Enantioselective butenolide preparation for straightforward asymmetric syntheses of γ-lactones - Paraconic acids, avenaciolide, and hydroxylated eleutherol

Article abstract of DOI:10.1002/ejoc.200500961

The naturally occurring γ-lactones (+)-methylenolactocin (13) and its enantiomer, (+)-protolichesterinic acid (14) and its enantiomer, (+)-rocellaric acid (15), and the methylene bis(γ-lactone) (-)-avenaciolide (16) were synthesized with 95-98 % ees in very few steps. Enantiocontrol was imposed by the asymmetric dihydroxylation of trans-configured β,γ-unsaturated carboxylic esters (namely compounds 1i, 1j, and 1n) with AD mix-α [for the levorotatory target structures, except for (-)-avenaciolide] or AD mix-β [for the dextrorotatory target structures plus (-)-avenaciolide]. β,γ-Unsaturated carboxylic ester 1e required increased amounts of the oxidant and auxiliary to produce the hydroxy lactone R,R-3e, a precursor of the naphtho-γ-lactone (+)-9-hydroxyeleutherol (12; 96 % ee). Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500961

FULL PAPER
DOI: 10.1002/ejoc.200500961
Enantioselective Butenolide Preparation for Straightforward Asymmetric
Syntheses of γ-Lactones – Paraconic Acids, Avenaciolide, and Hydroxylated
Eleutherol
Stefan Braukmüller[a] and Reinhard Brückner*[a]
Keywords: Asymmetric dihydroxylation / Butyrolactones / α-Methylene lactones / Naphthalene annulation / Natural prod-
uct synthesis / β,γ-Unsaturated carboxylic esters
The naturally occurring γ-lactones (+)-methylenolactocin (13)
and its enantiomer, (+)-protolichesterinic acid (14) and its en-
antiomer, (+)-rocellaric acid (15), and the methylene bis(γ-
lactone) (–)-avenaciolide (16) were synthesized with 95–
98% ees in very few steps. Enantiocontrol was imposed by
the asymmetric dihydroxylation of trans-configured β,γ-un-
saturated carboxylic esters (namely compounds 1i, 1j, and
cept for (–)-avenaciolide] or AD mix-β® [for the dextrorota-
tory target structures plus (–)-avenaciolide]. β,γ-Unsaturated
carboxylic ester 1e required increased amounts of the oxi-
dant and auxiliary to produce the hydroxy lactone R,R-3e, a
precursor of the naphtho-γ-lactone (+)-9-hydroxyeleutherol
(12; 96% ee).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
1n) with AD mix-α® [for the levorotatory target structures, ex- Germany, 2006)
It is noteworthy that β,γ-unsaturated carboxylic esters
Introduction
containing an α-alkylidene substituent are also amenable to
this kind of lactone synthesis – albeit with diminished yields
and enantioselectivities.[20] Moreover, the lactone strategy
of Scheme 1 has been extended to include β,γ-unsaturated
carboxylic esters with tri- rather than disubstituted C=C
double bonds.[13,21]
Saturated, enantiomerically pure γ-lactones abound in
nature.[1] They are not only synthetic targets but also valu-
able intermediates en route to enantiomerically pure but
possibly quite different-looking molecules, including acyclic
compounds.[2] Accordingly, numerous syntheses of γ-lac-
tones have been – and still are being – developed.[3]
One straightforward method for the construction of
enantiopure γ-lactones is based on the asymmetric dihy-
droxylation (AD)[4] of β,γ-unsaturated carboxylic esters
(Scheme 1). This strategy was pioneered by Sharpless et al.,
who showed that esters 1a–c, through the intermediacy of
non-isolable β,γ-dihydroxy esters 2a–c, delivered hydroxy
lactones 3a–c in a single operation upon oxidation with
AD mix-α® [Ǟ S,S-3a–c; 92% Ͻ ee Ͻ99%] and AD mix-
β® [Ǟ R,R-3a–c; 96% Ͻ ee Յ 99%].[5] To the best of our
knowledge, this transformation had been used only once –
namely in order to make lactone R,R-3d (86% ee)[6] – before
we recognized its virtue as a general route to γ-substituted
β-hydroxy γ-lactones (3e–q,[7–19] Scheme 1) and set out to
explore which kinds of saturated and unsaturated γ-lac-
tones – with substituents at C-γ (required), C-β (optional),
and/or C-α (optional) – can be reached subsequently.
Scheme 2 summarizes the substituent patterns of naturally
occurring lactones that have previously emerged from this
endeavor (lines 1–2) and adds those described in this study
(line 3).
Results and Discussion
Scheme 3 shows the incorporation of dihydroxylation
product R,R-3e, obtained[17] from methyl trans-pent-3-eno-
ate (1e) in Ն90% ee by an “improved procedure”,[22] into
naphtho-γ-lactone 12. The sequence comprises only two
steps: firstly, a dehydration of butanolide R,R-3e with
MsCl/NEt3 to give butenolide R-20e (90% ee), and sec-
ondly a Hauser–Kraus annulation[23] initiated by the
Michael addition of deprotonated (phenylsulfanyl)phthal-
ide 19[24] to R-20e. The phthalide was prepared from the
amide 17[25] in two steps.[26] Unlike in the literature,[24] we
used dimsyl-Li (in 3:2 THF/DMSO) for deprotonation of
this phthalide. Enantiomeric purities were 90% ee at the bu-
tenolide stage (by GLC) and 96% ee after naphthalene an-
nulation (by HPLC). The higher value might be more trust-
worthy, since our previous preparation of butenolide R-20e
had exhibited a similar value (94% ee).[17] Compound 12 is
the 9-hydroxy derivative of the natural product (+)-eleu-
therol.[27]
[a] Institut für Organische Chemie and Biochemie, Albert-Lud-
wigs-Universität,
Scheme 4 and Scheme 5 illustrate the usefulness of dihy-
droxylation products R,R-3i and R,R-3n – obtained from
the underlying esters 1i and 1n, respectively, under
Albertstr. 21, 79104 Freiburg, Germany
Fax: + 49-761-2036100
E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
2110
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Straightforward Asymmetric Syntheses of γ-Lactones
FULL PAPER
Scheme 1. Preparation of enantiopure β-hydroxy-γ-lactones by Sharpless’ asymmetric dihydroxylation (AD) of β,γ-unsaturated carboxylic
esters.
Scheme 2. γ-Lactone substitution patterns accessible from lactones of type 3: (–)-grandinolide (4), (–)-sapranthin (5), (+)-kalafungin (6),
aglycon of (–)-ranunculin (7), (+)-dodecanolide (8), (–)-quercus lactone (9), (–)-montecristin (10), (+)-9-hydroxyeleutherol (12), (+)-methyleno-
lactocin (13) and its enantiomer, (+)-protolichesterinic acid (14) and its enantiomer, (+)-rocellaric acid (15), and (–)-avenaciolide (16).
Sharpless’ “standard conditions”[28] – for the preparation 3n, needed for determination of the enantiopurities of the
of paraconic acids (+)-methylenolactocin[29] [(+)-13], (+)- previously mentioned hydroxy lactones, were prepared anal-
protolichesterinic acid[30] [(+)-14], and (+)-rocellaric acid[31] ogously. Apart from that, the reference specimens were car-
[(+)-15]. The antipodal hydroxy lactones S,S-3i and S,S- ried on to give (–)-methylenolactocin [(–)-13] and (–)-proto-
Eur. J. Org. Chem. 2006, 2110–2118
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S. Braukmüller, R. Brückner
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Scheme 4. Syntheses of (+)-methylenolactocin (13), (+)-protoli-
chesterinic acid (14), and their (–) enantiomers (not depicted).
Reagents and conditions: a) MsCl (1.1 equiv.), NEt3 (2.1 equiv.),
CH2Cl2, 0 °C, 15 min; 98% R-20i, 85% R-20n [enantiomeric series:
analogously Ǟ 92% S-20i, 83% S-20n]. b) HC(SMe)3 (1.1 equiv.),
THF, –78 °C, nBuLi (1.1 equiv.), 2–2.5 h; addition of R-20i or R-
20n, respectively, 1.5–2 h; 90% (4S,5R)-21i, 85% (4S,5R)-21n [en-
antiomeric series: analogously Ǟ 93% (4R,5S)-21i, 86% (4R,5S)-
21n]. c) HgO (5.0 equiv.), THF/H2O (4:1), BF3·OEt2 (15 equiv.),
room temp., 2.5 h; 93% (4S,5R)-22i, 91% (4S,5R)-22n (enantio-
meric series: analogously Ǟ 94% (4R,5S)-22i, 93% (4R,5S)-22n.
d) (i) MeOMg[O(C=O)OMe] (38 equiv.) in DMF, 135–140 °C,
70 h; isolation of the crude product; (ii) crude product from pre-
vious reaction, HOAc/NaOAc/formalin (= 35–40% aq. solution of
formaldehyde)/N-methylaniline (excess; 4:0.03:3:1), room temp.,
2 h; 67% (+)-13, 72% (+)-14 [enantiomeric series: analogously Ǟ
64% (–)-13 (ref.[34] 66%), 68% (–)-14 (ref.[30a]: 68%)].
Scheme 3. Synthesis of (+)-9-hydroxyeleutherol (12). Reagents and
conditions: a) 17 and TMEDA (1.1 equiv.) in Et2O, –78 °C; ad-
dition of sBuLi (1.1 equiv.) over 1 h, –78 °C, 1 h; addition of DMF
(1.2 equiv.), 1 h, room temp.; aq. KOH (2 ), 12 h; 51% (ref.[26]
66%). b) PhSH (1.2 equiv.), pTsOH (cat.), benzene, reflux, azeo-
tropic removal of water, 6 h; 79% (ref.[26] 85%). c) MsCl
(1.1. equiv.), NEt3 (2.1 equiv.), CH2Cl2, 0 °C, 20 min; 89% (ref.[8]
70%, 94% ee). d) THF/DMSO (1:1), 0 °C, addition of MeLi
(1.1 equiv.); addition of 19 in DMSO, 30 min; addition of R-20e,
5 h; 56%.
lichesterinic acid [(–)-14]. No matter which substrate or
AD mix® we used or whether we measured the stereochemi-
cal integrity at the hydroxy lactone 3 or subsequent buteno-
lide 20 stage (butenolide formation was accomplished by
treatment of hydroxy lactones 3i and 3n with MsCl and
NEt3 at 0 °C), ee values were reliably 95–97%. Overall, we
produced butenolides R-20i and R-20n – and their enantio-
mers – in no more than three steps from heptanal and pen-
tadecanal, respectively (cf. above and Exp. Sect.).
As shown in Scheme 4, the step requirement for finishing
the paraconic acids (+)- and (–)-methylenolactocin [(+)-
and (–)-13] from butenolides R- and S-3i, respectively, or
the paraconic acids (+)- and (–)-protolichesterinic acid [(+)-
and (–)-14] from butenolides R- and S-3n, respectively, was
four. Transformations 20Ǟ21 and 21Ǟ22 were directly
analogous to literature reports[32,33] while the transforma-
tion (4R,5S)-22iǞǞ(–)-13 was taken from the literature.[33]
Scheme 5. Synthesis of (+)-rocellaric acid (15). Reagents and condi-
tions: a) HC(SMe)3 (1.1 equiv.), THF, –78 °C, nBuLi (1.1 equiv.),
1 h; addition of R-20n, 2 h; addition of MeI (3.0 equiv.), 4 h; Ǟ
room temp.; 92%. b) HgO (5.0 equiv.), BF3·OEt2 (15 equiv.), THF/
H2O (4:1), room temp., 3 h; 93%.
Li–C(SMe)3 was first added trans-selectively to the C=C HgII- and Lewis acid-assisted hydrolysis (Ǟ 91–94% 22).
bond of each of the mentioned butenolides R- and S-20i α-Activation of 22 by Stiles’ reagent, followed by amino-
and -20n (Ǟ 85–93% 21). This reaction had been used with methylation/in situ fragmentation – as published for
racemic 20n by Schlessinger and Damon, but their enolate (–)-13[34] and (–)-14[30a] – provided the target structures
was functionalized further[32] rather than protonated and (+)- and (–)-13 and -14 in 64–72% yields.[35]
isolated. A Japanese group had described the trans-addition
Scheme 5 shows that (+)-rocellaric acid [(+)-15] was ob-
of the related reagent Li–C(SPh)3 to enantiopure butenolide tained in just two steps from the already mentioned buten-
S-20i.[33] Like their (PhS)3C analogue[33] of our (MeS)3C- olide R-20n by what is effectively a regio- and trans-selective
containing lactones R- and S-21i and -21n, our compounds addition of a carboxy and a methyl group to the C=C bond
released the underlying HO2C-substituted lactones upon (86% overall yield). We did so by employing Li–C(SMe)3
2112
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Straightforward Asymmetric Syntheses of γ-Lactones
FULL PAPER
and MeI,[36] while Takahata, Uchida, and Momose had
done the same with Li–C(SPh)3 and MeI.[33]
Experimental Section
All reactions were performed in oven-dried (110 °C) glassware un-
der N2. THF was freshly distilled from K, CH2Cl2 was distilled
from CaH2. Products were purified by flash chromatography[43] [el-
uents in brackets; volume of each collected fraction (mL)/column
diameter (cm): 1.3/1.0, 4/1.5, 8/2.0, 14/2.5, 14(!)/3.0, 30/4, 50/5, 80/
6; fractions containing the isolated products are indicated in each
description as “#xx–yy”] on silica gel (Macherey–Nagel, 230–400
The last synthesis application in this study of an asym-
metrically dihydroxylated β,γ-unsaturated carboxylic ester
(R,R-3j) began with a repetition of our previously described
dehydration to give butenolide R-20j[7] (Scheme 6). This
time the ee was 98% (ref.[7] 95%). From R-20j, (–)-avenaci-
olide[37] [(–)-16] was synthesized by the four steps reported
by Schlessinger et al. for making racemic 16.[38]
1
mesh). Yields refer to analytically pure samples. H NMR [CHCl3
(δ = 7.26) as internal standard in CDCl3]: Varian Mercury VX 300,
Varian Unity 300, and Bruker AC 300. Integrals in accordance with
assignments; coupling constants in Hz. Assignments of 1H and 13
C
NMR resonances refer to IUPAC nomenclature except within sub-
stituents (where primed numbers are used). Combustion analyses:
F. Hambloch, Institut für Organische Chemie, Universität
Göttingen. MS: Dr. J. Wörth and C. Warth, Institut für Organische
Chemie and Biochemie, Universität Freiburg. IR spectra: Perkin–
Elmer FT-IR 1600. Optical rotations were measured with a Perkin–
Elmer polarimeter 241 MC at 589 nm/20 °C and were calculated by
the Drude equation {[α]D = (αexp ×100)/(c×d)}; rotational values
are the average of five measurements of αexp in a given solution of
the respective sample. Melting points were measured on a Dr. Tot-
toli apparatus (Büchi) and are uncorrected. The ee values were de-
termined by chiral GC, with
HRC 5160 Mega series apparatus with
a
Carlo Erba Instruments
heptakis-(2,6-di-O-
a
methyl-3-O-pentyl)-β-cyclodextrin/OV 1701 column.
Methyl trans-Pent-3-enoate (1e) is commercially available.
Methyl trans-Non-3-enoate (1i): A mixture of heptanal (46.0 mL,
37.7 g, 330 mmol), monomethyl malonate (39.0 g, 330 mmol,
1.0 equiv.), and NEt3 (46.0 mL, 33.6 g, 330 mmol, 1.0 equiv.) was
heated for 12 h at 90–95 °C.[44] The mixture was cooled to room
temp. and poured at 0 °C into aq. H2SO4 (20%; 120 mL). The or-
ganic phase was separated and the aqueous phase was extracted
with CH2Cl2 (3×100 mL). The combined organic phases were
dried with MgSO4. After removal of the solvent, vacuum distil-
lation (b.p.2.0 kPa 75–76 °C) gave a 95:5 mixture (41.3 g, 74%) of 1i
(content1i = 39.2 g, 70%) and methyl trans-non-2-enoate as a color-
Scheme 6. Synthesis of (–)-avenaciolide (16). Reagents and condi-
tions: a) MsCl (1.1 equiv.), NEt3 (2.1 equiv.), CH2Cl2, 0 °C, 15 min;
83% (ref.[7] 91% and 95% ee). b) 25 (1.1 equiv.), THF, –78 °C, ad-
dition of R-20j, 3 h; I2 (1.2 equiv.), 2 h; aq. HCl, –78 °CǞ0 °C;
82% (ref.[38] 93% for racemic material). c) pTsOH (0.4 equiv.), ben-
zene, reflux, 3 h; aq. NaHCO3, room temp., 45 min; 47% 27, 42%
epi-27 (ref.[38] 95% of a racemic mixture of these diastereomers).
d) Starting from the pure diastereomer 27: MCPBA (1.05 equiv.),
CH2Cl2, 0 °C, 30 min; 81% of an inseparable mixture (50:50) of
sulfoxide diastereomers. e) Mixture of sulfoxides from previous re-
action, succinic anhydride (1.0 equiv.), 140 °C, 1 h; 75% (ref.[38]
73% starting from a racemic 26/epi-26 mixture).
1
less liquid. H NMR (300 MHz): δ = 0.88 (t, J9,8 = 6.8 Hz, 9-H3),
1.22–1.42 (m, 6-H2, 7-H2, 8-H2), 2.02 (mc, interpretable as dt,
J5,4 Ϸ J5,6 = 6.4 Hz, 5-H2), 3.03 (d, J2,3 = 5.7 Hz, 2-H2), 3.68 (s,
OCH ), 5.45–5.62 (m, 3-H, 4-H) ppm. IR (film): ν = 2955, 2925,
˜
3
2855, 1745, 1460, 1435, 1410, 1345, 1250, 1195, 1165, 1120, 1015,
970 cm–1. Elemental analysis calcd. (%) for C10H18O2 (170.3): C
70.55, H 10.66; found: C 70.61, H 10.82.
Methyl trans-Dodec-3-enoate (1j): This compound was prepared
from decanal (18.9 mL, 15.6 g, 100 mmol), monomethyl malonate
(11.8 g, 100 mmol, 1.0 equiv.), and NEt3 (13.8 mL, 10.1 g,
100 mmol, 1.0 equiv.) by a method similar to that specified for
compound 1i. Distillation (b.p.2.0 kPa 97 °C) provided a 92:8 mix-
ture (28.8 g, 78%) of 1j (content1j = 26.2 g, 73%) and methyl trans-
dodec-2-enoate as a colorless liquid. 1H NMR (300 MHz): δ = 0.88
(t, J12,11 = 6.6 Hz, 12-H3), 1.26–1.38 (m, 6-H2, 7-H2, 8-H2, 9-H2,
Conclusions
This investigation underscores the versatility of ADs of
trans-configured β,γ-unsaturated carboxylic esters for ac-
cessing γ-lactones of widely variable substitution patterns.
Our syntheses of methylenolactocin (13, both enantiomers),
protolichesterinic acid (14, both enantiomers), rocellaric
10-H2, 11-H2), 2.02 (dt, J5,4 = J5,6 = 5.9 Hz, 5-H2), 3.03 (d, J2,3
5.7 Hz, 2-H2), 3.68 (s, OCH3), 5.46–5.62 (m, 3-H, 4-H) ppm. IR
(film): ν = 2955, 2925, 2855, 1745, 1710, 1460, 1435, 1410, 1350,
=
˜
acid (15, dextrorotatory enantiomer), and avenaciolide (16, 1325, 1250, 1195, 1165, 1125, 1075, 1015, 970, 885, 845 cm–1. Ele-
mental analysis calcd. (%) for C13H24O2 (212.3): C 73.54, H 11.39;
found: C 73.75, H 11.38.
levorotatory enantiomer) are straightforward and high-
yielding, thus comparing favorably with most of the pub-
lished syntheses of these compounds.[39–42] The synthesis of
naphtho-γ-lactone 12 is a noteworthy combination of our
lactone approach with a naphthalene synthesis.
Methyl trans-Heptadec-3-enoate (1n): This compound was obtained
from pentadecanal (30.0 g, 133 mmol), monomethyl malonate
(15.7 g, 133 mmol, 1.0 equiv.), and NEt3 (18.4 mL, 13.4 g,
Eur. J. Org. Chem. 2006, 2110–2118
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1
133 mmol, 1.0 equiv.) in a manner similar to that specified for com-
pound 1i. Distillation (b.p.0.1 kPa 154–155 °C) gave a 97:3 mixture
(24.4 g, 65%) of 1n (content1n = 23.7 g, 63%) and methyl trans-
heptadec-2-enoate as a colorless liquid. 1H NMR (300 MHz,
slightly contaminated): δ = 0.88 (t, J17,16 = 6.6 Hz, 17-H3), 1.26–
2.32, CHCl3); ref.[33]: [α]2D5 = +40.05 (c = 1.89, CHCl3). H NMR
(300 MHz): δ = 0.88 (t, J13Ј,12Ј = 6.6 Hz, 13Ј-H3), 1.30–1.52 (m, 2Ј-
H2, 3Ј-H2, 4Ј-H2, 5Ј-H2, 6Ј-H2, 7Ј-H2, 8Ј-H2, 9Ј-H2, 10Ј-H2, 11Ј-
H2,12Ј-H2), 1.65–2.14 (m, 1Ј-H2), superimposed by 1.90 (d, JOH,4
= 4.9 Hz, OH), AB signal (δA = 2.56, δB = 2.79, JAB = 17.7 Hz, A
1.40 (m, 6-H2, 7-H2, 8-H2, 9-H2, 10-H2, 11-H2, 12-H2, 13-H2, 14- part additionally split by JA,4 = 1.0 Hz, B part additionally split by
H2, 15-H2, 16-H2), 2.02 (dt, J5,4 Ϸ J5,6 = 6.4 Hz, 5-H2), 3.03 (d, J2,3
= 5.3 Hz, 2-H2), 3.68 (s, OCH3), 5.45–5.62 (m, 3-H, 4-H) ppm. IR
JB,4 = 5.3 Hz, 3-H2), 4.37 (ddd, J5,1Ј-H(1) = 8.9, J5,1-H(2) = 5.7, J5,4
= 3.8 Hz, 5-H), 4.47 (br.dddd, J4,5 Ϸ J4,3-H(B) Ϸ J4,OH = 4.5,
J4,3-H(A) = 0.8 Hz, 4-H) ppm. The ee (97%) was determined after
conversion into compound R-20n.
(film): ν = 2925, 2855, 1745, 1465, 1435, 1355, 1250, 1195, 1165,
˜
1125, 1015, 970, 720 cm–1. Elemental analysis calcd. (%) for
C18H34O2 (282.5): C 76.54, H 12.13; found: C 76.48, H 11.86.
(4S,5S)-4-Hydroxy-5-tridecyl-4,5-dihydro-3H-furan-2-one (S,S-3n):
This compound (3.63 g, 85%) was prepared from AD mix-α®
(21.0 g), methanesulfonamide (1.43 g, 15.0 mmol, 1.0 equiv.), and
the β,γ-unsaturated ester 1n (4.24 g, 15.0 mmol; 97:3 mixture with
methyl trans-heptadec-2-enoate) as a colorless solid [m.p. 87 °C;
ref.[33] for the enantiomer: m.p. 87–88 °C]. [α]2D5 = –37.7 (c = 2.16,
CHCl3); ref.[33]: for the (+) enantiomer [α]2D5 = +40.05 (c = 1.89,
CHCl3); the ee (96%) was determined after conversion into com-
pound S-20n.
(4R,5R)-4-Hydroxy-5-methyl-4,5-dihydro-3H-furan-2-one (R,R-3e):
This compound was prepared as published.[17] The ee (90%) was
determined after conversion into compound R-20e.
(4R,5R)-4-Hydroxy-5-pentyl-4,5-dihydro-3H-furan-2-one (R,R-3i):
AD mix-β® (21.0 g), methanesulfonamide (1.43 g, 15.0 mmol,
1.0 equiv.), and the β,γ-unsaturated ester 1i (2.53 g, 15.0 mol; 95:5
mixture with methyl trans-non-2-enoate) was added to a 1:1 mix-
ture (100 mL) of tBuOH and H2O at 0 °C. Stirring at this tempera-
ture was continued for 40 h. The reaction was terminated by the
addition of aq. Na2SO3 followed by extraction with tBuOMe
(3×100 mL). The combined organic phases were dried with
Na2SO4 and the solvent was removed in vacuo. Purification by
flash chromatography (5 cm, petroleum ether/tBuOMe, 1:1 Ǟ #13,
1:3 Ǟ #43, # 21–42) yielded the title compound (2.18 g, 84%) as
a colorless solid (m.p. 43 °C; ref.[33]: oil, b.p.0.5 kPa 115–120 °C).
[α]2D5 = +49.5 (c = 2.08, CHCl3); ref.[33]: [α]2D5 = +49.42 (c = 1.175,
1
CHCl3). H NMR (300 MHz): δ = 0.91 (t, J5Ј,4Ј = 6.4 Hz, 5Ј-H3),
1.34–1.57 (m, 2Ј-H2, 3Ј-H2, 4Ј-H2), 1.66–1.93 (m, 1Ј-H2), 2.14 (d,
(R)-4,9-Dihydroxy-5-methoxy-3-methyl-3H-naphtho[2,3-c]furan-1-
one [“(R)-9-Hydroxyeleutherol”, (+)-12]: MeLi (0.71  in Et2O,
3.90 mL, 2.75 mmol, 1.1 equiv.) was added dropwise at 0 °C to a
1:1 mixture (16 mL) of THF/DMSO. After the mixture had been
stirred for 30 min, phthalide 19 (715 mg, 2.63 mmol, 1.05 equiv.) in
DMSO (5 mL) was added, and 20 min later neat R-20e (245 mg,
2.50 mmol). Stirring at 0 °C was continued for 5 h. Quenching with
aq. KHSO4 (1 , 25 mL), extractive workup with CH2Cl2
(3×20 mL), drying over MgSO4, removal of the solvent in vacuo,
and flash chromatography (3 cm, cyclohexane/ethyl acetate 4:1, #
34–62) provided the title compound (361 mg, 56%) as a yellow so-
lid (melting starts around 121 °C but is still incomplete at 140 °C
JOH,4 = 4.5 Hz, OH), AB signal (δA = 2.56, δB = 2.81, JAB
17.7 Hz, B part additionally split by JB,4 = 5.3 Hz, 3-H2), 4.37 (ddd,
J4,5 = 8.7, J4,3-H(B) = 5.6, J4,OH = 3.7 Hz, 4-H), 4.48 (ddd, J5,4
=
=
J5,1Ј-H(1) = J5,1Ј-H(2) = 4.5 Hz, 5-H) ppm. The ee (95%) was deter-
mined by chiral GLC [138 °C, pH2 = 70 kPa, tret = 81.3 min,
tret,(S,S)-3i = 82.4 min (determined with co-injected enantiomer)].
(4S,5S)-4-Hydroxy-5-pentyl-4,5-dihydro-3H-furan-2-one
(S,S-3i):
This compound (2.20 g, 85%) was prepared from AD mix-α®
(21.0 g), methanesulfonamide (1.43 g, 15.0 mmol, 1.0 equiv.), and
the β,γ-unsaturated ester 1i (2.53 g, 15.0 mol; 95:5 mixture with
methyl trans-non-2-enoate) as specified for R,R-3i as a colorless
1
solid (m.p. 42 °C). [α]2D5 = –61.0 (c = 1.73, CHCl3); ref.[33]: [α]2D5
=
due to charcoal formation). H NMR (300 MHz): δ = 1.79 (d, J3-
= 6.9 Hz, 3-CH3), 4.10 (s, OCH3), 5.78 (q, J3,3-CH3 = 7.0 Hz,
–49.2 (c = 2.23, CHCl3). The ee (95%) was determined by chiral
GLC [138 °C, pH2 = 100 kPa, tret = 55.5 min, tret,(R,R)-3i = 54.6 min
(determined with co-injected enantiomer)].
CH3,3
3-H), 7.01 (d, J6,7 = 7.4 Hz, 6-H), 7.43 (dd, J7,6 = J7,8 = 7.3 Hz, 7-
H), 7.97 (d, J8,7 = 7.2 Hz, 8-H), 8.05 and 9.12 (2 s, 2 × Ar–OH)
ppm. The ee (96%) was determined by chiral HPLC [propan-2-ol,
MeCN, H2O (15:15:70), 0.5 mL min–1, UV detection at 238 nm,
OJ-R column, tret = 17.6 min, tret,(–)-12 = 23.05 min (determined
with racemic material)].
(4R,5R)-4-Hydroxy-5-octyl-4,5-dihydro-3H-furan-2-one (R,R-3j):
This compound (8.55 g, 89%) was prepared from AD mix-β®
(63.0 g), methanesulfonamide (4.28 g, 45.0 mmol, 1.0 equiv.), and
the β,γ-unsaturated ester 1j (9.56 g, 45.0 mol; 97:3 mixture with
methyl trans-dodec-2-enoate) as a colorless solid (m.p. 63 °C) as
(4S,5R)-Methylenolactocin [(+)-13]: This compound (142 mg, 67%)
was prepared from carboxy lactone (4S,5R)-22i (201 mg,
1.00 mmol), methoxymagnesium monomethylcarbonate (2.95  in
DMF, 12.9 mL, 38.0 mmol, 38.0 equiv.), and a mixture of acetic
acid, formalin, N-methylaniline, and NaOAc as a colorless solid
(m.p. 82 °C, ref.[29b]: 83–84 °C) as described for (–)-13. [α]2D5 = 2.25
(c = 1.46, MeOH); ref.[29b]: for (–) enantiomer [α]2D5 = –2.37 (c =
3.0, MeOH).
specified for R,R-3i. 1H NMR (300 MHz): δ = 0.88 (t, J8Ј,7Ј
=
6.8 Hz, 8Ј-H3), 1.21–1.56 (m, 2Ј–H2, 3Ј-H2, 4Ј-H2, 5Ј-H2, 6Ј-H2, 7Ј-
H2), 1.66–1.93 (m, 1Ј-H2), 2.24 (s, OH), AB signal (δA = 2.57, δB
= 2.81, JAB = 17.8 Hz, B part additionally split by JB,4 = 5.3 Hz,
3-H2), 4.37 (ddd, J5,1Ј-H(1) = 8.7, J5,1-H(2) = 5.7, J5,4 = 3.3 Hz, 5-H),
4.47 (mc, 4-H) ppm. The ee was determined after conversion into
compound R-20j.
(4R,5R)-4-Hydroxy-5-tridecyl-4,5-dihydro-3H-furan-2-one
(R,R- (4R,5S)-Methylenolactocin [(–)-13]: Carboxy lactone (4R,5S)-22i
3n): This compound (3.45 g, 83%) was prepared from AD mix-β®
(384 mg, 1.92 mmol) was heated at 135–140 °C in a solution of
methoxymagnesium monomethylcarbonate (2.95  in DMF,
(21.0 g), methanesulfonamide (1.43 g, 15.0 mmol, 1.0 equiv.), and
the β,γ-unsaturated ester 1n (4.24 g, 15.0 mol; 97:3 mixture with 24.7 mL, 72.9 mmol, 38.0 equiv.) for 70 h. After the system had
methyl trans-heptadec-2-enoate) as a colorless solid (m.p. 88 °C;
cooled to room temp., aq. HCl (10%, 60 mL) and CH2Cl2 (30 mL)
were added. The organic phase was separated and the aqueous
ref.[33]: m.p. 87–88 °C) as specified for R,R-3i. [α]2D5 = +40.9 (c =
2114
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2110–2118

Straightforward Asymmetric Syntheses of γ-Lactones
FULL PAPER
phase was extracted with CH2Cl2 (3×40 mL). The combined or-
ganic phases were dried with MgSO4 and the solvent was removed
in vacuo (Ͻ 30 °C). The resulting brown oil (503 mg) was dissolved
in 18.6 mL of a solution prepared from acetic acid (20 mL), forma-
lin (15 mL), N-methylaniline (5.20 mL), and NaOAc (600 mg). Af-
ter stirring for 2 h at room temp. the mixture was poured into aq.
8.80 mmol, 1.1 equiv.) were added dropwise at 0 °C to hydroxy lac-
tone R,R-3i (1.38 g, 8.00 mmol) in CH2Cl2 (50 mL). After having
been stirred at this temperature for another 15 min the reaction
mixture was quenched by addition of satd. aq. NH4Cl (10 mL) and
H2O (40 mL). The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (3×40 mL). The combined or-
HCl (10%, 15 mL). Extraction with tBuOMe (3×20 mL), washing ganic phases were dried with MgSO4 and the solvent was removed
of the combined organic phases with brine (10 mL), drying over
MgSO4, and removal of the solvent in vacuo followed by flash
chromatography (4 cm, CHCl3/EtOAc/HOAc, 90:8:2, #8–19)
yielded (–)-13 (262 mg, 64%) as a colorless solid (m.p. 83–84 °C,
in vacuo. Flash chromatography (3 cm, petroleum ether/tBuOMe,
3:1 Ǟ #14, 1:1 Ǟ #26, #13–24) gave the title compound (1.12 g,
91%) as a colorless liquid. [α]2D5 = –90.1 (c = 1.76, CHCl3); ref.[33]
:
[α]2D5 = –85.53 (c = 1.36, CHCl3); the ee (97%) was determined by
ref.[34]: 82–84 °C). [α]2D5 = –2.23 (c = 1.56, MeOH); ref.[29b]: [α]2D5
–2.37 (c = 3.0, MeOH).
=
chiral GLC [110 °C, pH2 = 70 kPa, tret = 25.9 min, tret,(S)-20i =
27.6 min (determined with co-injected enantiomer)].
(S)-5-Pentyl-5H-furan-2-one (S-20i): This compound (1.28 g, 89%)
was prepared as a colorless liquid from hydroxy lactone S,S-3i
(1.60 g, 9.30 mmol), NEt3 (2.71 mL, 1.98 g, 19.5 mmol, 2.1 equiv.),
and mesyl chloride (795 µL, 1.17 g, 10.2 mmol, 1.1 equiv.) in a
manner analogous to that described for R-20i. [α]2D5 = +89.9 (c =
1.55, CHCl3); ref.[33]: [α]2D5 = +85.3 (c = 1.85, CHCl3); the ee (95%)
(4S,5R)-Protolichesterinic Acid [(+)-14]: This compound (304 mg,
72%) was prepared from carboxy lactone (4S,5R)-22n (406 mg,
1.30 mmol), methoxymagnesium monomethylcarbonate (2.95  in
DMF, 16.7 mL, 49.8 mmol, 38.0 equiv.), and a mixture of acetic
acid, formalin, N-methylaniline, and NaOAc as a colorless solid
(m.p. 104–105 °C, ref.[30b]: 103–105 °C) as described for (–)-13.
[α]2D5 = +13.6 (c = 1.72, CHCl3); ref.[30b]: [α]2D5 = +14.2 (c = 0.95,
CHCl3).
was determined by chiral GLC [110 °C, pH2 = 70 kPa, tret
=
27.4 min, tret,(R)-20i = 26.7 min (determined with co-injected enanti-
omer)].
(4R,5S)-Protolichesterinic Acid [(–)-14]: This compound (198 mg,
68%) was prepared from carboxy lactone (4R,5S)-22n (281 mg,
900 µmol), methoxymagnesium monomethylcarbonate (2.95  in
DMF, 11.6 mL, 34.2 mmol, 38.0 equiv.), and a mixture of acetic
acid, formalin, N-methylaniline, and NaOAc as a colorless solid
(m.p. 104–106 °C, ref.[30a]: 103–105 °C) as described for (–)-13.
[α]2D5 = –13.2 (c = 1.52, CHCl3); ref.[30a]: [α]2D5 = –15 (c = 1.0,
CHCl3).
(R)-5-Octyl-5H-furan-2-one (R-20j): This compound (5.23 g, 83%)
was prepared as colorless crystals (m.p. 52 °C) from hydroxy lac-
tone R,R-3j (6.86 g, 32.0 mmol), NEt3 (9.32 mL, 6.80 g, 67.2 mmol,
2.1 equiv.), and mesyl chloride (2.74 mL, 4.03 g, 35.2 mmol,
1
1.1 equiv.) in a manner analogous to that described for R-20i. H
NMR (300 MHz): δ = 0.88 (t, J8Ј,7Ј = 6.6 Hz, 8Ј-H3), 1.27–1.48 (m,
2Ј-H2, 3Ј-H2, 4Ј-H2, 5Ј-H2, 6Ј-H2, 7Ј-H2), 1.61–1.83 (m, 1Ј-H2), 5.04
(mc, approximately interpretable as dddd, J5,1-H(1) = 7.2 Hz, J5,1-
´
´
(3S,4S,5R)-Rocellaric Acid [(+)-15]: BF3·OEt2 (3.20 mL, 3.62 g,
25.5 mmol, 15.0 equiv.) was added dropwise to a suspension of lac-
tone 23 (739 mg, 1.70 mmol) and HgO (1.84 g, 8.50 mmol,
5.0 equiv.) in THF/H2O (4:1, 10 mL). After the system had been
stirred at room temp. for 3 h, H2O (7 mL) and EtOAc (10 mL) were
added. The organic phase was separated and the aqueous phase
was extracted with EtOAc (3×10 mL). The combined organic
phases were washed with brine (1×7 mL) and dried with MgSO4.
After removal of the solvent in vacuo, flash chromatography
(2.5 cm, petroleum ether/tBuOMe 1:1 Ǟ #15, 1:4 Ǟ 32, #10–28)
furnished the title compound (514 mg, 93%) as a colorless solid
(m.p. 106–107 °C; ref.[33]: 107–108 °C). [α]2D5 = +23.6 (c = 1.60,
CHCl3); ref.[33]: [α]2D0 = +27 (c = 0.87, CHCl3).
4
= 5.5 Hz, J5,4 = J5,3 = 1.7 Hz, 5-H), 6.11 (dd, J3,4 = 5.9 Hz,
H(2)
4J3,5 = 2.1 Hz, 3-H), 7.45 (dd, J4,3 = 5.7 Hz, J4,5 = 1.5 Hz, 4-H)
ppm. The ee (98%) was determined by chiral GLC [110 °C, pH2
70 kPa, tret = 53.6 min, tret,(S)-20j = 54.8 min (determined with race-
mic material)].
=
(R)-5-Tridecyl-5H-furan-2-one (R-20n): This compound (2.23 g,
86%) was prepared as colorless crystals (m.p. 45 °C, ref.[33]: m.p.
44–46 °C) from hydroxy lactone R,R-3n (2.76 g, 9.70 mmol), NEt3
(2.82 mL, 2.06 g, 20.4 mmol, 2.1 equiv.), and mesyl chloride
(830 µL, 1.22 g, 10.7 mmol, 1.1 equiv.) in a manner analogous to
that described for R-20i. [α]2D5 = –62.8 (c = 2.11, CHCl3); ref.[33]
:
[α]2D5 = –56.6 (c = 2.285, CHCl3). 1H NMR (300 MHz): δ = 0.88 (t,
J13Ј,12Ј = 6.6 Hz, 13Ј-H3), 1.26–1.47 (m, 2Ј-H2, 3Ј-H2, 4Ј-H2, 5Ј-H2,
6Ј-H2, 7Ј-H2, 8Ј-H2, 9Ј-H2, 10Ј-H2, 11Ј-H2, 12Ј-H2), 1.60–1.82 (m,
(3aR,4R,6aR)-Avenaciolide [(–)-16]: Succinic anhydride (51 mg,
505 µmol, 1.0 equiv.) and the 1:1 mixture of epimeric bislactones
26 and epi-26 (173 mg, 505 µmol) was heated at 140 °C for 1 h.
Unreacted succinic anhydride was removed by sublimation. The
remaining material was recrystallized from Et2O/petroleum ether
(1:10), giving the title compound (95 mg, 75%) as a colorless solid
(m.p. 50–51 °C, ref.[37]: 49–50 °C). [α]2D5 = –39.8 (c = 1.01, EtOH);
ref.[37]: [α]2D6 = –41.6 (c = 1.2, EtOH).
1Ј-H2), 5.04 (mc, approximately interpretable as dddd, J5,1-H(1)
=
´
4
7.2 Hz, J5,1-H(2) = 5.7 Hz, J5,4 = J5,3 = 1.8 Hz, 5-H), 6.11 (dd, J3,4
´
= 5.9 Hz, 4J3,5 = 2.1 Hz, 3-H), 7.45 (dd, J4,3 = 5.8 Hz, J4,5 = 1.3 Hz,
4-H) ppm. The ee (97%) was determined by chiral HPLC (courtesy
of Dr. Olivier Lohse, Novartis AG, Basel, Switzerland).
(S)-5-Tridecyl-5H-furan-2-one (S-20n): This compound (2.18 g,
91%) was prepared as colorless crystals (m.p. 45 °C) from hydroxy
lactone S,S-3n (2.56 g, 9.00 mmol), NEt3 (2.62 mL, 1.91 g,
18.9 mmol, 2.1 equiv.), and mesyl chloride (769 µL, 1.13 g,
9.90 mmol, 1.1 equiv.) in a manner analogous to that described for
R-20i. [α]2D5 = +60.6 (c = 2.27, CHCl3); ref.[33]: for (–) enantiomer
[α]2D5 = –56.6 (c = 2.285, CHCl3). The ee (96%) was determined by
chiral HPLC (courtesy of Dr. Olivier Lohse, Novartis AG, Basel,
Switzerland).
(R)-5-Methyl-5H-furan-2-one (R-20e): This compound (412 mg,
89%, ref.[8]: 70%) was prepared as a colorless liquid from hydroxy
lactone R,R-3e (550 mg, 4.73 mmol), NEt3 (1.38 mL, 1.01 g,
9.95 mmol, 2.1 equiv.), and mesyl chloride (405 µL, 597 mg,
5.21 mmol, 1.1 equiv.) in a manner analogous to that described for
R-20i. [α]2D5 = –95.6 (c = 1.81, CHCl3); ref.[8]: [α]2D5 = –89.8 (c =
0.78, CHCl3); the ee (90%) was determined by chiral GLC [80 °C,
pH2 = 70 kPa, tret = 6.78 min, tret,(S)-20e = 7.04 min (determined with
co-injected enantiomer)].
(4S,5R)-5-Pentyl-4-[tris(methylthio)methyl]-4,5-dihydro-3H-furan-2-
one [(4S,5R)-21i]: This compound (1.37 g, 90%) was prepared from
(R)-5-Pentyl-5H-furan-2-one (R-20i): NEt3 (2.33 mL, 1.70 g, tris(methylsulfanyl)methane
(695 µL,
764 mg,
4.95 mmol,
16.8 mmol, 2.1 equiv.) and mesyl chloride (680 µL, 1.01 g, 1.1 equiv.), nBuLi (1.50  in hexane, 3.30 mL, 4.95 mmol,
Eur. J. Org. Chem. 2006, 2110–2118
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2115

S. Braukmüller, R. Brückner
FULL PAPER
1.1 equiv.), and butenolide R-20i (694 mg, 4.50 mmol) as described
for (4S,5R)-21n. [α]2D5 = +13.2 (c = 2.67, CHCl3). 1H NMR
(300 MHz): δ = 0.90 (t, J5Ј,4Ј = 7.0 Hz, 5Ј-H3), 1.27–1.52 (m, 2Ј-H2,
3Ј-H3, 4Ј-H2), 1.59–1.67 (m, 1Ј-H2), 2.17 (s, 3 × SCH3), 2.59 (ddd,
Ǟ #27, #13–25) furnished the title compound (670 mg, 94%) as a
colorless solid (m.p. 105 °C; ref.[33] for the enantiomer: 105–
107 °C). [α]2D5 = +53.7 (c = 1.82, CHCl3), ref.[33] for the enantiomer:
[α]2D1 = –54 (c = 0.50, CHCl3).
J4,3-H(A) = 9.8 Hz, J4,3-H(B) = J4,5 = 2.5 Hz, 4-H), AB signal (δA
2.69, δB = 2.98, JAB = 17.8 Hz, A part additionally split by JA,4
9.8 Hz, B part additionally split by JB,4 = 2.4 Hz, 3-H2), 4.77 (ddd,
=
=
(4R,5S)-4-Carboxy-5-pentyl-4,5-dihydro-3H-furan-2-one [(4R,5S)-
22i]: This compound (652 mg, 93%) was prepared from BF3·OEt2
(6.60 mL, 7.45 g, 52.5 mmol, 15.0 equiv.), lactone (4R,5S)-21i
(1.08 g, 3.50 mmol), and HgO (3.79 g, 17.5 mmol, 5.0 equiv.) as a
colorless solid (m.p. 104–105 °C; ref.[33]: 105–107 °C) as described
for (4S,5R)-22i. [α]2D5 = –53.3 (c = 1.26, CHCl3)[33]: [α]2D1 = –54 (c =
0.50, CHCl3).
J5,1Ј-H(1) = J5,1Ј-H(2) = 6.4 Hz, J5,4 = 2.5 Hz, 5-H) ppm. IR (film): ν
˜
= 2950, 2920, 2855, 1770, 1470, 1425, 1410, 1375, 1355, 1305, 1225,
1180, 1120, 1055, 1005, 945 cm–1. Elemental analysis calcd. (%) for
C13H24O2S3 (308.5): C 50.61, H 7.84; found: C 51.19, H 8.15.
(4R,5S)-5-Pentyl-4-[tris(methylsulfanyl)methyl]-4,5-dihydro-3H-
furan-2-one [(4R,5S)-21i]: This compound (1.44 g, 93%) was pre-
pared from tris(methylsulfanyl)methane (732 µL, 849 mg,
5.50 mmol, 1.1 equiv.), nBuLi (1.50  in hexane, 3.67 mL,
5.50 mmol, 1.1 equiv.), and butenolide S-20i (770 mg, 5.00 mmol)
as described for (4S,5R)-21n. [α]2D5 = –12.5 (c = 2.651, CHCl3). Ele-
mental analysis calcd. (%) for C13H24O2S3 (308.5): C 50.61, H 7.84;
found: C 51.01, H 7.80.
(4S,5R)-4-Carboxy-5-tridecyl-4,5-dihydro-3H-furan-2-one [(4S,5R)-
22n]: This compound (826 mg, 72%) was prepared from BF3·OEt2
(4.71 mL, 5.32 g, 37.5 mmol, 15.0 equiv.), lactone (4S,5R)-21n
(1.05 g, 2.50 mmol), and HgO (2.71 g, 12.5 mmol, 5.0 equiv.) as a
colorless solid (m.p. 110 °C; ref.[30a] for the enantiomer: 109–
111 °C) as described for (4S,5R)-22i.
(4R,5S)-4-Carboxy-5-tridecyl-4,5-dihydro-3H-furan-2-one [(4R,5S)-
22n]: This compound (391 mg, 91%) was prepared from BF3·OEt2
(2.58 mL, 2.92 g, 20.6 mmol, 15.0 equiv.), lactone (4R,5S)-21n
(577 mg, 1.37 mmol), and HgO (1.46 g, 6.86 mmol, 5.0 equiv.) as a
colorless solid (m.p. 112 °C; ref.[30a]: 109–111 °C) as described for
(4S,5R)-22i. [α]2D5 = –42.8 (c = 1.76, CHCl3); ref.[30a] [α]2D1 = –41 (c
= 0.50, CHCl3).
(4S,5R)-5-Tridecyl-4-[tris(methylsulfanyl)methyl]-4,5-dihydro-3H-
furan-2-one [(4S,5R)-21n]: nBuLi (1.50  in hexane, 2.93 mL,
4.40 mmol, 1.1 equiv.) was added dropwise at –78 °C to tris(methyl-
sulfanyl)methane (585 µL, 679 mg, 4.40 mmol, 1.1 equiv.) in THF
(40 mL). After the system had been stirred at –78 °C for 1.5 h, but-
enolide R-20n (1.07 g, 4.00 mmol) in THF (8 mL) was added drop-
wise over 15 min. After the system had been stirred at –78 °C for
another 2 h, HCl (2 , 20 mL) and tBuOMe (10 mL) were added.
The mixture was allowed to reach room temp, the organic phase
was separated, and the aqueous phase was extracted with tBuOMe
(3×20 mL). The combined organic phases were washed success-
ively with satd. aq. NaHCO3 (10 mL) and brine (1×10 mL). Dry-
ing over MgSO4, removal of the solvent in vacuo, and purification
by flash chromatography (4 cm, petroleum ether/tBuOMe 8:1, #10–
27) provided the title compound (1.61 g, 87%) as a colorless oil.
(3S,4S,5R)-3-Methyl-5-tridecyl-4-[tris(methylsulfanyl)methyl]-4,5-
dihydro-3H-furan-2-one (23): nBuLi (1.50  in hexane, 1.82 mL,
2.75 mmol, 1.1 equiv.) was added dropwise at –78 °C to tris(methyl-
sulfanyl)methane (366 µL, 424 mg, 2.75 mmol, 1.1 equiv.) in THF
(20 mL). After the system had been stirred at –78 °C for 1 h, buten-
olide R-20n (666 mg, 2.50 mmol) in THF (5 mL) was added drop-
wise over 30 min. After the system had been stirred at –78 °C for
another 2 h, MeI (469 µL, 1.06 g, 7.50 mmol, 3.0 equiv.) was added
slowly. After the system had been stirred at –78 °C for another 3 h,
H2O (20 mL) and EtOAc (15 mL) were added. The mixture was
allowed to reach room temp., the organic phase was separated, and
the aqueous phase was extracted with EtOAc (3×20 mL). The
combined organic phases were washed with brine (20 mL) and
dried with MgSO4. The solvent was removed in vacuo. Flash
chromatography (4 cm, petroleum ether/tBuOMe, 10:1, #10–17)
[α]2D5 = +13.0 (c = 1.95, CHCl3). H NMR (300 MHz): δ = 0.88 (t,
1
J5Ј,4Ј = 6.6 Hz, 13Ј-H3), 1.26–1.48 (m, 2Ј-H2, 3Ј-H2, 4Ј-H2, 5Ј-H2,
6Ј-H2, 7Ј-H2, 8Ј-H2, 9Ј-H2, 10Ј-H2, 11Ј-H2, 12Ј-H2), 1.56–1.66 (m,
1Ј-H2), 2.17 (s, 3× SCH3), 2.60 (ddd, J4,3-H(A) = 9.8 Hz, J4,3-H(B)
=
J4,5 = 2.5 Hz, 4-H), AB signal (δA = 2.68, δB = 2.97, JAB = 17.7 Hz,
A part additionally split by JA,4 = 9.8 Hz, B part additionally split
by JB,4 = 2.4 Hz, 3-H2), 4.76 (ddd, J5,1Ј-H(1) = J5,1Ј-H(2) = 6.4 Hz,
yielded the title compound (1.10 g, 92%) as a colorless oil. [α]2D5
=
1
+8.07 (c = 2.33, CHCl3). H NMR (300 MHz): δ = 0.88 (mc, ap-
proximately interpretable as t, J13Ј,12Ј Ϸ 6.8 Hz, 13Ј-H3), 1.26–1.68
(m, 1Ј-H2, 2Ј-H2, 3Ј-H2, 4Ј-H2, 5Ј-H2, 6Ј-H2, 7Ј-H2, 8Ј-H2, 9Ј-H2,
10Ј-H2, 11Ј-H2, 12Ј-H2), superimposed by 1.42 (d, J3-Me,3 = 8.0 Hz,
3-CH3), 2.19 (s, 3 × SCH3), 2.65 (dd, J4,3 = J4,5 = 3.4 Hz, 4-H),
3.07 (qd, J3,3-Me = 7.7 Hz, J3,4 = 3.8 Hz, 3-H), 4.68 (mc, 5-H) ppm.
Elemental analysis calcd. (%) for C22H42O2S3 (434.8): C 60.78,
H 9.74; found: C 60.95, H 9.70.
J5,4 = 2.5 Hz, 5-H) ppm. IR (film): ν = 2955, 2920, 2855, 1775,
˜
1465, 1430, 1415, 1380, 1355, 1310, 1230, 1180, 1120, 1055, 1010,
950 cm–1. Elemental analysis calcd. (%) for C21H40O2S3 (420.7):
C 59.95, H 9.58; found: C 59.88, H 9.44.
(4R,5S)-5-Tridecyl-4-[tris(methylsulfanyl)methyl]-4,5-dihydro-3H-
furan-2-one [(4R,5S)-21n]: This compound (780 mg, 86%) was pre-
pared from tris(methylsulfanyl)methane (293 µL, 340 mg,
2.20 mmol, 1.1 equiv.), nBuLi (1.50  in hexane, 1.45 mL,
2.20 mmol, 1.1 equiv.), and butenolide S-19n (533 mg, 2.00 mmol)
as a colorless oil as described for (4S,5R)-21n. [α]2D5 = –12.8 (c =
2.47, CHCl3).
Michael Addition Products 24 and epi-24: These compounds (enan-
tiomerically pure 1:1 mixture) were prepared by the procedure used
for the racemic material.[38]
(3aR,4R,6aR)-3-Methyl-3-(methylsulfanyl)-4-octyl-2,3,3a,4,6,6a-
(4S,5R)-4-Carboxy-5-pentyl-4,5-dihydro-3H-furan-2-one [(4S,5R)- hexahydrofuro[3,4-b]furan-2,6-dione (1:1 mixture of unassigned epi-
22i]: BF3·OEt2 (6.60 mL, 7.45 g, 52.5 mmol, 15.0 equiv.) was added
dropwise to a suspension of lactone (4S,5R)-21i (1.08 g, 3.50 mmol)
and HgO (3.79 g, 17.5 mmol, 5.0 equiv.) in THF/H2O (4:1, 20 mL).
After the system had been stirred at room temp. for 2.5 h, H2O
(12 mL) and EtOAc (12 mL) were added. The organic phase was
separated and the aqueous phase was extracted with EtOAc
(3×20 mL). The combined organic phases were washed with brine
(1×10 mL) and dried with MgSO4. After removal of the solvent in
vacuo, flash chromatography (4 cm, EtOAc/CH2Cl2 2:1 Ǟ #12, 4:1
mers 26 and epi-26): MCPBA (90%, 234 mg, 1.22 mmol,
1.05 equiv.) in CH2Cl2 was added dropwise at 0 °C to the dia-
stereopure bislactone 27 (265 mg, 812 µmol) in CH2Cl2 (5 mL). Af-
ter stirring at 0 °C for 30 min the reaction mixture was washed with
satd. aq. NaHCO3 (3×1 mL) and dried with MgSO4. The solvent
was removed in vacuo and flash chromatography (2 cm, petroleum
ether/tBuOMe 1:5, # 15–24) gave the title compound (225 mg,
81%) as a yellowish oil. It was a 1:1 mixture of epimers 26 and epi-
26.
2116
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Eur. J. Org. Chem. 2006, 2110–2118

Straightforward Asymmetric Syntheses of γ-Lactones
FULL PAPER
6410; b) Related AD reactions of the Weinreb amides of β,γ-
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(3R,3aR,4R,6aR)- and (3S,3aR,4R,6aR)-3-Methyl-3-(methylsul-
fanyl)-4-octyl-2,3,3a,4,6,6a-hexahydrofuro[3,4-b]furan-2,6-dione (27
and epi-27): These compounds were synthesized as separated but
unassigned diastereomers as described for the racemic materials
(albeit without separation of the diastereomers).[38] A solution of
the epimeric iodolactones 24 and epi-24 (1:1 mixture, 1.51 g,
3.03 mmol) and p-toluenesulfonic acid (225 mg, 0.4 equiv.) in ben-
zene (30 mL) was heated at reflux for 3 h. At room temp. satd. aq.
NaHCO3 (12 mL) was added. The resulting mixture was stirred at
room temp. for 45 min, the organic phase was separated, and the
aqueous phase was extracted with tBuOMe (3×15 mL). The com-
bined organic phases were dried with MgSO4. The solvent was re-
moved in vacuo. Purification by flash chromatography (3 cm, pe-
troleum ether/tBuOMe 10:1, #8–15 and #22–30) provided the title
compounds 27 (460 mg, 47%) and epi-27 (420 mg, 42%), each of
them as a somewhat contaminated, yellowish oil.
[6]
[7]
[8]
[9]
[10]
C. Harcken, Dissertation, University of Göttingen, 2000,
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[14]
[15]
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Acknowledgments
T. Berkenbusch, Diplomarbeit, University of Göttingen, 1998,
p. 148.
This work was financially supported by the Fonds der Chemischen
Industrie. We express our gratitude to Ruth Weber for skilful tech-
nical assistance and to Dr. Olivier Lohse (Novartis AG, Basel,
Switzerland) for the HPLC determination of the ees of butenolides
R- and S-20n.
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[10]
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2117

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Received: December 8, 2005
Published Online: March 8, 2006
(–)-15: M. P. Sibi, P. K. Deshpande, A. J. La Loggia, Synlett
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2118
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