Studies directed towards the enantioselective synthesis of ethisolide and isoavenaciolide

Article abstract of DOI:10.1002/ejoc.200500884

An asymmetric synthesis of an analog of ethisolide has been achieved by using as key steps two σ[3,3]rearrangements stereocontrolled by a sulfinyl group. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500884

FULL PAPER
DOI: 10.1002/ejoc.200500884
Studies Directed towards the Enantioselective Synthesis of Ethisolide and
Isoavenaciolide
Virginie Blot,[a] Vincent Reboul,*[a] and Patrick Metzner*[a]
Dedicated to the memory of Pierre Potier
Keywords: (–)-Isoavenaciolide / (–)-Ethisolide / σ[3,3] Rearrangement / Sulfoxides / Lactones
An asymmetric synthesis of an analog of ethisolide has been
achieved by using as key steps two σ[3,3] rearrangements
stereocontrolled by a sulfinyl group.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
5 and dichloroketene. In contrast with all the published syn-
theses, we decided to introduce the alkyl side chain at a late
stage of the synthesis, by nucleophilic substitution of the
known lactone 6. Indeed, our group already prepared this
compound by the iodolactonization of 7, which was synthe-
sized by a second σ[3,3] rearrangement from thioamide 8.
Introduction
The asymmetric synthesis of bis-fused γ-lactones,[1] such
as (–)-ethisolide (1) or (–)-isoavenaciolide (2) (Scheme 1),[2]
has received much attention due to the combination of their
unique structural features and biological activities: antifun-
gal and antibacterial properties, and inhibition of VHR
(vaccinia-H1-related) phosphatase activity.[3] Thus, numer-
ous asymmetric total[4–12] or formal syntheses[13–17] have
been reported.
Scheme 1. Structure of the bis(lactone)s.
In connection with our studies of a σ[3,3] rearrangement
stereocontrolled by a sulfinyl group,[18,19] we were interested
to apply this methodology in an asymmetric synthesis of
similar bis(butyrolactone)s. We report herein our new ap-
proach to such compounds.
Our retrosynthetic analysis for these natural products is
depicted in Scheme 2. Our strategy was to avoid the use of
protecting groups and to employ two σ[3,3] rearrangements
induced by the same chiral inductor, an enantiopure sulfinyl
group, to control the three contiguous chiral centers. Thus,
the first disconnection is to remove the methylene function,
as described previously,[20] to obtain the lactones 3. For the
synthesis of the bis(lactone) core 4, the first σ[3,3] transpo-
sition is then envisaged, involving the enantiopure lactone
Scheme 2. Retrosynthetic analysis.
Results and Discussion
Our synthesis began with the first σ[3,3] rearrangement,
a thio-Claisen transposition.[18,19] It enabled alkylation of
sulfinyl thioamide 8 into thioamide 9, which was followed
by oxidation to amide 7 (Scheme 3). This compound was
obtained in 69% overall yield, and with both absolute and
relative stereocontrol (dr 99:1; ee 96%).
We recently demonstrated the influence of a sulfur sub-
stituent on the selectivity of the iodolactonization
(Scheme 3).[21] Indeed, whereas the sulfinyl group was not
efficient (11: dr 72:28; yield: 60%), an excellent 1,3-induc-
tion has been observed with the α-sulfanylamide 10, and
the desired lactone 6 (dr 96:4) was obtained in quantitative
yield.
[a] Laboratoire de Chimie Moléculaire et Thio-organique (UMR
CNRS # 6507), ENSICAEN – Université de Caen,
6, Boulevard du Maréchal Juin, 14050 Caen, France
Fax: +33-231-452-877
E-mail: vincent.reboul@ensicaen.fr
1934
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Enantioselective Synthesis of Ethisolide and Isoavenaciolide
FULL PAPER
affording the vinyl sulfide 20. Indeed, compound 20 was
1
observed by H NMR spectroscopy during the analysis of
compound 18.
Scheme 5. Reagents and conditions: (a) Bu3SnH, AIBN, THF,
65 °C, 97%; (b) LiHMDS, THF, –78 °C, then PhSeCl, 60 to 82%
(c) m-CPBA, pyridine, CH2Cl2, 0 °C, 97 %.
Scheme 3. Reagents and conditions: (a) tBuLi, THF, –40 °C, then
allyl bromide; (b) CeCl3 (10%), THF, room temp., 20 h; (c) di-
methyldioxirane (formed in situ), 69% overall, dr 99:1; (d) P4S10,
CH2Cl2, room temp., 90%; (e) I2, THF/H2O, 60%; (f) I2, THF/
H2O, 98 %.
At this stage, we preferred to use another reaction to
introduce the unsaturation and decided to work with lac-
tone 6. We chose the Pummerer reaction,[25] which required
oxidation of 6 to the corresponding sulfoxide (Scheme 6).
Classical conditions were used: TFAA in the presence of
NEt3. However, we were not able to isolate sulfide 22. For-
tunately, this compound was formed quantitatively by re-
moving the base. The enantiomeric excess was checked by
chiral HPLC after reduction (to avoid the formation of 16)
to lactone 20 (ee 94% on Daicel Chiralpak AD column).
The oxidation reaction of 20 afforded sulfoxide 21 as a mix-
ture of two diastereomers (dr 1:1).
The next step was the formation of unsaturated lactone
5. We chose to explore this pathway with lactone 11 as a
model. We first used the chlorination of lactone 11 by NCS
(98% yield), followed by an elimination reaction under ba-
sic conditions (Scheme 4).[22] Unfortunately, the expected
lactone 14 was not obtained. We then tested the selenenyl-
ation of lactone 11 followed by oxidation with m-CPBA or
H2O2 (in the presence of base).[23] We isolated only the 5-
methylenefuran-2(5H)-one 16, probably by elimination of
the corresponding iodoso intermediate 15.[24]
Scheme 6. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 °C,
95%; (b) TFAA, CH2Cl2, 0 °C, 93%; (c) Bu3SnH, AIBN, THF,
65 °C, 97%; (d) m-CPBA, CH2Cl2, 0 °C, 98 %.
For the introduction of the alkyl side chain, we first used
the conditions developed in an analogous series: nucleo-
philic substitution of the iodine atom in 6 by a cuprate
(Scheme 7).[26–28] Unfortunately, the corresponding lactones
24 or 25 were not obtained, regardless of the organocup-
rates or conditions used (RMgBr, CuBr·Me2S; RLi, CuCN;
Scheme 4. Reagents and conditions: (a) NCS, K2CO3, CH2Cl2,
98%; (b) LDA, THF, –78 °C, then PhSeCl, 53% (c) LiBr or Li2CO3
or NEt3; (d) m-CPBA or H2O2, K2CO3 or pyridine, CH2Cl2, room
temp., 90%.
To avoid this side reaction, this process was tested with RLi, CuI; MeMgBr, CuI). However, we were able to per-
the reduced lactone 17 (Scheme 5). The desired lactone 21 form this transformation in two steps: formation of the ep-
was indeed prepared in moderate yield (step b not easily oxide 26 (K2CO3/MeOH), then ring opening in the presence
reproducible) but we were very surprised to obtain four ste- of the suitable dialkylcuprate (formed in situ from the cor-
reoisomers according to chiral HPLC analysis (70:14:10:6), responding alkyl Grignard reagent and CuI). Under these
as a result of partial epimerization of the sulfoxide moiety. unoptimized conditions, lactones 24 and 25 were obtained
This observation could be explained by the transfer of an in yields of 70% and 22%, respectively. The low yield of 25
oxygen atom from the sulfur to the selenium atom (18 to prompted us to continue the synthesis with sulfanyl lactone
19) and subsequent elimination of selenenic acid (19 to 20) 24.
Eur. J. Org. Chem. 2006, 1934–1939
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1935

V. Blot, V. Reboul, P. Metzner
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during purification on silica gel. So, this compound was
immediately reduced by Bu3SnH/AIBN (Scheme 9). We
were surprised not to obtain the desired lactone 30 but lac-
tone 29 instead, with a dr of 92:8 after purification (40%
overall yield). Unfortunately, other reducing agents, Raney
Ni or SmI2/HMPA, did not bring about the reduction of
the cyclohexylsulfanyl group. The stereochemistry of the
stereocenters in 29 was clearly confirmed by NOE studies:
(3aR,4S,6aS)-29 (Scheme 9).
Scheme 7. Reagents and conditions: (a) K2CO3, MeOH, room
temp., 96%, dr 1:1; (b) RMgBr, CuI, THF, 0 °C, R = Me (70%, dr
7:3), R = Heptyl (22%, dr 99:1).
The substrate for the second σ[3,3] rearrangement was
easily obtained in three steps (Scheme 8) according to the
sequence developed in Scheme 6: oxidation of the sulfanyl
to a sulfinyl lactone and the Pummerer reaction in the pres-
ence of TFAA. Under these conditions, lactone 27 was ob-
tained in quantitative yield and with an excellent enantio-
meric excess of 99% (chiral HPLC, Daicel AD-H column).
The oxidation of this compound with m-CPBA led to the
sulfoxide 5 in quantitative yield and with the expected dia-
stereomeric ratio of 1:1.
Scheme 9. Reagents and conditions: (a) CCl3COCl, Zn-Cu, THF,
10 min, 0 °C; (b) Bu3SnH, AIBN, toluene, 110 °C, 40% (2 steps).
However, the bis(lactone) 29 should have a dr of 1:1 ac-
cording to the stereochemical outcome of this transposition
(Scheme 10). With the mechanism reported by Marino, the
oxygen atom of the sulfinyl group is acylated by the car-
bonyl group of dichloroketene to give rise to a zwitterionic
intermediate (A, AЈ) that adopts a chairlike conformation
in which the bulky group (Cy) is located in an equatorial
position. After the σ[3,3] rearrangement step, the Pumm-
Scheme 8. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 °C,
91%; (b) TFAA (2 equiv.), CH2Cl2, 0 °C, 98 %, ee: 99%; (c) m-
CPBA, CH2Cl2, 0 °C, 98 %, dr 1:1.
The last key step was the formation of the bis(lactone) 4 erer type intermediate (B, BЈ) cyclized to afford the bis(lac-
by a second σ[3,3] rearrangement stereocontrolled by a sul- tone).
finyl group[29–32] and effected by reaction with dichloroke-
According to transition states A or AЈ, the alkyl side
tene.[33] This efficient methodology, developed by Marino chain on the lactone did not seem to play any role in the
and his group, has been recently used in the total synthesis stereoselectivity of the rearrangement. In order to confirm
of natural compounds.[34]
this observation, the bis(lactone) formation was performed
Dichloroketene was generated in situ by treating trichlo- on lactone 5, which bears an ethyl group (Scheme 11). As
roacetyl chloride in the presence of a zinc-copper couple in previously, the analog of ethisolide 4 was obtained, after
THF.[35] The transposition was first tested on model lactone reduction of 31 (dr 8:2) with Raney nickel, with a dr of 95:5
21 (obtained in four steps from 6; 84% overall yield; dr 1:1). (48% yield for two steps) after purification. The stereo-
After 10 min at 0 °C (no reaction at –40 °C), the expected chemistry of the stereocenters of 4 was also confirmed by
bis(lactone) 28 was formed (dr 77: 23), but was unstable NOE studies. As previously, other reducing agents,
Scheme 10. Reagents and conditions: (a) CCl3COCl, Zn-Cu, THF, 10 min, 0 °C; (b) Bu3SnH, AIBN, toluene, 110 °C.
1936
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Eur. J. Org. Chem. 2006, 1934–1939

Enantioselective Synthesis of Ethisolide and Isoavenaciolide
FULL PAPER
n-hexane (7×20 mL). Then the acetonitrile was removed under re-
duced pressure and the crude product was purified by column
chromatography on silica gel (EtOAc) to afford 17 (1.06 g, 96%)
as a white solid, as a mixture of four diastereomers. To a cooled
(0 °C) solution of 17 (1.0 g, 4.5 mmol, 1 equiv.) in CH2Cl2 (20 mL)
was added TFAA (1.27 mL, 9.0 mmol, 2 equiv.). After 1.5 h, the
solution was hydrolyzed with a solution of saturated NaHCO3
(2×20 mL) and then washed with brine. The organic layer was
dried with MgSO4 and concentrated to dryness to afford pure 20
(0.86 g, 93%) as a yellow solid. M.p.: 58 °C. 1H NMR (CDCl3,
400 MHz): δ = 1.25–2.07 (m, 10 H), 1.46 (d, J = 6.6 Hz, 3 H), 3.34–
3.26 (m, 1 H), 5.01 (dq, J = 6.6, 1.8 Hz, 1 H), 6.92 (d, J = 1.8 Hz,
1 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 19.6, 25.7, 25.8,
32.9, 44.1, 78.9, 130.1, 145.4, 171.0 ppm. GC–MS: m/z (%) = 212
(49), 130 (100), 112 (20), 102 (30), 85 (51), 67 (15), 55 (50), 43
(32), 83 (34), 67 (20), 55 (71), 41 (18). HRMS (EI): m/z calcd. for
C11H16O2S: 212.08709; found 212.08693. HPLC analysis: column:
Daicel Chiralpak AD; temperature: 10 °C; flow rate: 1 mL/min;
eluent: n-hexane/2-propanol (9:1); detection at 202.9 nm and
269.8 nm; tR = 9.2 min, (S)-20; tR = 10.6 min, (R)-20; ee = 94%.
Bu3SnH/AIBN or SmI2/HMPA, did not effect the re-
duction of cyclohexylsulfanyl moiety 4 to the corresponding
bis(lactone) 3.
Scheme 11. Synthesis of an analog of ethisolide. Reagents and con-
ditions: (a) CCl3COCl, Zn-Cu, THF, 10 min, 0 °C; (b) Raney
nickel, EtOH, room temp., 48% (2 steps).
Conclusion
We have developed a convergent asymmetric synthesis of
an analog of ethisolide 4 (28% yield by seven steps from
known lactone 6) that could be employed for the synthesis
of the isoavenaciolide series from epoxide 26.
Our strategy involved, as key steps, two σ[3,3] rearrange-
ments stereocontrolled by a sulfinyl group. The first one,
followed by an iodolactonization reaction, afforded the lac-
tone skeleton. The second transposition was used for the
synthesis of the bis(lactone) core.
Further transformation of compounds 29 and 4 is being
investigated with the aim of synthesizing natural biolo-
gically active compounds and understanding the observed
stereoconvergence during the formation of the bis(lactone)
core.
(5S)-3-Cyclohexanesulfinyl-5-methyl-5H-furan-2-one (21): To
a
cooled (0 °C) solution of (5S)-20 (ee = 94%, 0.70 g, 3.3 mmol,
1 equiv.) in CH2Cl2 (55 mL) was added m-CPBA (0.75 g, 4.3 mmol,
1.3 equiv.). The reaction was monitored by TLC. After completion,
the organic layer was washed with a solution of saturated NaHCO3
(4×30 mL), then with brine, and then dried with MgSO4 and con-
centrated to dryness. Pure white solid 21 (0.75 g, 98%) was ob-
tained as a mixture of two diastereomers (dr 1:1). M.p.: 118 °C.
1
21a: H NMR (CDCl3, 400 MHz): δ = 1.22–2.10 (m, 10 H), 1.54
(d, J = 6.8 Hz, 1 H), 3.05 (tt, 1 H), 5.31 (m, 1 H), 7.83 (d, J =
1.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 19.5, 22.2,
1
25.5, 25.6, 26.2, 27.5, 58.4, 80.1, 138.2, 159.5, 167.4 ppm. 21b: H
NMR (CDCl3, 400 MHz): δ = 1.22–2.10 (m, 10 H), 1.54 (d, J = 6.
8 Hz, 1 H), 3.05 (tt, 1 H), 5.31 (m, 1 H), 7.88 (m, 1 H) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ = 19.2, 22.4, 25.6, 25.9, 26.9, 58.6,
77.7, 138.2, 159.5, 167.5 ppm. IR (KBr): ν = 3078, 2936, 2860,
˜
1746, 1456, 1378, 1316, 1266, 1160, 1044, 904 cm–1. C11H16O3S
(228.31): calcd. C 57.87, H 7.06, S 14.04; found C 57.69, H 7.16, S
13.76.
Experimental Section
General: THF was freshly distilled from sodium-benzophenone be-
fore use. Toluene was freshly distilled from sodium before use. All
non-aqueous reactions were carried out in oven-dried, septum-
capped flasks, and under an atmospheric pressure of nitrogen.
Commercial reagents were used directly as received. All liquid rea-
gents were transferred by oven-dried syringes. All reactions were
monitored by TLC carried out on analytical silica gel TLC plates,
purchased from Merck silica gel and were visualized with UV light
or iodine. Preparative flash liquid chromatography was performed
with Merck 60 silica gel (62–200 microns).
Methyl (4R)-2-Cyclohexylsulfanyl-3-oxiranylpropanoate (26): To a
solution of (3S,5R)-6 (dr 99:1, 600 mg, 1.76 mmol, 1 equiv.) in
methanol (6 mL) was added K2CO3 (269 mg, 1.94 mmol,
1.1 equiv.). After 2 h of stirring, the suspension was hydrolyzed
with water (15 mL). The aqueous layer was extracted with CH2Cl2
(15 mL). The organic layer was washed with water (2×15 mL) and
brine, and then it was dried with MgSO4 and concentrated to dry-
ness to afford (4R)-26 (413 mg, 96%) as a pale yellow oil, as a
mixture of two diastereomers (dr 1:1). 1H NMR (CDCl3,
400 MHz): δ = 1.15–2.07 (m, 23 H), 2.20 (ddd, J = 14.3, 9.9, 4.5 Hz,
1 H), 2.53 (dd, J = 4.9, 2.6 Hz, 2 H), 2.76 (dd, J = 4.9, 2.6 Hz, 1
H), 2.80 (dd, J = 4.9, 4.2 Hz, 2 H), 2.80–2.88 (m, 2 H), 2.93–2.99
(m, 1 H), 3.11–3.17 (m, 1 H), 3.49–3.55 (m, 2 H), 3.74 (s, 3 H),
3.75 (s, 3 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 25.7, 25.9,
26.1, 33.5, 33.6, 33.8, 35.0, 35.5, 42.1, 42.7, 44.3, 44.3, 44.5, 47.2,
(3R,5S)-6: This compound was synthesized according to ref.[21]
(5S)-3-Cyclohexylsulfanyl-5-methyl-5H-furan-2-one (20): To a co-
oled (0 °C) solution of (3S,5R)-6 (dr 99:1, 1.85 g, 5.4 mmol) in
CH2Cl2 (80 mL) was added m-CPBA (1.48 g, 8.6 mmol). The reac-
tion was monitored by TLC. After completion, the organic layer
was washed with a solution of saturated NaHCO3 (3×80 mL), then
with brine, and then it was dried with MgSO4, and concentrated
to dryness. The white solid (dr 62:38) was purified on silica gel
(EtOAc) to afford the sulfoxide 11 (1.83 g, 95%) as white powder,
as a mixture of four diastereomers. This compound (1.70 g,
4.8 mmol, 1 equiv.) was diluted in THF (32 mL); then Bu3SnH
(2.57 mL, 9.5 mmol, 2 equiv.) and solid AIBN (133 mg, 0.8 mmol,
0.17 equiv.) were added. After 20 min at 65 °C, the solvent was re-
moved. The oil was diluted in acetonitrile (20 mL) and washed with
47.5, 49.9, 50.0, 52.4, 52.4, 173.1, 173.4 ppm. IR (NaCl): ν = 2928,
˜
2852, 1734, 1442, 1342, 1264, 1158 cm–1. MS (70 eV, EI): m/z (%)
= 245 (42) [MH]+, , 212 (11), 145 (20), 130 (38), 115 (100), 102
(25), 81 (62), 55 (20). HRMS (EI): m/z calcd. for C12H20O3S:
244.1133; found 244.1182.
(5S)-3-Cyclohexylsulfanyl-5-ethyl-dihydrofuran-2-one (24): To
a
cooled (0 °C) suspension of CuI (486 mg, 2.55 mmol, 1.5 equiv.) in
THF (8 mL) was slowly added a commercial solution of MeMgBr
Eur. J. Org. Chem. 2006, 1934–1939
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V. Blot, V. Reboul, P. Metzner
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in Et2O (3 , 1.70 mL, 2.55 mmol, 3 equiv.). The reaction mixture
was stirred at 0 °C for 20 min, and then a solution of 26 (dr 1:1,
415 mg, 1.70 mmol, 1 equiv.) in THF (0.5 mL) was slowly added.
After 1.5 h, the reaction mixture was hydrolyzed with a solution of
saturated NH4Cl (10 mL). The aqueous layer was extracted with
CH2Cl2 (3×10 mL). The combined organic layers were washed
with a solution of saturated NH4Cl (20 mL), brine, dried with
MgSO4, and then concentrated to dryness. Chromatography on sil-
ica gel (n-pentane-EtOAc 9:1) afforded 24 (248 mg, 64%) as a yel-
low oil, as a mixture of two diastereomers (dr 7:3). Major isomer
(m, 1 H), 4.92–4.97 (m, 1 H), 6.92 (d, J = 1.9 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ = 9.1, 25.7, 26.9, 32.8, 44.0, 83.6,
130.2, 144.2, 171.1 ppm. IR (NaCl film): ν = 2928, 2854, 1754,
˜
1450, 1336, 1276, 1168 cm–1. GC–MS (70 eV, EI): m/z (%) = 226
(50) [M]+, 144 (100), 129 (51), 116 (18), 99 (30), 83 (12), 65 (15),
55 (51), 41 (13). HRMS (EI): m/z calcd. for C12H18O2S: 226.10274;
found 226.10048. HPLC analysis: column: Daicel Chiralpak AD-
H; temperature: 20 °C; flow rate: 1 mL/min; eluent: n-heptane/2-
propanol (99:1); detection at 201.9 nm and 268.8 nm; tR
21.5 min, (S)-27; tR = 26.1 min, (R)-27; ee = 99%.
=
1
(Rf: 0.21): H NMR (CDCl3, 400 MHz): δ = 1.02 (t, J = 7.4 Hz, 3
(5S)-3-Cyclohexanesulfinyl-5-ethyl-5H-furan-2-one (5): To a cooled
(0 °C) solution of (5S)-27 (ee = 99%, 212 mg, 0.94 mmol, 1 equiv.)
in CH2Cl2 (14 mL) was added m-CPBA (236 mg, 1.37 mmol,
1.5 equiv.). The reaction was monitored by TLC. After completion,
the organic layer was washed with a solution of saturated NaHCO3
(3×20 mL), then brine, and then it was dried with MgSO4 and
concentrated to afford pure 5 (222 mg, 98%) as a white solid as a
mixture of two diastereomers (dr 1:1). M.p.: 65 °C. 1H NMR
(CDCl3, 400 MHz): δ = 1.01 (t, J = 7.5 Hz, 3 H), 1.02 (t, J =
7.4 Hz, 3 H), 1.22–2.10 (m, 24 H), 2.90–3.12 (m, 2 H), 5.07–5.11
(m, 1 H), 5.13–5.16 (m, 1 H), 7.85 (d, J = 1.5 Hz, 1 H), 7.86 (d, J
= 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 9.0, 9.1,
21.9, 22.0, 25.1, 25.2, 25.7, 26.4, 26.5, 27.0, 58.0, 58.0, 84.3, 84.4,
H), 1.18–2.12 (m, 13 H), 2.74 (ddd, J = 13.2, 9.3, 6.4 Hz, 1 H),
3.08–3.19 (m, 1 H), 3.70 (t, J = 9.3 Hz, 1 H), 4.33–4.40 (m, 1 H)
ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 9.5, 25.7, 26.0, 28.7,
33.2, 33.6, 36.0, 38.9, 43.6, 80.1, 176.1 ppm. Minor isomer (Rf:0.13):
1H NMR (CDCl3, 400 MHz): δ = 1.03 (t, J = 7.5 Hz, 3 H), 1.20–
1.90 (m, 11 H), 2.14 (ddd, J = 13.6, 5.8, 2.2 Hz, 1 H), 2.15–2.20
(m, 1 H), 2.25 (ddd, J = 13.6, 9.2, 8.1 Hz, 1 H), 3.07–3.19 (m, 1
H), 3.65 (dd, J = 8.1, 2.2 Hz, 1 H), 4.33–4.40 (m, 1 H) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ = 9.5, 25.6, 25.7, 25.8, 28.2, 32.7,
33.5, 35.9, 38.9, 43.1, 80.0, 176.3 ppm. MS (70 eV, EI): m/z (%) =
228 (23) [M]+, 147 (7), 114 (100), 101 (15), 81 (59), 73 (30), 55 (49),
41 (16). HRMS (EI): m/z calcd. for C12H20O2S: 228.11839; found
228.11893.
138.1, 157.9, 167.1, 167.2 ppm. IR (KBr): ν = 3060, 2934, 2854,
˜
1748, 1450, 1384, 1332, 1302, 1268, 1166, 1104, 1064, 912 cm–1.
C12H18O3S (242.33): calcd. C 59.47, H 7.49, S 13.23; found C 59.17,
H 7.79, S 13.13.
(5S)-3-Cyclohexylsulfanyl-5-octyl-dihydrofuran-2-one (25): A solu-
tion of heptylMgBr was prepared by mixing Mg (100 mg,
4.11 mmol, 1 equiv.) and heptyl bromide (0.65 mL, 4.11 mmol,
1 equiv.) in THF (1.4 mL) at room temperature until disappearance
of Mg. To a cooled (0 °C) suspension of CuI (82 mg, 0.43 mmol,
1.5 equiv.) in THF (2.4 mL) was slowly added a solution of hep-
tylMgBr in THF (3 , 1.70 mL, 2.55 mmol, 3 equiv.). The reaction
mixture was stirred at 0 °C for 20 min, and then a solution of 26
(dr 1:1, 70 mg, 0.290 mmol, 1 equiv.) in THF (0.2 mL) was slowly
added. After 1.5 h, the reaction mixture was hydrolyzed with a
solution of saturated NH4Cl (5 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3×5 mL). The combined organic layers were
washed with a solution of saturated NH4Cl (5 mL), then with brine,
dried with MgSO4 and then concentrated to dryness. Chromatog-
raphy on silica gel (n-pentane-EtOAc 9:1; Rf: 0.4) afforded 25
(20 mg, dr 99:1, 22% yield) as a yellow oil. 1H NMR (CDCl3,
400 MHz): δ = 0.90 (t, J = 6.8 Hz, 3 H), 1.21–1.93 (m, 23 H), 2.14
(ddd, J = 13.5, 5.7, 2.2 Hz, 1 H), 2.24 (ddd, J = 13.5, 9.1, 8.2 Hz,
1 H), 2.20–2.15 (m, 1 H), 3.08–3.13 (m, 1 H), 3.63 (dd, J = 8.1,
2.2 Hz, 1 H), 4.33–4.40 (m, 1 H) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 14.2, 22.8, 25.4, 25.8, 25.9, 29.3, 29.4, 29.5, 29.8,
32.0, 32.9, 33.6, 35.4, 36.6, 39.0, 43.3, 79.6, 175.3 ppm. MS (70 eV,
EI): m/z (%) = 312 (15) [M]+, 198 (14), 180 (17), 162 (100), 136
(25), 115(65), 96 (14), 81 (67), 55 (55), 41 (28). HRMS (EI): m/z
calcd. for C18H32O2S: 312.21229; found 312.21097.
Preparation of the Zn-Cu couple:[35] A suspension of Zn dust (5 g,
76.4 mmol) in water was degassed for 15 min with N2; then
CuSO4·5H2O (587 mg, 2.3 mmol, 0.03 equiv.) was added. The sus-
pension was stirred and degassed for 45 min. Then this was filtered
under nitrogen, washed with degassed water (2×25 mL), degassed
acetone (3×25 mL), and degassed Et2O (3×25 mL). The black Zn-
Cu powder was dried under reduced pressure (110 °C, 0.1 mbar)
for 2 h.
Lactone 29: To a cooled (–10 °C) suspension of 21 (80 mg,
0.35 mmol, 1 equiv.) and the freshly prepared Zn-Cu couple
(460 mg, 7.0 mmol, 20 equiv.) in THF (12 mL) was added dropwise
a solution of trichloroacetyl chloride (200 µL, 1.78 mmol, 5 equiv.)
in THF (320 µL). After completion of the reaction as monitored
by TLC (10 min), the solution was filtered through a pad of Celite
and washed with CH2Cl2 (15 mL). The organic layer was washed
with a saturated solution of NaHCO3 (3×15 mL), with brine and
then it was dried with MgSO4 and concentrated to afford 28
(193 mg) as a brown oil (dr 77:23). This compound was diluted in
toluene (4 mL), then Bu3SnH (0.37 mL, 1.39 mmol, 4 equiv.) and
AIBN (10 mg, 0.016 mmol, 0.17 equiv.) were added. The mixture
was heated at reflux (110 °C) for 1.5 h, and then it was concen-
trated. The oil was diluted in acetonitrile (6 mL) and washed with
petroleum ether (7×6 mL). Then the acetonitrile was removed un-
der reduced pressure, and the crude product was purified by col-
umn chromatography on silica gel (CH2Cl2) to afford 29 (38 mg,
40% for 2 steps) as a white solid (dr 92:8). M.p. 103 °C. Minor
(5S)-3-Cyclohexylsulfanyl-5-ethyl-5H-furan-2-one (27): To a cooled
(0 °C) solution of (5S)-24 (dr 70:30, 242 mg, 1.06 mmol, 1 equiv.)
in CH2Cl2 (16 mL) was added m-CPBA (182 mg, 1.65 mmol,
1.5 equiv.). The reaction was monitored by TLC. After completion,
the organic layer was washed with a solution of saturated NaHCO3
(3×20 mL), then brine, and then it was dried with MgSO4 and
concentrated to dryness. The residue (235 mg, 0.96 mmol, 1 equiv.)
was diluted in CH2Cl2 (1.7 mL) and then cooled to 0 °C. A solution
of TFAA (272 µL, 1.93 mmol, 2 equiv.) in CH2Cl2 (2.3 mL) was
added. After 1.5 h of stirring, the solution was diluted with CH2Cl2
(10 mL), washed with a solution of saturated NaHCO3 (2×15 mL)
and brine, then was dried with MgSO4 and concentrated to dryness
to afford pure 27 (212 mg, 88%) as a yellow oil. 1H NMR (CDCl3,
1
isomer (Rf: 0.5): (3aS,4S,6aR)-29: H NMR (CDCl3, 400 MHz): δ
= 1.18–2.32 (m, 10 H), 1.42 (d, J = 6.7 Hz, 3 H), 2.67 (d, J =
9.7 Hz, 2 H), 3.00–3.07 (m, 1 H), 3.35–3.43 (m, 1 H), 4.85–4.92 (m,
1 H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 16.2, 25.4, 25.6,
27.8, 26.1, 32.9, 35.8, 44.0, 48.5, 73.7, 89.2, 168.0, 172.6 ppm.
Major isomer (Rf: 0.4): (3aR,4S,6aS)-29: 1H NMR (CDCl3,
400 MHz): δ = 1.18–2.32 (m, 10 H), 1.55 (d, J = 6.4 Hz, 3 H), 2.60
(dd, J = 18.1, 5.3 Hz, 1 H), 2.70–2.74 (m, 1 H), 3.03 (dd, J = 18.1,
400 MHz): δ = 0.98–1.02 (m, 3 H), 1.24–2.05 (m, 12 H), 3.25–3.34 9.6 Hz, 1 H), 3.64–3.70 (m, 1 H), 4.43 (dq, J = 6.4, 3.9 Hz, 1 H)
1938
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Eur. J. Org. Chem. 2006, 1934–1939

Enantioselective Synthesis of Ethisolide and Isoavenaciolide
FULL PAPER
ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 25.4, 25.4, 25.7, 26.1,
[6]
[7]
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33.1, 33.9, 35.9, 43.8, 48.9, 79.6, 88.5, 168.5, 173.0 ppm. IR (KBr):
ν = 2934, 2854, 1802, 1764, 1450, 1384, 1206, 1164, 1106 cm–1.
˜
GC–MS: m/z (%) = 270 (1) [M]+, 189 (5), 172 (8), 156 (29), 115
(100), 99 (5), 81 (45), 69 (15), 55 (72), 41 (13). C13H18O4S (270.34):
calcd. C 57.76, H 6.71, S 11.86; found C 58.09, H 6.87, S 12.11.
[9]
[10]
Bis(lactone) 4: To a cooled (–10 °C) suspension of 5 (dr 1:1, 23 mg,
0.095 mmol, 1 equiv.) and the freshly prepared Zn-Cu couple
(125 mg, 1.90 mmol, 20 equiv.) in THF (3.3 mL) was added a solu-
tion of trichloroacetyl chloride (54 µL, 0.475 mmol, 5 equiv.) in
THF (90 µL). After completion of the reaction (10 min), the solu-
tion was filtered through a pad of Celite and washed with CH2Cl2
(5 mL). The crude product was washed with a saturated solution
of NaHCO3 (3×10 mL) and brine, dried with MgSO4 and concen-
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was added. After 16 h of stirring at room temp., the reaction mix-
ture was filtered through a pad of Celite, washed with CH2Cl2, and
concentrated. The crude product was purified by column
chromatography on silica gel (n-pentane-EtOAc 8:2) to afford 4 (dr
95:5, 11 mg, 48% yield for two steps) as a yellow oil. Minor isomer:
(3aS,4S,6aR)-4: 1H NMR (CDCl3, 400 MHz): δ = 1.07 (t, J =
7.4 Hz, 3 H), 1.19–2.35 (m, 12 H), 2.65–2.66 (m, 2 H), 3.02–3.09
(m, 1 H), 3.37–3.47 (m, 1 H), 4.62–4.67 (m, 1 H) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 9.9, 25.5, 25.7, 26.5, 27.8, 29.5, 32.9, 35.7,
44.1, 47.7, 79.0, 89.0, 167.9, 172.6 ppm. Major isomer:
(3aR,4S,6aS)-4: 1H NMR (CDCl3, 400 MHz): δ = 1.06 (t, J =
7.5 Hz, 3 H), 1.19–2.35 (m, 12 H), 2.58 (dd, J = 18.3, 4.5 Hz, 1 H),
2.74 (dt, J = 9.6, 4.5 Hz, 1 H), 3.05 (dd, J = 18.3, 9.6 Hz, 1 H),
3.67–3.77 (m, 1 H), 4.43 (ddd, J = 7.7, 5.8, 4.5 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ = 9.7, 25.5, 25.8, 26.1, 28.3, 33.4,
34.2, 36.0, 43.7, 47.3, 84.7, 88.6, 168.5, 173.0 ppm. GC–MS (70 eV,
EI): m/z (%) = 285 (12) [MH]+, 203 (10), 170 (36), 128 (43), 115
(100), 81 (56), 67 (17), 55 (63), 41 (22). HRMS (EI): m/z calcd. for
C14H20O4S: 284.10821; found 284.10975.
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Received: November 9, 2005
Published Online: February 23, 2006
Eur. J. Org. Chem. 2006, 1934–1939
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1939