconol A (1). C6 and C7 stereocenters of 18
were opposite to those of the natural Heliconol A (1), which
was confirmed by NOESY experiment of compound 18 in
With the intermediate 11 in hand, the stage was set for the
synthesis of ketone 15 (Scheme 2). Wittig olefination of 11
with the ylide derived from n-decatriphenylphoshonium
bromide led to 12 as a single (Z)-isomer in 65% yield.
OAc
OAc
OAc
b
a
reagents
O
O
C9H19
OH
C9H19
O
O
OH
O
12
13
11
OAc
OAc
O
C9H19
OH
or
O
C9H19
O
14
15
Entry
reagents
IBX, DMSO
Yield (%)
93%
product
14
1
2
3
Dess-Martin periodinane,CH2Cl2
Swern oxidation
98%
80%
14
15
Scheme 2. Reagents and conditions: (a) n-BuLi, C10H21PPh+3Brꢀ, THF, 65%; (b) 80% AcOH, rt, 89%.
OH
OH
OAc
AcO
HO
HO
HO
8
6
C9H19
5
4
b
C9H19
a
7
3
1
C H
OH
9
19
2
O
OH
O
OH
O
16
15
18
c
OH
HO
HO
OH
8
6
5
4
d
C9H19
7
18
+
3
1
2
O
OH
C H
OH
9
19
O
(3:4)
(-)-1
17
17
15
Scheme 3. Reagents and conditions: (a) OsO4, NMO, THF/H2O, 30 h, rt, 75%; (b) K2CO3, MeOH, rt, 95%; (c) K2CO3, MeOH, rt, 98%; (d) OsO4, NMO, THF/
H2O, 48 h, rt, 70%.

W. Quan et al. / Tetrahedron 63 (2007) 9991–9996
9993
the NMR spectrum. Namely, osmylation of 15 did not
furnish our expected product. In general, regardless of the
double bond substitution pattern and geometry, the relative
stereochemistry between the pre-existing hydroxyl or alk-
oxyl group and the adjacent newly formed hydroxyl group
of the major diastereomer will be erythro (i.e. anti if the
carbon chain is drawn in the zig-zag convention).10 It was
an unusual phenomenon that the osmylation of 15 provided
the triol with a syn arrangement between the tertiary alcohol
and the newly installed 1,2-diol unit. The stereochemical
outcome of dihydroxylation could be rationalized by con-
sidering that the attack of OsO4 on the C]C double bond
occurs preferentially from the less hinder b-face of the
molecule under the influence of the C4 acetoxyl. To our
surprise, if the reaction sequences of osmylation/hydrolysis
were changed, a mixture of ent-1 and 18 with 3:4 diastereo-
selectivity was afforded. The formation of the two products
can be explained as follows: because the steric influence
of both sides of C6 alkene is similar, compounds ent-1
and 18 can be afforded by attack of OsO4 on the a- and
b-faces of the C6 alkene, respectively. The spectroscopic
properties (1H and 13C NMR, HRMS) of the synthetic target
ent-1 were fully identical with those of the natural product
Heliconol A (1), but the optical rotation of the syn-
thetic ent-1 ([a]2D5 ꢀ24 (c 0.2, acetone)) was opposite to
that of natural Heliconol A (1) ([a]2D5 +21 (c 1.6, acetone)).
The synthetic ent-1 was the enantiomer of natural Heliconol
(2.0 M in THF, 6.9 mL, 0.6 equiv) was slowly added over
10 min. After addition of BMS, TLC analyses indicated
completion of the reaction. Methanol (4.3 mL) was slowly
added until gas evolution was no longer evident. The mixture
was warmed to room temperature, treated with 1 N NaOH
(2.88 mL), and stirred for an additional 15 min. The mixture
was then poured into a separatory funnel containing ether
and brine. The aqueous layer was separated and extracted
with ether. The combined organic layers were washed with
1 N HCl, saturated NaHCO3, and brine, then dried with
NaSO4. The solvents were evaporated. The residue was flash
chromatographed using petroleum ether and ethyl acetate
(10:1, v/v) to give compound 5 (4.363 g, 93%) as a colorless
oil. (87% ee; Chiralcel OD, hexane/i-PrOH¼90:10, flow
1
rate¼0.7 mL/min, 254 nm.) [a]2D0 +26 (c 3.0, CHCl3); H
NMR (300 MHz, CDCl3): d 7.28–7.36 (m, 5H), 5.84 (br s,
1H), 4.85 (br s, 1H), 4.54 (s, 2H), 4.20 (q, J¼11.7 Hz,
2H), 2.53 (br s, 1H), 2.47–2.53 (m, 1H), 2.25–2.31 (m,
2H), 1.78–1.83 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 142.0, 137.9, 131.8, 128.4, 127.7, 127.6, 77.6, 72.5,
67.6, 33.3, 30.0. IR (KBr): 3397, 1656, 1604; HRMS calcd
for C13H16O2Na (M+Na): 227.1048. Found (M+Na)+:
227.1050.
3.3. (D)-2-(Benzyloxymethyl)cyclopent-2-enyl acetate (6)
The alcohol 5 (4.363 g, 21.4 mmol) was dissolved in dry
acetic anhydride (10.2 mL, 5 equiv) and cooled to 0 ꢁC.
To the stirred solution were added dry pyridine (3.3 mL,
42.8 mmol, 2 equiv) and N,N-dimethylaminopyridine
(261 mg, 2.14 mmol, 0.1 equiv). After stirring for 10 min,
the reaction was allowed to warm to room temperature for
1 h. The reaction was quenched with saturated aqueous
NaHCO3 solution and extracted with EtOAc. The organic
phase was washed with brine and dried over Na2SO4. The
solvents were evaporated. The residue was flash chromato-
graphed using petroleum ether and ethyl acetate (20:1, v/v)
to give compound 6 (5.159 g, 98%) as a colorless oil. [a]D20
A and its absolute configuration was shown as
(1S,4R,5R,6S,7S).
In conclusion, we have accomplished the first total synthesis
of (ꢀ)-Heliconol A (ent-1) and its diastereoisomer 18 start-
ing from the known enone 4. The synthesis proceeded with
a longest linear sequence of 11 steps, affording ent-1 in
9.0% overall yield and 18 in 22% overall yield. Key steps
include a catalytic asymmetric CBS reduction and twice
induced dihydroxylation.
1
+6 (c 3.6, CHCl3); H NMR (400 MHz, CDCl3): d 7.26–
3. Experimental
3.1. General
7.35 (m, 5H), 6.03 (d, J¼1.2 Hz, 1H), 5.76 (t, J¼3.8 Hz,
1H), 4.50 (q, J¼12 Hz, 2H), 4.08 (s, 2H), 2.47–2.53 (m,
1H), 2.32–2.43 (m, 2H), 1.99 (s, 3H), 1.81–1.87 (m, 1H);
13C NMR (100 MHz, CDCl3): d 170.9, 139.2, 138.1,
134.2, 128.3, 127.6, 127.5, 79.4, 72.4, 66.4, 30.9, 30.2,
21.2. IR (KBr): 1733, 1370, 1241, 1033; HRMS calcd
for C15H18O3Na (M+Na): 262.1148. Found (M+Na)+:
262.1144.
Melting points were measured on a Kofler apparatus and
1
were uncorrected. The H and 13C NMR data are recorded
in CDCl3 and DMSO-d solutions with a Varian Mercury
300, 400 and 600 BB spectrometer. The chemical shifts
are reported in parts per million relative to TMS. The optical
rotations were determined with a JASCO J-20C polarimeter
with 0.2 dm tube. The mass spectra were measured with EI
(70 eV) technique. Column chromatographies were gener-
ally performed on silica gel (200–300 meshes) eluting
with petroleum ether and ethyl acetate.
3.4. (L)-anti-2-(Benzyloxymethyl)-2,3-dihydroxycyclo-
pentyl acetate (7) and (L)-syn-2-(benzyloxymethyl)-2,3-
dihydroxycyclopentyl acetate (8)
A
sample of N-methylmorpholine-N-oxide (2.219 g,
18.9 mmol) and OsO4 (0.1 M in H2O, 7.9 mL, 0.79 mmol)
were sequentially added to a solution of acetate 6 (3.887 g,
15.8 mmol) in THF/H2O (4:1, 50 mL) at room temperature.
After stirring at room temperature for 12 h, the reaction was
quenched by the addition of Na2SO3 (2 g) and EtOAc
(200 mL). The organic phase was separated and the aqueous
phase extracted with EtOAc (2ꢂ50 mL). The combined
organic extracts were dried over Na2SO4, filtered, and evapo-
rated under reduced pressure to give a residue. This crude
material was purified by column chromatography using
3.2. (D)-2-(Benzyloxymethyl)cyclopent-2-enol (5)
(S)-Bu-CBS reagent (9.2 mL, 2.3 mmol, 0.25 M in toluene
solution) was transferred into a freshly flame-dried flask
and toluene was completely removed in vacuo. After the
CBS reagent was diluted with THF (55 mL), the resulting
solution was transferred to a flask containing compound
enone 4 (4.659 g, 23 mmol) at room temperature and the
reaction temperature cooled to ꢀ10 ꢁC. BH3$Me2S (BMS)

9994
W. Quan et al. / Tetrahedron 63 (2007) 9991–9996
petroleum ether and ethyl acetate (5:1, v/v) to afford diol 7
(3.716 g, 84%) as a colorless oil and diol 8 (265 mg, 6%)
as a colorless oil. (7: Rf¼0.25; 8: Rf¼0.22 (petroleum
ether/ethyl acetate¼4:1; v/v).)
filtered off by silica gel column chromatography using
EtOH. The solvent was distilled off to afford 10 (2.478 g,
1
98%) as a colorless oil. [a]2D0 ꢀ50 (c 1.75, CHCl3); H
NMR (300 MHz, CDCl3): d 5.14 (d, J¼5.1 Hz, 1H), 4.50
(dd, J¼4.2, 3.0 Hz, 1H), 3.76 (d, J¼7.2 Hz, 1H), 3.74 (d,
J¼7.2 Hz, 1H), 2.21–2.80 (m, 1H), 2.04 (s, 3H), 1.83–1.91
(m, 2H), 1.66–1.73 (m, 1H), 1.44 (s, 3H), 1.38 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 169.9, 111.3, 93.5, 82.5, 79.8,
62.7, 30.2, 29.8, 27.6, 26.9, 21.1; IR (KBr): 3484, 1739,
1374, 1240, 1029; HRMS calcd for C11H18O5Na (M+Na):
253.1046. Found (M+Na)+: 253.1051.
Compound 7: [a]2D0 ꢀ32 (c 3.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.26–7.37 (m, 5H), 5.05 (dd, J¼6.9,
4.2 Hz, 1H), 4.56 (d, J¼11.7 Hz, 1H), 4.51 (d, J¼11.7 Hz,
1H), 4.04 (dd, J¼12.9, 6.9 Hz, 1H), 3.61 (d, J¼9.3 Hz,
2H), 3.52 (d, J¼9.3 Hz, 2H), 3.46 (s, 1H), 2.72 (d,
J¼5.4 Hz, 1H), 2.27–2.33 (m, 1H), 2.03–2.10 (m, 1H),
1.94 (s, 3H), 1.62–1.73 (m, 1H), 1.46–1.54 (m, 1H); 13C
NMR (75 MHz, CDCl3): d 170.3, 137.5, 128.4, 127.8,
127.7, 79.7, 79.0, 74.5, 73.7, 71.5, 28.9, 27.3, 21.0; IR
(KBr): 3433, 1732, 1371, 1242, 1096, 1032; HRMS calcd
for C15H20O5Na (M+Na): 303.1203. Found (M+Na)+:
303.1204.
3.7. (L)-3a-Formyl-2,2-dimethyltetrahydro-3aH-cyclo-
penta[d][1,3]dioxol-4-yl acetate (11)
To a solution of oxalyl chloride (2.284 g, 18 mmol) in dry
CH2Cl2 (30 mL) at ꢀ78 ꢁC was added dropwise dry
DMSO (2.807 g, 2.55 mL, 36 mmol) in CH2Cl2 (5 mL). Af-
ter 30 min, alcohol 10 (2.760 g, 12 mmol) in CH2Cl2 (5 mL)
was added over 10 min giving copious white precipitate.
After stirring for 1 h at ꢀ78 ꢁC the reaction mixture was
brought to ꢀ60 ꢁC and Et3N (6.7 mL, 48 mmol) was added
slowly and stirred for 30 min allowing the reaction mixture
to warm to room temperature. The reaction mixture was then
diluted with water (30 mL) and CH2Cl2 (100 mL). The or-
ganic layer was separated and washed with water and brine,
dried (Na2SO4), filtered, and evaporated under reduced pres-
sure to give the crude oil. This crude material was purified by
column chromatography using petroleum ether and ethyl
acetate (10:1, v/v) to afford aldehyde 11 (2.462 g, 90%) as
a colorless crystal. Mp: 56–58 ꢁC; [a]D20 ꢀ55 (c 1.6,
Compound 8: [a]2D0 ꢀ2.3 (c 3.6, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.27–7.37 (m, 5H), 4.99 (t, J¼
7.4 Hz, 1H), 4.56 (d, J¼11.6 Hz, 1H), 4.49 (d, J¼11.6 Hz,
1H), 4.03 (dd, J¼12.8, 6.8 Hz, 1H), 3.53 (d, J¼9.2 Hz,
1H), 3.48 (d, J¼9.2 Hz, 1H), 3.07 (s, 1H), 2.65 (d,
J¼5.6 Hz, 1H), 2.05 (s, 3H), 1.76–2.04 (m, 4H); 13C NMR
(100 MHz, CDCl3): d 170.5, 137.6, 128.4, 127.8, 127.7,
77.8, 74.9, 73.7, 73.4, 73.3, 28.9, 26.6, 21.0; IR (KBr):
3442, 1733, 1370, 1245, 1099, 1070, 1043; HRMS calcd
for C15H20O5Na (M+Na): 303.1203. Found (M+Na)+:
303.1201.
3.5. (L)-3a-(Benzyloxymethyl)-2,2-dimethyltetrahydro-
3aH-cyclopenta[d][1,3]dioxol-4-yl acetate (9)
1
CHCl3); H NMR (300 MHz, CDCl3): d 9.70 (s, 1H), 5.01
(d, J¼4.5 Hz, 1H), 4.75 (d, J¼3.9 Hz, 1H), 2.12–2.20 (m,
1H), 1.93–2.03 (m, 2H), 1.93 (s, 3H), 1.77–1.89 (m, 1H),
1.45 (s, 3H), 1.18 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 200.4, 170.5, 111.6, 95.7, 82.6, 80.1, 31.4, 29.3, 26.2,
24.8, 20.9; IR (KBr): 2985, 2942, 2721, 1740, 1376, 1237,
1213; HRMS calcd for C11H16O5Na (M+Na): 251.0890.
Found (M+Na)+: 251.0891.
2,2-Dimethoxypropane (11.456 g, 110 mmol) and p-tolue-
nesulfonic acid (100 mg, 0.526 mmol) both were added to
a solution of diol 7 (3.079 g, 11 mmol) in CH2Cl2 (25 mL)
at room temperature. The reaction mixture was stirred at
room temperature overnight. Saturated aqueous NaHCO3
(20 mL) and ether (100 mL) were sequentially added. The
organic phase was separated and the aqueous phase was
extracted with ether (2ꢂ50 mL). The combined organic
extracts were dried over Na2SO4, filtered, and evaporated
under reduced pressure to give the crude oil. This crude
material was purified by column chromatography using
petroleum ether and ethyl acetate (20:1, v/v) to afford 9
(3.484 g, 99%) as a colorless oil. [a]2D0 ꢀ37.5 (c 4.0,
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.27–7.36 (m,
5H), 5.18 (dd, J¼3.2, 2.0 Hz, 1H), 4.60 (d, J¼12 Hz, 1H),
4.54 (d, J¼12 Hz, 1H), 4.51 (br s, 1H), 3.67 (s, 2H), 2.21–
2.25 (m, 1H), 1.93 (s, 3H), 1.83–1.88 (m, 1H), 1.76–2.04
(m, 4H), 1.70 (m, 1H), 1.45 (s, 3H), 1.37 (s, 3H); 13C
NMR (100 MHz, CDCl3): d 169.7, 138.0, 128.3, 127.5,
111.4, 92.8, 82.5, 79.6, 73.7, 70.3, 30.2, 29.7, 26.7, 21.0;
IR (KBr): 1739, 1451, 1373, 1238, 1103, 1209; HRMS calcd
for C18H24O5Na (M+Na): 343.1516. Found (M+Na)+:
343.1515.
3.8. (L)-2,2-Dimethyl-3a-((Z)-undec-1-enyl)tetrahydro-
3aH-cyclopenta[d][1,3]dioxol-4-yl acetate (12)
To a solution of n-decatriphenylphoshonium bromide
(3.388 g, 7 mmol) in THF (30 mL), n-BuLi (1.4 M, 4.7 mL)
was added dropwise and stirred for 30 min under a stream
of argon at 0 ꢁC. Compound 11 (998 mg, 4.38 mmol) in
THF (10 mL) was added dropwise to the above solution at
ꢀ40 ꢁC and stirred for 1 h. The reaction mixture was stirred
for another 30 min at 0 ꢁC. After quenching the reaction with
brine, it was extracted with ethyl acetate, dried, and evapo-
rated. The residue was flash chromatographed using petro-
leum ether and ethyl acetate (30:1, v/v) to give compound
12 (1.00 g, 65%) as a colorless oil. [a]2D0 ꢀ56 (c 1.0,
1
CHCl3); H NMR (300 MHz, CDCl3): d 5.45 (dt, J¼12.0,
6.8 Hz, 1H), 5.41 (d, J¼12.0 Hz, 1H), 5.17 (d, J¼3.9 Hz,
1H), 4.52 (d, J¼4.8 Hz, 1H), 2.10–2.25 (m, 3H), 1.95 (s,
3H), 1.91–2.03 (m, 1H), 1.84 (dd, J¼13.2, 6.3 Hz, 1H),
1.70 (dd, J¼13.2, 6.0 Hz, 1H), 1.41 (s, 3H), 1.29 (s, 3H),
1.25 (m, 14H), 0.86 (t, J¼6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 169.6, 134.4, 128.9, 110.1, 92.6, 86.9,
80.5, 31.9, 31.0, 29.7, 29.6, 29.5, 29.3, 29.1, 26.7, 25.3,
22.6, 21.2, 14.1; IR (KBr): 2926, 2854, 1748, 1653, 1461,
3.6. (L)-3a-(Hydroxymethyl)-2,2-dimethyl-tetrahydro-
3aH-cyclopenta[d][1,3]dioxol-4-yl acetate (10)
Compound 9 (3.484 g, 10.9 mmol) was hydrogenated using
10% Pd/C (300 mg) in dry EtOH (70 mL) for 8 h at room
temperature and atmospheric pressure. The catalyst was

W. Quan et al. / Tetrahedron 63 (2007) 9991–9996
9995
1373, 1236, 1209, 1029; HRMS calcd for C21H36O4Na
(M+Na): 375.2506. Found (M+Na)+: 375.2512.
(50 mL). The organic layer was separated and washed with
water and brine, dried over Na2SO4, filtered, and evaporated
under reduced pressure to give the crude oil. This crude
material was purified by column chromatography using
petroleum ether and ethyl acetate (10:1, v/v) to afford ketone
15 (179 mg, 80%) as a colorless oil. [a]2D0 +73 (c 1.5,
3.9. (D)-2,3-Dihydroxy-2-((Z)-undec-1-enyl)cyclopentyl
acetate (13)
1
Compound 12 (600 mg, 1.92 mmol) was dissolved in 8 mL
of AcOH and 2 mL of water and stirred at 85–90 ꢁC for
24 h. The reaction was quenched with solid saturated
NaHCO3 and extracted with EtOAc. The organic phase
was washed with brine and dried over Na2SO4. The solvents
were evaporated. The residue was flash chromatographed
using petroleum ether and ethyl acetate (8:1, v/v) to give
compound 13 (533 mg, 89%) as a colorless crystal. Mp:
CHCl3); H NMR (300 MHz, CDCl3): d 5.75 (dt, J¼11.7,
7.8 Hz, 1H), 5.46 (d, J¼11.7 Hz, 1H), 5.05 (dd, J¼8.4,
6.3 Hz, 1H), 3.28 (s, 1H), 2.51–2.61 (m, 1H), 2.21–2.43
(m, 4H), 2.10 (s, 3H), 1.73–1.97 (m, 1H), 1.24 (m, 14H),
0.86 (t, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 211.3, 170.9, 140.7, 121.1, 80.9, 79.3, 32.6, 31.8, 29.49,
29.46, 29.28, 29.26, 28.9, 23.3, 22.6, 20.9, 14.1; IR (KBr):
3463, 2925, 2854, 1750, 1462, 1371, 1237, 1042; HRMS
calcd for C18H31O4 (M+H): 311.2217. Found (M+H)+:
311.2214.
1
49–50 ꢁC; [a]D20 +6 (c 1.0, CHCl3); H NMR (300 MHz,
CDCl3): d 5.56 (dt, J¼11.7, 7.2 Hz, 1H), 5.32 (d,
J¼11.7 Hz, 1H), 5.05 (dd, J¼8.4, 6.0 Hz, 1H), 4.04 (br s,
1H), 3.96 (dd, J¼5.4, 3.6 Hz, 1H), 3.07 (br s, 1H), 2.25–
2.34 (m, 3H), 2.04 (s, 3H), 1.94–2.01 (m, 1H), 1.63–1.74
(m, 2H), 1.24 (m, 14H), 0.86 (t, J¼6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 172.5, 137.1, 126.1, 83.1, 82.6, 77.8,
31.8, 29.9, 29.5, 29.3, 29.2, 28.7, 27.9, 26.6, 22.6, 21.0,
14.0; IR (KBr): 3447, 2924, 2854, 1721, 1653, 1462,
1373, 1242, 1033; HRMS calcd for C18H32O4Na (M+Na):
335.2193. Found (M+Na)+: 335.2187.
3.12. (D)-3,3a,6a-Trihydroxy-2-nonylhexahydro-2H-
cyclopenta[b]furan-4-ylacetate (16)
A
sample of N-methylmorpholine-N-oxide (54.8 mg,
0.468 mmol) and OsO4 (0.1 M in H2O, 0.78 mL,
0.078 mmol) were sequentially added to a solution of acetate
15 (121 mg, 0.39 mmol) in THF/H2O (3:1) (4 mL) at room
temperature. After stirring at room temperature for 30 h,
the reaction was quenched by addition of Na2SO3 (55 mg)
and EtOAc (30 mL). The organic phase was separated and
the aqueous phase extracted with EtOAc (2ꢂ20 mL). The
combined organic extracts were dried over Na2SO4, filtered,
and evaporated under reduced pressure to give a residue.
This crude material was purified by column chromatography
using petroleum ether and ethyl acetate (2:1, v/v) to afford
product 16 (94 mg, 75%) as a colorless oil. [a]2D0 +60 (c
1.5, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.85 (dd,
J¼11.1, 6.9 Hz, 1H), 4.82 (br s, 1H), 4.41 (s, 1H), 3.49–
3.57 (m, 2H), 2.49 (d, J¼9.3 Hz, 1H), 2.10–2.17 (m, 1H),
2.11 (s, 3H), 1.92–1.98 (m, 1H), 1.62–1.74 (m, 3H), 1.36–
1.59 (m, 3H), 1.24 (m, 12H), 0.86 (t, J¼6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 173.6, 107.5, 82.5, 81.5, 80.2,
74.8, 33.6, 32.1, 31.8, 29.7, 29.5, 29.4, 29.3, 25.5, 25.1,
22.6, 20.6, 14.1; IR (KBr): 3421, 2926, 2855, 1726, 1462,
1376, 1252; HRMS calcd for C18H32O6Na (M+Na):
367.2091. Found (M+H)+: 367.2092.
3.10. (Z)-1,5-Dioxohexadec-6-en-4-yl acetate (14)
IBX (220 mg, 0.785 mmol) was dissolved in DMSO (2 mL)
at room temperature. After 20 min, compound 13 (123 mg,
0.394 mmol) was added. TLC analyses indicated completion
of the reaction. Work-up was easily performed by dilution of
the reaction mixture with water. The white precipitate was
filtered and the reaction mixture was extracted with ethyl
acetate (3ꢂ20 mL). The combined organic extracts were
dried over Na2SO4, filtered, and evaporated under reduced
pressure to give the crude oil. The residue was flash chroma-
tographed using petroleum ether and ethyl acetate (5:1, v/v)
to give compound 14 (113 mg, 93%) as a colorless oil. [a]D20
+10 (c 0.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 9.76 (s,
1H), 6.29 (dt, J¼11.1, 6.8 Hz, 1H), 6.20 (d, J¼11.1 Hz, 1H),
5.04 (dd, J¼8.1, 4.8 Hz, 1H), 2.53–2.63 (m, 4H), 2.15–2.21
(m, 1H), 2.12 (s, 3H), 2.00 (m, 1H), 1.40 (m, 2H), 1.24 (m,
12H), 0.85 (t, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 200.4, 196.1, 170.1, 153.3, 121.9, 77.4, 39.2, 31.8, 29.9,
29.5, 29.4, 29.3, 29.2, 28.9, 22.8, 22.6, 20.6, 20.5, 14.1; IR
(KBr): 2925, 2854, 1746, 1702, 1617, 1373, 1236, 1050;
HRMS calcd for C18H30O4Na (M+Na): 333.2036. Found
(M+Na)+: 333.2038.
3.13. (D)-2,3-Dihydroxy-2-((Z)-undec-1-enyl)cyclo-
pentanone (17)
To a solution of 15 (111 mg, 0.36 mmol) in dry CH3OH
(7 mL) at room temperature was added K2CO3 (4.9 mg,
0.036 mmol). After 2 h, the reaction mixture was diluted
with EtOAc (3ꢂ20 mL), dried (Na2SO4), filtered, and evapo-
rated under reduced pressure to give the crude oil. This
crude material was purified by column chromatography
using petroleum ether and ethyl acetate (3:1, v/v) to afford
product 17 (95 mg, 98%) as a colorless oil. [a]2D0 +31 (c
1.6, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.85 (dt,
J¼11.7, 7.8 Hz, 1H), 5.60 (d, J¼11.7 Hz, 1H), 4.14 (dd,
J¼7.2, 6.3 Hz, 1H), 2.87 (br s, 1H), 2.50–2.61 (m, 1H),
2.16–2.36 (m, 5H), 1.89–1.97 (m, 1H), 1.24 (m, 14H),
0.87 (t, J¼6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3):
d 214.3, 140.9, 121.7, 81.8, 76.7, 32.5, 31.9, 29.53,
29.52, 29.49, 29.32, 29.29, 29.2, 25.3, 22.6, 14.1; IR
(KBr): 3408, 2924, 2853, 1747, 1462; HRMS calcd for
3.11. (D)-2-Hydroxy-3-oxo-2-((Z)-undec-1-enyl)cyclo-
pentyl acetate (15)
To a solution of oxalyl chloride (141 mg, 1.11 mmol) in dry
CH2Cl2 (5 mL) at ꢀ78 ꢁC was added dropwise dry DMSO
(170 mg, 0.15 mL, 2.172 mmol) in CH2Cl2 (1 mL). After
30 min, alcohol 14 (226 mg, 0.724 mmol) in CH2Cl2
(1 mL) was added over 2 min giving copious white precipi-
tate. After stirring for 30 h at ꢀ78 ꢁC the reaction mixture
was brought to ꢀ60 ꢁC and Et3N (0.41 mL, 2.91 mmol)
was added slowly and stirred for 30 min allowing the reac-
tion mixture to warm to room temperature. The reaction
mixture was then diluted with water (5 mL) and CH2Cl2

9996
W. Quan et al. / Tetrahedron 63 (2007) 9991–9996
C16H32O3N (M+NH4): 286.2377. Found (M+NH4)+:
286.2381.
1H), 5.47 (d, J¼4.2 Hz, 1H), 4.57 (s, 1H), 4.03 (dt, J¼7.2,
4.2 Hz, 1H), 3.72 (t-like, J¼7.2 Hz, 1H), 3.55 (dt, J¼7.8,
4.8 Hz, 1H), 1.87 (ddd, J¼12, 6.6, 5.4 Hz, 1H), 1.80 (ddt,
J¼12, 7.2, 4.8 Hz, 1H), 1.58 (ddd, J¼12, 9.6, 7.2 Hz, 1H),
1.48–1.53 (m, 2H), 1.34–1.40 (m, 2H), 1.24 (m, 12H),
0.85 (t, J¼7.2 Hz, 3H); 13C NMR (150 MHz, DMSO):
d 108.5, 84.0, 83.2, 81.4, 80.0, 35.1, 34.0, 31.3, 30.5, 29.1,
29.0, 28.9, 28.7, 25.3, 22.1, 14.0; IR (KBr): 3374, 2923,
2853; HRMS calcd for C16H30O5N (M+NH4): 320.2431.
Found (M+NH4)+: 320.2432.
3.14. (D)-2-Nonylhexahydro-2H-cyclopenta[b]furan-
3,3a,4,6a-tetraol (18)
To a solution of 16 (28 mg, 0.08 mmol) in dry CH3OH
(2 mL) at room temperature was added K2CO3 (1.1 mg,
0.008 mmol). After 2 h, the reaction mixture was diluted
with EtOAc (3ꢂ20 mL), dried (Na2SO4), filtered, and evapo-
rated under reduced pressure to give the crude oil. This
crude material was purified by column chromatography
using petroleum ether and ethyl acetate (1:2, v/v) to afford
product 18 (23 mg, 95%) as a colorless oil. [a]2D0 +20 (c
0.4, acetone); 1H NMR (300 MHz, DMSO): d 5.63 (s, 1H),
4.90 (d, J¼4.8 Hz, 1H), 4.78 (d, J¼6.6 Hz, 1H), 4.43 (s,
1H), 3.73 (dt, J¼11.1, 6.9, 4.8 Hz, 1H), 3.56 (dd, J¼8.1,
6.6 Hz, 1H), 3.42 (t-like, J¼8.1 Hz, 1H), 1.68 (dd, J¼12,
6.9 Hz, 1H), 1.58 (m, 2H), 1.34 (m, 2H), 1.24 (m, 13H),
1.09–1.16 (m, 1H), 0.87 (t, J¼5.7 Hz, 3H); 13C NMR
(75 MHz, DMSO): d 108.2, 82.6, 79.0, 78.0, 72.9, 33.3,
32.3, 31.4, 29.3, 29.1, 28.8, 28.1, 25.5, 22.2, 14.1; IR
(KBr): 3378, 2924, 2854; HRMS calcd for C16H30O5N
(M+NH4): 320.2431. Found (M+NH4)+: 320.2429. The ste-
reostructure of 18 was confirmed by NOESY experiment in
Acknowledgements
We are grateful for the generous financial support by the
Special Doctorial Program Funds of the Ministry of Educa-
tion of China (20040730008), NSFC (QT program, Nos.
20572036 and 20572037), NCET-05-0879, the key grant
project of Chinese Ministry of Education (No. 105169),
and Gansu Science Foundation (3ZS051-A25-004).
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.07.053.
1
the 300 Hz NMR spectra. The key NOESY correlation is
depicted in the following figure:
References and notes
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HO
H
H
OH
CH2
H
8
O
H
OH
CH3
OH
H
H
H
NOESY 18
3.15. (L)-Heliconol A (ent-1)
sample of N-methylmorpholine-N-oxide (39 mg,
A
0.331 mmol) and OsO4 (0.1 M in H2O, 1.3 mL, 0.13 mmol)
were sequentially added to a solution of 17 (74 mg,
0.276 mmol) in THF/H2O (4:1, 5 mL) at room temperature.
After stirring at room temperature for 48 h, the reaction
was quenched by addition of Na2SO3 (56 mg) and EtOAc
(40 mL). The organic phase was separated and the aqueous
phase extracted with EtOAc (2ꢂ20 mL). The combined
organic extracts were dried over Na2SO4, filtered, and evapo-
rated under reduced pressure to give a residue. This crude
material was purified by column chromatography using pe-
troleum ether and ethyl acetate (1:2, v/v) to afford compound
18 (33 mg, 40%) and product ent-1 (25 mg, 30%) as a color-
less oil. (ent-1: Rf¼0.10; 18: Rf¼0.08 (petroleum ether/ethyl
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815.
1
acetate¼2:1; v/v)). [a]2D0 ꢀ24 (c 0.2, acetone); H NMR
(600 MHz, DMSO): d 5.82 (s, 1H), 5.56 (d, J¼7.2 Hz,