Enantioselective syntheses and configuration assignments of γ-chiral butenolides from Plagiomnium undulatum: Butenolide synthesis from tetronic acids

Article abstract of DOI:10.1002/chem.200401135

Both enantiomers of the γ-chiral α,β-dimethylated butyrolactones nat-1 and nat-2 from the moss Plagiomnium undulatum were synthesized stereoselectively through butenolides and tetronic acids, respectively. The configuration of the natural products was determined by GLC comparisons with mono(3-O-acetyl-6-O-tert-butyldimethylsilyl-2-O-methyl) hexakis(6-O-tert-butyldimethylsilyl-2,3-di-O-methyl)-β-cyclodextrin as a stationary phase.

Full text of DOI:10.1002/chem.200401135

Enantioselective Syntheses and Configuration Assignments of g-Chiral
Butenolides from Plagiomnium undulatum: Butenolide Synthesis from
Tetronic Acids
Tobias Kapferer,[a] Reinhard Brꢀckner,*[a] Axel Herzig,[a] and Wilfried A. Kçnig†[b]
Abstract: Both enantiomers of the g-chiral a,b-dimethylated butyrolactones nat-1
Keywords: Arndt-Eistert homolo-
and nat-2 from the moss Plagiomnium undulatum were synthesized stereoselec-
gation
butyrolactones
determination · dihydroxylation ·
tetronic acids
·
asymmetric synthesis
·
tively through butenolides and tetronic acids, respectively. The configuration of
the natural products was determined by GLC comparisons with mono(3-O-acetyl-
6-O-tert-butyldimethylsilyl-2-O-methyl)hexakis(6-O-tert-butyldimethylsilyl-2,3-di-
O-methyl)-b-cyclodextrin as a stationary phase.
·
configuration
Introduction
Bryophytes (mosses) are known to generate a great variety
of secondary metabolites. However, this property mainly ap-
Scheme 1. Butenolides from Plagiomnium undulatum.[2]
plies to liverworts (Hepaticae), whereas common mosses
(Musci) are considered to be poor in their production of vol-
atile constituents. A recent investigation of the hydrodistilla-
tion products of a selection of mosses revealed that many of
them also produce complex mixtures of volatiles, although
in much smaller amounts (approximately 10%) than liver-
worts. From the genus Plagiomnium undulatum, in addition
to (+)-dauca-8,11-diene (a new sesquiterpene hydrocarbon),
two D2-butenolides,[1] nat-1 and nat-2 (Scheme 1), with the
latter exhibiting a very intense, pleasant, floral fragrance,
were isolated and their structures were derived by NMR
spectroscopy and mass spectrometry analysis.[2] However,
the absolute configuration at their stereocenters remained
unknown.
and nat-2 (plus other compounds), with synthetic specimens
of (S)-1, (R)-1, (S)-2, and (R)-2 by enantioselective gas chro-
matography with appropriately modified cyclodextrins.[3]
This was the only way of determining the absolute configu-
ration of compound nat-1 because it had been inaccessible
in pure form from the natural source. In contrast, GLC com-
parisons between nat-2 (which had been isolated in pure
form) and stereochemically unambiguously assigned refer-
ence compounds (S)-2 and (R)-2 were an obvious means of
absolute configuration assignment, since “easier” methods
1
like CD spectroscopy[4] or H NMR spectroscopy analysis in
the presence of an enantiopure lanthanide shift reagent[5]
were not readily applicable.
In order to establish the latter, we compared extracts
from Plagiomnium undulatum, which contained both nat-1
Reference compounds (S)-1, (R)-1, (S)-2, and (R)-2 quali-
fied, in principle, for being accessible by the asymmetric di-
hydroxylation[6] (AD) of sterically homogeneous b,g-unsatu-
rated carboxylic esters, since this reaction provides b-hy-
droxy-g-butyrolactones in a single step and in essentially
enantiopure form.[7] Having accessed a variety of saturated[8]
and unsaturated butyrolactones[9] in this manner,[7,10] we
found the latter did not include trisubstituted (for example,
1) or tetrasubstituted (for example, 2) D2-butenolides. This
gap is closed by the present study. Concomitantly, we dis-
close the first examples each of a novel access to optically
active tetronic acids (11!10!18; 5!4!21) and of a novel
preparation of b-substituted butenolides (18!19!2).
[a] Dipl.-Chem. T. Kapferer, Prof. Dr. R. Brꢀckner, Dr. A. Herzig
Institut fꢀr Organische Chemie und Biochemie
Albert-Ludwigs-Universitꢁt
Albertstrasse 21, 79104 Freiburg (Germany)
Fax : (+49)40-4283-82893
E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
[b] Prof. Dr. W. A. Kçnig†
Institut fꢀr Organische Chemie
Universitꢁt Hamburg
Martin-Luther-King-Platz 6, 20146 Hamburg (Germany)
Fax : (+49)761-203-6100
E-mail: wkoenig@chemie.uni-hamburg.de
[†] Deceased, November 19, 2004.
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DOI: 10.1002/chem.200401135
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FULL PAPER
Results and Discussion
Following the b,g-unsaturated ester!b-hydroxy-g-lactone
strategy, the two enantiomers of trisubstituted butenolides
(S)- and (R)-1 were traced back to ester trans-5[11]
(Scheme 2). This originated from the deconjugative Knoeve-
Scheme 3. Approaching butenolides (S)- and (R)-2, variant 1. a) SOCl2
(1.0 equiv), DMF (cat.), CH2Cl2, 08C!RT, 3 h; b) CH2N2 (2.0 equiv),
Hꢀnigꢃs base (1.0 equiv), Et2O, 0 8C!RT, 1 h; 55% over 2 steps;
c) AgOBz (0.3 equiv), NEt3 (4.7 equiv), MeOH, RT, 5 h; 88%;
d) K2OsO2(OH)4 (0.8 mol%), (DHQ)2PHAL (0.016 equiv), K3Fe(CN)6
(3.0 equiv), K2CO3 (3.0 equiv), MeSO2NH2 (1.0 equiv), tBuOH/H2O
(1:1), 08C, 1 d; 83%; e) K2OsO2(OH)4 (0.8 mol%), (DHQD)2PHAL
(0.016 equiv), K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv), MeSO2NH2
(1.0 equiv), tBuOH/H2O (1:1), 08C, 1 d; 82%. DMF=N,N-dimethylform-
amide.
Scheme 2. Approaching butenolides (S)- and (R)-1. a) Malonic acid
(1.1 equiv), NEt3 (3.0 equiv), 908C, 18 h; b) H2SO4 (cat.), MeOH, D, 2 h;
82%; c) K2OsO2(OH)4 (0.8 mol%), (DHQ)2PHAL (0.01 equiv),
K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv), MeSO2NH2 (1.0 equiv),
tBuOH/H2O (1:1), 08C, 12 h; 91%; d) K2OsO2(OH)4 (0.8 mol%),
(DHQD)2PHAL (0.01 equiv), K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv),
MeSO2NH2 (1.0 equiv), tBuOH/H2O (1:1), 08C, 12 h; 90%;
e) pBrC6H4CO2H (1.1 equiv), DCC (1.1 equiv), DMAP (cat.), CH2Cl2,
RT, 4 h, D, 1 h; 81%. A Pluton/Povray plot[15] of the solid-state structure
of (S,S)-6 is also depicted. Pent=pentyl, (DHQ)2PHAL=1,4-bis(dihy-
droquininyl)phthalazine, (DHQD)2PHAL=1,4-bis(dihydroquinidinyl)-
phthalazine, DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-dimethyl-
aminopyridine.
nagel condensation[12] of aldehyde 3 with malonic acid fol-
lowed by methyl esterification. Oxidation of ester trans-5
with AD mixes a and b (containing (DHQ)2PHAL and
(DHQD)2PHAL, respectively, as the chiral auxiliary) pro-
vided hydroxylactones (S,S)-4 (94% ee;[13] absolute configu-
ration ascertained by X-ray crystal structure analysis[14] of a
crystal of the para-bromobenzoate (S,S)-6) and (R,R)-4
(97% ee[13]), respectively.
Application of our unsaturated ester!b-hydroxy-g-lac-
tone strategy to obtain the optically active tetrasubstituted
butenolides (S)- and (R)-2 allowed us to start both from
ester (E)-11[16] (Scheme 3) or from its isomer (Z)-11
(Scheme 4). AD mix a converted the former into a hydroxy-
lactone, (4S,5S)-10, with 91% ee,[13] and the latter into the
hydroxylactone (4S,5R)-10 with 80% ee.[13] Likewise, dihy-
droxylation of esters (E)- and (Z)-11 with AD mix b occur-
red with 97% ee[13] (!(4R,5R)-10) and 85% ee[13] (!
Scheme 4. Approaching butenolides (S)- and (R)-2, variant 2. a) SOCl2
(1.1 equiv), DMF (cat.), CH2Cl2, 08C!RT, 2.5 h; b) CH2N2 (3.0 equiv),
Hꢀnigꢃs base (1.0 equiv), Et2O, 0 8C!RT; 57% over 2 steps; c) AgOBz
(0.3 equiv), NEt3 (4.7 equiv), MeOH, RT, 4 h; 95%; d) K2OsO2(OH)4
(0.8 mol%), (DHQD)2PHAL (0.016 equiv), K3Fe(CN)6 (3.0 equiv),
K2CO3 (3.0 equiv), MeSO2NH2 (1.0 equiv), tBuOH/H2O (1:1), 08C, 1 d;
85%; e) K2OsO2(OH)4 (0.8 mol%), (DHQ)2PHAL (0.016 equiv),
K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv), MeSO2NH2 (1.0 equiv),
tBuOH/H2O (1:1), 08C, 1 d; 92%; f) pBrC6H4COCl (1.2 equiv), NEt3
(1.3 equiv), DMAP (cat.), CH2Cl2, RT, 6 h, D, 2 h; 56%. A Pluton/Povray
plot[15] of the solid-state structure of (4S,5R)-12 is also depicted.
(4R,5S)-10), respectively. The b,g-unsaturated C10 esters (E)-
and (Z)-11 had been obtained stereospecifically from the
a,b-unsaturated C9 acids (E)-7[17] and (Z)-7,[18] respectively
by Arndt–Eistert homologations[19] proceeding through the
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R. Brꢀckner, W. A. Kçnig et al.
corresponding acid chlorides (E)- and (Z)-8 and the derived
diazoketones (E)- and (Z)-9.[20]
“bond-to-be” (96% yield). Enolate formation with LDA
and treatment with methyl iodide afforded a D2:D1 mixture
The anomalous X-ray diffraction[14] of the para-bromo-
benzoate first obtained from these lactones as nice crystals
revealed its stereostructure to be that depicted for (4S,5R)-
12; this proves that the configuration of the underlying hy-
droxylactone, namely the a-osmylation product of ester (Z)-
11, is (4S,5R)-10 (Scheme 4). The configurations of the hy-
droxylactone isomers obtained according to Scheme 3
emerged from correlations with those shown in Scheme 4.
According to chiral GLC,[13] a-methylation/oxidation of the
a-osmylation product (4S,5S)-10 of ester (E)-11 (Scheme 3)
provided the same tetronic acid enantiomer ((S)-18,
Scheme 6) as a-methylation/oxidation of compound
(4R,5S)-10 from Scheme 4. Similarly, a-methylation/oxida-
tion of the b-osmylation product of ester (E)-11
(Scheme 3)—which was hence designated (4R,5R)-10—gave
the identical tetronic acid enantiomer (not depicted) to that
obtained by a-methylation/oxidation of hydroxylactone
(4S,5R)-10 (Scheme 4).
of pyrazolines 14 and 15, thereby establishing the C Me
a
ꢀ
bond (80% yield). Pyrolysis in refluxing dioxane provided
the desired butenolide (S)-1 in 75% yield with an undimin-
ished ee value (95%). A specimen of (R)-1 (97% ee) was
similarly obtained.
The methodology of Hanessian and Murray[21] was unsuit-
able for converting hydroxylactones (4R,5S)-10 and (4S,5R)-
10 into the tetrasubstituted butenolides (S)-2 and (R)-2, re-
spectively, since butenolide 16—obtained by dehydrating an
isomeric mixture of hydroxylactones 10—did not react with
diazomethane (Scheme 6). We circumvented this inertia by
Hydroxylactones (S,S)-4 and (R,R)-4 were transformed
Scheme 6. Completing the synthesis of butenolides (S)- and (R)-2.
a) CH2N2 (5.0 equiv), Et2O, RT, 5 d; b) LDA (2.8 equiv), THF, ꢀ788C,
30 min; MeI (1.8 equiv), THF/DMPU, ꢀ788C!ꢀ408C, 14 h; 74%;
c) DMSO (3.5 equiv), (F3CCO)2O (2.0 equiv), CH2Cl2, ꢀ788C, 2 h; NEt3
(4.0 equiv), ꢀ788C, 14 h; 99%; d) MeLi (2.0 equiv), THF, ꢀ508C!08C,
ꢀ
2 h; HCl, 30 min, RT; 87%, 86% ee; e) Me3O+·BF4 (3.0 equiv), CH2Cl2,
Scheme 5. Completing the synthesis of butenolides (S)- and (R)-1.
a) MsCl (1.5 equiv), NEt3 (2.8 equiv), CH2Cl2, 08C, 30 min; 92%, 94%
ee; b) CH2N2 (5.0 equiv), Et2O, 0 8C!RT, 15 h; 96%; c) LDA (1.7 equiv),
THF, ꢀ788C, 30 min; MeI (1.8 equiv), ꢀ788C, 18 h; 80%; d) 1,4-dioxane,
1108C, 5 d; 75%. Ms =mesyl=methanesulfonyl, LDA=lithium diisopro-
pylamide, THF=tetrahydrofuran.
RT, 28 h; 85%. DMPU=1,3-dimethyltetrahydro-2-(1H)-pyrimidinone.
adding tetronic acids to the product palette of AD reactions
of b,g-unsaturated esters and by establishing a novel way for
b
b
ꢀ
ꢀ
converting the C OH motif of tetronic acids into the C
hydrocarbon subunit of D2-butenolides.
into the trisubstituted butenolides (S)-1 and (R)-1, respec-
tively, as detailed in Scheme 5 for the former compound.
Dehydration with mesyl chloride/triethylamine produced
the expected D1-butenolide in 94% ee (92% yield). Its
CbH=CaH moiety was elaborated into the desired CbMe=
CaMe moiety by Hanessian and Murrayꢃs b-methylation/a-
alkylation protocol for butenolides.[21] Cycloaddition of di-
The S enantiomer of butenolide 2 was targeted from hy-
droxylactone (4R,5S)-10 by lithioalkoxide/enolate formation
followed by methylation[22] (Scheme 6). A single diastereo-
mer of the expected a-methyl-b-hydroxylactone was isolat-
ed. Working in THF/DMPU, the a-methyl and b-hydroxy
groups were probably oriented trans.[10a,22] Swern oxida-
tion[23] including enol formation yielded tetronic acid (S)-18
almost quantitatively. There appears to be little prece-
1
b
ꢀ
azomethane gave the D -pyrazoline 13 with the C Me
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g-Chiral Butenolides
FULL PAPER
dence[24] for such an approach to these compounds.[25] The
method could be extended to tetronic acid 21 which, unlike
(S)-18, might—but did not—racemize due to the possibility
of Cg,H acidity (Scheme 7).
Scheme 7. Synthesis of an optically active tetronic acid, 21, from a b,g-un-
saturated ester. a) Same as step d of Scheme 2; b) LDA (5.0 equiv), THF,
ꢀ788C, 1 h; MeI (10 equiv), THF, ꢀ788C, 2 h; 83%; c) DMSO
(3.5 equiv), (F3CCO)2O (2.0 equiv), CH2Cl2, ꢀ788C, 1 h; NEt3
(4.0 equiv), ꢀ788C, 45 min; 92%.
Tetronic acid (S)-18 was methylated by Meerweinꢃs salt
2
4
ꢀ
regioselectively at C =O, rather than at C OH, thereby
yielding methoxyfuranone (S)-19 (Scheme 6).[26] Addition of
MeLi followed by acid hydrolysis provided target structure
(S)-2 in 87% yield. This reaction, to the best of our knowl-
edge, represents the first example of the overall transforma-
1
2
2
1
ꢀ
ꢀ
ꢀ
tion O=C C=C(OR )2 + R M ! R C=C C(=O)(OR ) in
heterocycle synthesis. It consists of the sequential transfor-
Figure 1. GLC analyses of natural plant extract and synthetic reference
compounds by using a 25 m fused-silica capillary column with monokis(3-
O-acetyl-6-O-tert-butyldimethylsilyl-2-O-methyl)hexakis(6-O-tert-butyldi-
methylsilyl-2,3-di-O-methyl)-b-cyclodextrin[3a] at 1508C (isothermal). H2
at an inlet pressure of 0.5 bar was used as the carrier gas with split injec-
tion (ratio 1:30). Bottom: natural plant extract; center: synthetic refer-
ence compounds; top: coinjection of natural plant extract and synthetic
reference compounds.
1
1
ꢀ ꢀ ꢀ
1) HO C=CH C(=O)OR + R X ! O=C C=
1 2 2
mations
C(OR1)2 and 2) O=C C=C(OR )2 + R M ! R C=C C(=
O)(OR1). The same sequence of steps might be applicable
to the conversion of other b-ketolactones into other a,b-un-
saturated lactones containing a b-substituent; conceivably,
this could entail the two-step conversion of tetrahydropyr-
an-2,4-diones into 4-substituted 5,6-dihydro-(2H)-2-pyra-
nones or the two-step conversion of benzo-3,4-dihydro-
(2H)-2,4-pyrandiones into 4-substituted cumarins. It should
ꢀ
ꢀ
ꢀ
as the internal standard in CDCl3; C6HD5 (d=7.15 ppm) as the internal
standard in C6D6) and 13C NMR (CDCl3 (center peak of the triplet d=
77.0 ppm) as the internal standard in CDCl3; C6D6 (center peak of the
triplet d=128.0 ppm) as the internal standard in C6D6) spectroscopy was
performed on Varian Mercury VX 300 and Bruker DRX 500 spectrome-
ters. Integrals are in accordance with the assignments; coupling constants
ꢀ
ꢀ
be noted that the related transformation O=C C=C
1
2
2
ꢀ
ꢀ
OR + R M ! R C=C C=O, which proceeds at a lower
oxidation state than (S)-19!(S)-2, has been amply used for
the preparation of 3-substituted 2-cycloalken-1-ones.[27]
Having made enantiomer (R)-2 available by the same se-
quence of steps (Scheme 6, bottom), we were in possession
of all the materials needed for the GLC analysis of com-
pounds nat-1 and nat-2. As demonstrated by enantioselec-
tive GLC (Figure 1), the predominant nat-2 is the enantio-
pure S enantiomer, while the minor component nat-1 is a
mixture of enantiomers with a small excess of the R enantio-
mer (9% ee).
1
are given in Hz. The assignments of H and 13C NMR signals refer to the
IUPAC nomenclature except within substituents where primed numbers
are used. Combustion analyses were performed by E. Hickl, Institut fꢀr
Organische Chemie und Biochemie, Universitꢁt Freiburg. MS analyses
were obtained by Dr. J. Wçrth and C. Warth, Institut fꢀr Organische
Chemie und Biochemie, Universitꢁt Freiburg. IR spectra were obtained
on a Perkin–Elmer Paragon 1000 apparatus. Optical rotations measured
with a Perkin–Elmer polarimeter 341 at 589 nm and 208C and were cal-
culated according to the Drude equation ([a]D =(aexp ꢄ100)/(cꢄd)); rota-
tional values are the average of five measurements of aexp in a given so-
lution of the respective sample. Melting points were measured on a Dr.
Tottoli apparatus (Bꢀchi) and are uncorrected. The ee values were deter-
mined by chiral GC, by using a Carlo Erba Instruments HRC 5160 Mega
series apparatus with a Varian CP7502 (b-cyclodextrin/dimethylpolysilox-
ane) column.
Experimental Section
General: All reactions were performed in oven-dried (1108C) glassware
under N2. THF was freshly distilled from K, CH2Cl2 was distilled from
CaH2. Diazomethane was prepared as an ethanol-free diethyl ether so-
lution according to the literature[28] by using the ALDRICH Diazald kit;
the diazomethane concentrations were determined prior to use.[28] Prod-
ucts were purified by flash chromatography[29] on Merck silica gel 60.
(S)-3,4-Dimethyl-5-pentyl-2-(5H)-furanone ((S)-1):
A solution of 15
(70 mg, 0.33 mmol) in 1,4-dioxane (3 mL) was heated at 1108C for 5 d.
The solvent was evaporated in vacuo. Subsequent purification by flash
chromatography (cyclohexane/EtOAc 10:1) afforded the title compound
(45 mg, 75%): [a]D =ꢀ6.5 (c=0.6 in CHCl3); IR (film): n˜ =2955, 2930,
2860, 1755, 1685, 1465, 1460, 1440, 1385, 1330, 1130, 1115, 1095, 1060,
1
Yields refer to analytically pure samples. H NMR (CHCl3 (d=7.26 ppm)
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R. Brꢀckner, W. A. Kçnig et al.
1010, 965, 925, 765, 745, 730, 660, 610, 575, 550 cmꢀ1; tr(S)=18.25 min,
tr(R)=17.27 min (1208C, 100 kPa); 95% ee.
3-H2), 4.37 (ddd, J5,1’-H(B) =8.5, J5,1’-H(A) =5.7, J5,4 =3.6 Hz, 5-H)**, 4.48
(brddd, J4,5 ꢁJ4,4-OH ꢁJ4,3-H(B) ꢁ4.4 Hz, J4,3-H(A) not resolved, 4-H)** ppm;
13C NMR (125 MHz, CDCl3; *=distinguishable by a C,H correlation
spectrum, **=assignment is based on increment calculation[30] which pre-
dicts d=30.5 ppm (C-3’), ***=distinction is based on increment calcula-
tion[30] which predicts d=65.0 ppm (C-4) and d=77.9 ppm (C-5)): d=
13.92 (C-5’), 22.44 and 25.20 (C-2’, C-4’), 28.20 (C-1’)*, 31.59 (C-3’)**,
39.47 (C-3), 69.01 (C-4)***, 84.95 (C-5)***, 175.84 (C-2) ppm; elemental
analysis calcd (%) for C9H16O3 (172.2): C 62.77, H 9.36; found: C 62.60,
H 9.27.
(R)-3,4-Dimethyl-5-pentyl-2-(5H)-furanone ((R)-1): The neat enantio-
mer of 15 (“ent-15”; 99 mg, 0.47 mmol) was heated for 4 h at 1508C. Puri-
fication by flash chromatography (cyclohexane/EtOAc 9:1) afforded the
title compound (58 mg, 68%): [a]D =+7.1 (c=0.6 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=0.89 (mc, 5’-CH3), 1.25–1.48 (m, 1’-H1, 2’-H2, 3’-H2,
4’-H2), 1.81 (mc, 3-CH3), 1.84–1.91 (m, 1’-H2), 1.94 (mc, 4-CH3), 4.71–4.73
(m, 5-H) ppm; 13C NMR (125 MHz, CDCl3; *,**=distinguishable by a
C,H correlation spectrum): d=8.39 (3-CH3)*, 11.93 (4-CH3)*, 13.92 (C-
5’), 22.41, 24.10, and 31.49 (C-2’, C-3’, C-4’), 32.08 (C-1’)**, 83.21 (C-5),
123.38 (C-3), 159.17 (C-4), 174.67 (C-2) ppm; tr(S)=15.81 min, tr(R)=
17.07 min (1208C, 100 kPa); 97% ee; HRMS: m/z calcd for C11H18O2:
182.130694; found 182.130680; elemental analysis calcd (%) for C11H18O2
(182.3): C 72.50, H 9.96; found: C 72.47, H 10.07.
(4R,5R)-4,5-Dihydro-4-hydroxy-2-(3H)-furanone ((R,R)-4): The title
compound (1.13 g, 90%) was prepared from trans-5 (1.24 g, 7.30 mmol)
by an analogous procedure to that described for (S,S)-4 but with
(DHQD)2PHAL as a ligand: [a]D =+62.9 (c=1.1 in CHCl3).
Methyl (trans-3-nonenoate) (trans-5):
A mixture of triethylamine
(R)-3,4,5-Trimethyl-5-pentyl-2-(5H)-furanone ((R)-2): Methyllithium
(1.08m in diethyl ether, 1.48 mL, 1.60 mmol, 2.0 equiv) was added at
ꢀ508C to a solution of (R)-19 (170 mg, 0.802 mmol) and stirred for
15 min. The solution was allowed to warm to 08C and stirred for 2 h.
After addition of aq. HCl (0.5m, 10 mL) the mixture was stirred for
30 min at room temperature. The solution was extracted with EtOAc (5ꢄ
15 mL) and the combined organic extracts were dried over MgSO4. After
evaporation in vacuo, the residue was purified by flash chromatography
(cyclohexane/EtOAc 10:1) to afford the title compound (148 mg, 94%):
(8.8 mL, 6.4 g, 63 mmol, 3.0 equiv), heptanal (2.40 g, 21.0 mmol), and ma-
lonic acid (2.40 g, 23.1 mmol, 1.1 equiv) was heated at 908C for 18 h.
After the mixture had been cooled to room temperature, the solution
was poured into precooled (08C) aq. H2SO4 (20%, 12.5 mL). The so-
lution was extracted with CH2Cl2 (3ꢄ15 mL) and evaporated in vacuo.
The residue was dissolved in methanol (12.5 mL). After addition of conc.
H2SO4 (0.60 mL, 0.11 g, 1.1 mmol, 0.05 equiv), the mixture was heated
for 2 h under reflux and then cooled to 08C. Aq. NaHCO3 (9.5 mL) was
added. After extraction with CH2Cl2 (3ꢄ10 mL) the combined organic
extracts were washed with aq. NaCl (3ꢄ10 mL) and dried over MgSO4.
The solvent was evaporated in vacuo and the residue was purified by dis-
tillation (110–1128C, 30 mbar) to afford the title compound (2.95 g,
82%): 1H NMR (300 MHz, CDCl3): d=0.88 (t, J9,8 =6.8 Hz, 9-H3), 1.20–
1.42 (m, 6-H2, 7-H2, 8-H2), 1.98–2.07 (m, 5-H2), 3.03 (mc, presumably in-
terpretable as brd, J2,3 =5.4 Hz, 2-H2), 3.68 (s, COOCH3), 5.46–5.62 (m,
3-H, 4-H) ppm.
1
[a]D =ꢀ7.8 (c=0.4 in CHCl3); H NMR (500 MHz, C6D6; *=distinguish-
able by a C,H correlation spectrum): d=0.80 (t, J5’,4’ =7.23 Hz, 5’-CH3),
0.98 (s, 5-CH3), 0.84–0.94 and 1.00–1.20 (2m, 1- and 6-H, 1’-H1, 2’-H2, 3’-
H2, 4’-H2), superimposed with 1.19 (s, 4-CH3)*, 1.44–1.49 (m, 1’-H2), 1.58
(s, 3-CH3)* ppm; 13C NMR (125 MHz, C6D6; *=distinguished by compar-
ison with the corresponding signals of a CDCl3 solution of (R)-2 (d=8.58
(3-CH3), 11.23 (4-CH3) ppm); **,***=distinguishable by a C,H correla-
tion spectrum): d=8.51 (3-CH3)*, 10.35 (4-CH3)*, 14.13 (C-5’)**, 22.69,
22.93, and 31.98 (C-2’, C-3’, C-4’), 23.63 (5-CH3)**, 37.07 (C-1’)***, 86.75
(C-5), 123.34 (C-3), 161.03 (C-4), 172.71 (C-2) ppm; tr(R)=12.07 min,
tr(S)=12.57 min (1208C, 100 kPa); 81% ee; HRMS: m/z calcd for
C12H20O2: 196.146330; found 196.145939; elemental analysis calcd (%)
for C12H20O2 (196.2): C 73.43, H 10.27; found: C 73.32, H 10.41.
(4S,5S)-4-(4-Bromobenzoyloxy)-4,5-dihydro-5-pentyl-2-(3H)-furanone
((S,S)-6): DCC (0.12 g, 0.57 mmol, 1.1 equiv), p-bromobenzoic acid
(0.11 g, 0.57 mmol, 1.1 equiv), and DMAP (cat.) were added to a solution
of (4S,5S)-4. After heating for 1 h under reflux, the mixture was cooled
to room temperature and stirred for 4 h. After addition of aq. NH4Cl
(15 mL) and extraction with CH2Cl2 (4ꢄ20 mL), the combined organic
extracts were dried over MgSO4. Purification by flash chromatography
(cyclohexane/EtOAc 10:1) afforded the title compound (149 mg, 81%)
(S)-3,4,5-Trimethyl-5-pentyl-2-(5H)-furanone ((S)-2): The title compound
(125 mg, 87%) was prepared from (S)-19 (159 mg, 0.736 mmol) by an
analogous procedure to that described for (R)-2: [a]D =+10.3 (c=0.9 in
CHCl3); 1H NMR (500 MHz, CDCl3; *=distinguishable by the NOE ob-
served at 4-CH3 (d=1.88 ppm) while irradiating 5-CH3 (d=1.38 ppm)):
d=0.86 (t, J5’,4’ =7.0 Hz, 5’-H3), 0.95–1.07 and 1.18–1.31 (2m, 1- and 5-H,
2’-H2, 3’-H2, 4’-H2), 1.38 (s, 5-CH3), 1.52–1.60 and 1.77–1.83 (2m, 1-H, 1’-
H2), superimposed by 1.80 (q, 5J3-Me,4-Me =1.0 Hz, 3-CH3)*, 1.88 (q,
5J4-Me,3-Me =1.1 Hz, 4-CH3)* ppm; 13C NMR (125 MHz, CDCl3; *,**,***=
distinguishable by a C,H correlation spectrum;): d=8.58 (3-CH3)*, 11.23
(4-CH3)*, 14.02 (C-5’)**, 22.50, 22.72 and 31.77 (C-2’, C-3’, C-4’), 23.76
(5-CH3)**, 37.01 (C-1’)***, 88.00 (C-5), 122.96 (C-3), 162.69 (C-4), 173.99
(C-2) ppm; tr(S)=12.24 min, tr(R)=11.95 min (1208C, 100 kPa); 86% ee.
1
as a white solid: m.p. 818C; H NMR (500 MHz, CDCl3; *=interchange-
able): d=0.84–0.89 (m, 5’-H3), 1.25–1.34 (m, 3’-H2, 4’-H2), 1.35–1.44 (m,
2’-H1), 1.49–1.60 (m, 2’-H2), 1.68–1.75 (m, 1’-H1), 1.84–1.91 (m, 1’-H2),
AB signal (dA =2.72, dB =3.00, JAB =18.3 Hz, A part in addition split by
JA,4 ꢁ0.5 Hz, B part in addition split by JB,4 =5.9 Hz, 3-H2), 4.62 (ddd,
J
J
5,1’-H(1) =8.8*, J5,1’-H(2) =4.9*, J5,4 =4.1 Hz, 5-H), 5.71 (ddd, J4,3-H(B) =5.4,
4,5 =4.1, J4,3-H(A) ꢁ1.1 Hz, 4-H), AA’BB’ signal with signal centers at 7.62
and 7.88 (2ꢄ2ArH) ppm; IR (film): n˜ =3035, 3025, 3015, 3010, 2960,
2935, 2875, 2860, 1925, 1785, 1725, 1590, 1485, 1400, 1355, 1270, 1235,
1195, 1175, 1165, 1145, 1115, 1100, 1070, 1050, 1015, 920, 850, 800 cmꢀ1
;
proof of the absolute configuration was obtained by X-ray crystal struc-
ture analysis.[14]
(4S,5S)-4,5-Dihydro-4-hydroxy-2-(3H)-furanone ((S,S)-4): (DHQ)2PHAL
(63 mg, 0.081 mmol, 1 mol%), K3Fe(CN)6 (8.00 g, 24.3 mmol, 3.0 equiv),
K2CO3 (3.36 g, 24.3 mmol, 3.0 equiv), MeSO2NH2 (771 mg, 8.11 mmol,
1.0 equiv), and K2OsO2(OH)4 (24 mg, 0.065 mmol, 0.8 mol%) were dis-
solved in tBuOH (50 mL) and H2O (50 mL). After cooling to 08C trans-5
(1.38 g, 8.11 mmol) was added. After 12 h at 08C, aq. Na2SO3 (34 mL)
was added and the mixture was stirred for 1 h at room temperature. The
solution was extracted with EtOAc (3ꢄ50 mL) and the combined organic
extracts were dried over MgSO4. After evaporation in vacuo the residue
was purified by flash chromatography (cyclohexane/EtOAc 2:1) to afford
the title compound (1.27 g, 91%): [a]D =ꢀ60.7 (c=1.1 in CHCl3);
1H NMR (500 MHz, CDCl3; *=interchangeable, **=distinguishable by
a C,H correlation spectrum): d=0.89–0.93 (m, 5’-H3), 1.30–1.56 (m, 2’-H2,
3’-H2, 4’-H2), AB signal (dA =1.72, dB =1.87, JAB =13.8 Hz, A part in ad-
dition split by JA,2’-H(1) =10.2, JA,5 =JA,2’-H(2) =5.7 Hz, B part in addition
split by JB,2’-H(2) =9.9*, JB,5 =8.3, JB,2’-H(1) =5.4* Hz, 1’-H2), 2.22 (brd, J4-
OH,4 =4.8 Hz, 4-OH), AB signal (dA =2.55, dB =2.79, JAB =17.7 Hz, A part
in addition split by JA,4 =0.9 Hz, B part in addition split by JB,4 =5.5 Hz,
(E)-3-Methyl-2-octenoic acid ((E)-7): At ꢀ788C, tBuLi (1.7m in pentane,
14.3 mL, 24.3 mmol, 9.7 equiv) was added to a solution of pentyl iodide
(1.50 mL, 2.28 g, 11.5 mmol, 4.6 equiv) in pentane (45 mL) and diethyl
ether (30 mL). After being stirred for 5 min, the solution was allowed to
reach room temperature then it was stirred for 1.5 h. The mixture was
cooled to 08C and added to a cooled (ꢀ58C) suspension of CuI (1.10 g,
5.75 mmol, 2.3 equiv) in THF (5 mL). After 10 min, the solution was
cooled to ꢀ788C and a solution of 2-butynoic acid (210 mg, 2.50 mmol)
in THF (5 mL) was added. The mixture was stirred for 10 min at ꢀ788C
and was then allowed to reach ꢀ158C. After 30 min, the mixture was
poured into cold (08C) aq. HCl (1m, 40 mL) and the solution was
warmed to room temperature. After extraction with EtOAc (4ꢄ50 mL),
the combined organic extracts were dried over MgSO4 and evaporated in
vacuo. The residue was purified by flash chromatography (cyclohexane/
EtOAc 10:1) to afford the title compound (336 mg, 86%): 1H NMR
(500 MHz, CDCl3): d=0.90 (t, J8,7 =7.2 Hz, 8-H3), 1.24–1.36 (m, 6-H2, 7-
H2), 1.46–1.52 (m, 5-H2), 2.14–2.18 (m, 4-H2), superimposed by 2.16 (mc,
2158
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2154 – 2162

g-Chiral Butenolides
FULL PAPER
4
presumably interpretable as d, Jallyl =1.2 Hz, 3-CH3), 5.69 (incomplete re-
solved qd, 4J2,3-Me =4J2,4 =1.2 Hz, 2-H), 11.89 (brs, COOH) ppm; elemen-
tal analysis calcd (%) for C9H16O2 (156.21): C 69.20, H 10.32; found: C
69.32, H 10.16.
was purified by flash chromatography (cyclohexane/EtOAc 2:1) to afford
the title compound (76 mg, 82%): [a]D =+15.7 (c=1.2 in CHCl3);
1H NMR (500 MHz, CDCl3; *=interchangeable): d=0.90 (mc, 5’-H3),
1.29–1.47 (m, 2’-H2, 3’-H2, 4’-H2), superimposed with 1.33 (s, 5-CH3), AB
signal (dA =1.73, dB =1.81, JAB =13.8 Hz, A part in addition split by
(Z)-3-Methyl-2-octenoic acid ((Z)-7): At ꢀ58C MeLi (1.6m in diethyl
ether, 57.5 mL, 92.0 mmol, 4.6 equiv) was added to a suspension of CuI
(8.76 g, 46.0 mmol, 2.3 equiv) in THF (200 mL). The solution was stirred
for 20 min at this temperature and then cooled to ꢀ788C. A solution of
2-octynoic acid (2.80 g, 20.0 mmol) in THF (9 mL) was added. After stir-
ring for 1.5 h at this temperature, the mixture was warmed to ꢀ158C and
stirred for another 5 h. The mixture was poured into cold (08C) aq. HCl
(1m, 400 mL). After extraction with EtOAc (4ꢄ100 mL), the combined
organic extracts were dried over MgSO4 and evaporated in vacuo. The
residue was purified by flash chromatography (cyclohexane/EtOAc 10:1)
to afford the title compound (3.04 g, 97%): 1H NMR (500 MHz, CDCl3):
d=0.89 (mc, 8-H3), 1.28–1.37 (m, 6-H2, 7-H2), 1.47 (mc, 5-H2), 1.92 (d,
4J3-Me,2 =1.4 Hz, 3-CH3), 2.63 (mc, 4-H2), 5.67 (mc, 2-H), 11.89 (brs,
COOH) ppm.
J
J
A,2’-H(1) =10.1, JA,2’-H(2) =6.1 Hz, B part in addition split by JB,2’-H(1) =10.5*,
B,2’-H(2) =5.8* Hz, 1’-H2), 2.46 (brs, 4-OH), 2.52 (dd, Jgem =18.0, J3-H(1),4
2.5 Hz, 3-H1), 2.95 (dd, 3-H(2),4 =6.2 Hz, 3-H2), 4.21 (mc,
gem =18.0,
4-H) ppm; IR (film): n˜ =3445, 2955, 2935, 2870, 1755, 1460, 1385, 1320,
1295, 1265, 1235, 1200, 1170, 1135, 1120, 1100, 1075, 955, 930 cmꢀ1
=
J
J
;
tr(4R,5R)=39.82 min, tr(4S,5S)=45.61 min (1408C, 100 kPa); 97% ee; el-
emental analysis calcd (%) for C10H18O3 (186.2): C 64.50, H 9.74; found:
C 64.46, H 9.72.
(4S,5S)-4,5-Dihydro-4-hydroxy-5-methyl-5-pentyl-2-(3H)-furanone
((4S,5S)-10): The title compound (167 mg, 83%) was prepared from (E)-
11 (200 mg, 1.09 mmol) by an analogous procedure to that described for
(4R,5R)-10 but with (DHQ)2PHAL as the ligand: [a]D =ꢀ16.1 (c=1.1 in
CHCl3); tr(4S,5S)=42.19 min, tr(4R,5R)=37.79 min (1408C, 100 kPa);
91% ee.
(E)-3-Methyl-2-octenoyl chloride ((E)-8): At 08C, SOCl2 (0.33 mL,
0.53 g, 4.5 mmol, 1.0 equiv) and DMF (1 drop) were added to a solution
of (E)-3-methyl-2-octenoic acid (701 mg, 4.49 mmol) in CH2Cl2 (19 mL).
The solution was stirred for 3 h at room temperature. After evaporation
in vacuo, the crude residue was used for the preparation of (E)-9 without
further purification.
(4R,5S)-4,5-Dihydro-4-hydroxy-5-methyl-5-pentyl-2-(3H)-furanone
((4R,5S)-10): The title compound (909 mg, 85%) was prepared from (Z)-
11 (1.06 g, 5.75 mmol) by an analogous procedure to that described for
(4R,5R)-10 but with (DHQD)2PHAL as the ligand: [a]D =ꢀ4.0 (c=1.2
in CHCl3); tr(4R,5S)=39.50 min, tr(4S,5R)=37.33 min (1408C, 100 kPa);
85% ee.
(Z)-3-Methyl-2-octenoyl chloride ((Z)-8): At 08C, SOCl2 (0.051 mL,
83 mg, 0.70 mmol, 1.1 equiv) and DMF (1 drop) were added to a solution
of (Z)-3-methyl-2-octenoic acid (0.10 g, 0.64 mmol) in CH2Cl2 (4 mL).
The solution was stirred for 2.5 h at room temperature. After evaporation
in vacuo, the crude residue was used for the preparation of (Z)-9 without
further purification.
(4S,5R)-4,5-Dihydro-4-hydroxy-5-methyl-5-pentyl-2-(3H)-furanone
((4S,5R)-10): The title compound (618 mg, 92%) was prepared from (Z)-
11 (665 mg, 3.61 mmol) by an analogous procedure to that described for
(4R,5R)-10: [a]D =+3.8 (c=1.1 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=0.89 (t, J5’,4’ =7.0 Hz, 5’-H3), 1.25–1.45 (m, 2’-H2, 3’-H2, 4’-H2), super-
imposed with 1.40 (s, 5-CH3), 1.59 (mc, 1’-H2), 2.55 (dd, Jgem =18.1,
(E)-1-Diazo-4-methyl-3-nonen-2-one ((E)-9): At 08C, the crude acid
chloride (E)-8 was added to a solution of CH2N2 (0.42m in diethyl ether,
21.4 mL, 8.98 mmol, 2.0 equiv) and Hꢀnigꢃs base (0.78 mL, 0.58 g,
4.5 mmol, 1.0 equiv). After the mixture had been stirred for 1 h at room
temperature, the solvent was evaporated in vacuo. The residue was puri-
fied by flash chromatography (cyclohexane/EtOAc 30:1) to afford the di-
azoketone (E)-9 (447 mg, 55% over 2 steps) as a yellow oil: 1H NMR
(500 MHz, CDCl3; *=distinguishable by a C,H correlation spectrum):
d=0.89 (t, J9,8 =7.2 Hz, 9-H3), 1.23–1.36 (m, 7-H2, 8-H2), 1.43–1.50 (m, 6-
H2), 2.10 (mc, 5-H2), 2.19 (d, 4J4-Me,3 =0.8 Hz, 4-CH3), 5.18 (brs, 1-H)*,
5.74 (brs, 3-H)* ppm; IR (film): n˜ =2960, 2930, 2870, 2860, 2095, 1690,
1645, 1615, 1445, 1385, 1335, 1145, 1115, 1085, 785 cmꢀ1; HRMS: m/z
calcd for C10H16N2O: 180.126211; found 180.126263.
J
3-H(1),4 =4.1 Hz, 3-H1; superimposes, in line with the integral, on the brs
of 4-OH), 2.91 (dd, gem =18.1, 3-H(2),4 =6.8 Hz, 3-H2), 4.26 (mc, 4-
J
J
H) ppm; IR (film): n˜ =3445, 2955, 2935, 2870, 1755, 1385, 1320, 1295,
1265, 1195, 1175, 1135, 1120, 1105, 1065, 1040, 950 cmꢀ1; tr(4S,5R)=
36.79 min, tr(4S,5R)=40.54 min (1408C, 100 kPa); 80% ee; elemental
analysis calcd (%) for C10H18O3 (186.2): C 64.49, H 9.74; found: C 64.27,
H 9.87.
Methyl (E)-4-methyl-3-nonenoate ((E)-11): Under exclusion of light, a
solution of silver benzoate (130 mg, 0.568 mmol, 0.29 equiv) in triethyl-
amine (1.28 mL, 929 mg, 9.18 mmol, 4.70 equiv) was added dropwise to a
solution of (E)-9 (352 mg, 1.95 mmol) in methanol (8 mL). After the mix-
ture had been stirred for 5 h at room temperature, the solvent was evapo-
rated in vacuo and the residue was purified by flash chromatography (pe-
(Z)-1-Diazo-4-methyl-3-nonen-2-one ((Z)-9): At 08C, a solution of the
crude acid chloride (Z)-8 in Et2O (3 mL) was added to a solution of
CH2N2 (0.43m in diethyl ether, 4.5 mL, 1.92 mmol, 3.0 equiv) and Hꢀnigꢃs
base (0.11 mL, 84 mg, 0.65 mmol, 1.0 equiv). After the mixture had been
stirred for 15 min at 08C and for 1 h at room temperature, the solvent
was evaporated in vacuo. The residue was purified by flash chromatogra-
phy (petroleum ether/diethyl ether 10:1) to afford the diazoketone (Z)-9
(66 mg, 57% over 2 steps) as a yellow oil: 1H NMR (500 MHz, CDCl3;
*=distinguishable by a C,H correlation spectrum): d=0.89 (mc, 9-H3),
troleum ether/diethyl ether 50:1) to afford the title compound (318 mg,
88%) as a colorless liquid: H NMR (500 MHz, CDCl3): d=0.88 (t, J9,8
1
=
7.2 Hz, 9-H3), 1.21–1.34 (m, 7-H2, 8-H2), 1.37–1.43 (m, 6-H2), 1.62 (brs, 4-
CH3), 2.01 (brt, J5,6 =7.6 Hz, 5-H2), 3.05 (brd, J2,3 =7.1 Hz, 2-H2), 3.68 (s,
COOCH3), 5.31 (tmc, J3,2 =6.7 Hz, 3-H) ppm; proof of the E configura-
tion was obtained from the NOE observed at 3-H (d=5.31 ppm) while ir-
radiating 5-H2 (d=2.01 ppm).
Methyl (Z)-4-methyl-3-nonenoate ((Z)-11): The title compound (799 mg,
95%) was prepared from (Z)-9 (824 mg, 4.58 mmol) by an analogous
procedure to that described for (E)-11: 1H NMR (500 MHz, CDCl3): d=
0.89 (t, J9,8 =7.2 Hz, 9-H3), 1.19–1.41 (m, 6-H2, 7-H2, 8-H2), 1.73 (dt,
4
1.29–1.37 (m, 7-H2, 8-H2), 1.43–1.51 (m, 6-H2), 1.87 (d, J4-Me,3 =1.4 Hz, 4-
CH3), 2.65 (brt,
J5,6 =7.9 Hz, 5-H2), 5.16 (brs, 1-H)*, 5.73 (brs, 3-
H)* ppm; IR (film): n˜ =3080, 2960, 2930, 2870, 2860, 2095, 1645, 1615,
1445, 1385, 1335, 1145, 1115, 1085, 1005, 960, 845, 785, 725 cmꢀ1; elemen-
tal analysis calcd (%) for C10H16N2O (180.1): C 66.69, H 8.88, N 15.55;
found: C 66.57, H 8.97, N 15.62.
4J4-Me,3 =5J4-Me,2 =1.3 Hz, 4-CH3), 2.01 (brt, J5,6 =7.7 Hz, 5-H2), 3.04 (mc,
5
presumably interpretable as a incomplete resolved dq, J2,3 =7.2, J2,4-Me
1.2 Hz, 2-H2), 3.68 (s, COOCH3), 5.31 (tmc, J3,2 =7.2 Hz, 3-H) ppm.
=
(4R,5R)-4,5-Dihydro-4-hydroxy-5-methyl-5-pentyl-2-(3H)-furanone
((4R,5R)-10): (DHQD)2PHAL (6 mg, 0.008 mmol, 1.6 mol%),
K3Fe(CN)6 (494 mg, 1.50 mmol, 3.0 equiv), K2CO3 (207 mg, 1.50 mmol,
3.0 equiv), MeSO2NH2 (48 mg, 0.50 mmol, 1.0 equiv), and K2OsO2(OH)4
(1.5 mg, 0.004 mmol, 0.8 mol%) were dissolved in tBuOH (2.5 mL) and
H2O (2.5 mL). After the solution had been cooled to 08C, (E)-11 (92 mg,
0.50 mmol) was added. After 24 h at 08C, aq. Na2SO3 (2.5 mL) was
added and the mixture was stirred for 30 min at room temperature. The
solution was extracted with EtOAc (3ꢄ40 mL). The combined organic
extracts were dried over MgSO4. After evaporation in vacuo, the residue
(4S,5R)-4-(4-Bromobenzoyloxy)-4,5-dihydro-5-methyl-5-pentyl-2-(3H)-
furanone ((4S,5R)-12): Triethylamine (0.08 mL, 0.05 g, 0.5 mmol,
1.3 equiv), p-bromobenzoyl chloride (0.11 g, 0.49 mmol, 1.2 equiv), and
DMAP (cat.) were added to a solution of (4S,5R)-10 (70 mg, 0.41 mmol)
in CH2Cl2 (1 mL). After the mixture had been stirred for 6 h at room
temperature, the solution was heated under reflux for 2 h. It was then al-
lowed to cool to room temperature, diluted with H2O (15 mL), and ex-
tracted with CH2Cl2 (4ꢄ15 mL). The combined organic extracts were
dried over MgSO4 and evaporated in vacuo. The residue was purified by
flash chromatography (cyclohexane/EtOAc 8:1) to afford the title com-
Chem. Eur. J. 2005, 11, 2154 – 2162
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2159

R. Brꢀckner, W. A. Kçnig et al.
pound (85 mg, 56%): 1H NMR (300 MHz, CDCl3): d=0.91 (mc, 5’-H3),
1.22–1.55 (m, 2’-H2, 3’-H2, 4’-H2), superimposed with 1.44 (s, 5-CH3),
1.63–1.79 (m, 1’-H2), AB signal (dA =2.69, dB =3.15, JAB =18.6 Hz, A part
in addition split by JA,4 =2.6 Hz, B part in addition split by JB,4 =7.0 Hz,
3-H2), 5.48 (dd, J4,3-H(B) =7.0, J4,3-H(A) =2.6 Hz, 4-H), AA’BB’ signal with
signal centers at 7.62 and 7.89 (2ꢄ2ArH) ppm; proof of the absolute
configuration was obtained by X-ray crystal structure analysis.[14]
15: IR (film): n˜ =2955, 2935, 2860, 1770, 1550, 1455, 1435, 1375, 1355,
1290, 1255, 1240, 1175, 1110, 1015, 995, 945, 935, 905 cmꢀ1; elemental
analysis calcd (%) for C11H18N2O2 (210.3): C 62.84, H 8.63, N 13.32;
found: C 62.94, H 8.75, N 13.05.
(3aR,4R,6aR)-1,3a,4,6a-Tetrahydro-6a-methyl-4-pentylfuro[3,4c]pyrazol-
6-one (ent-14) and (3aS,4R,6aR)-3,3a,4,6a-tetrahydro-6a-methyl-4-pentyl-
furo[3,4c]pyrazol-6-one (ent-15): The title compounds (ent-14: 62 mg,
32%; ent-15: 98 mg, 51%) were prepared in a 42:58 ratio from ent-13
(180 mg, 0.917 mmol) by an analogous procedure to that described for 14
and 15.
ent-14: 1H NMR (500 MHz, CDCl3; *=interchangeable): d=0.90–0.93
(m, 5’’-H3), 1.30–1.56 (m, 2’’-H2, 3’’-H2, 4’’-H2), superimposed by 1.54 (s,
1’-H3), 1.63–1.70 (m, 1’’-H1), 1.76–1.84 (m, 1’’-H2), 3.24 (m, 3a-H), 4.38
(ddd, J4,1’’-H(1) =8.6*, J4,1’’-H(2) =5.9*, J4,3a =3.1 Hz, 4-H), 6.03 (brs, NH),
6.70 (d, J3,3a =1.1 Hz, 3-H) ppm.
(3aR,4S,6aS)-3,3a,4,6a-Tetrahydro-4-pentylfuro[3,4c]pyrazol-6-one (13):
a) At 08C, triethylamine (2.70 mL, 1.97 g, 19.5 mmol, 2.8 equiv) and
MeSO2Cl (0.81 mL, 1.2 g, 11 mmol, 1.5 equiv) were added to a solution
of (S,S)-4 (1.20 g, 6.97 mmol) in CH2Cl2 (20 mL). After the mixture had
been stirred for 30 min, aq. NH4Cl (15 mL) was added. The mixture was
extracted with CH2Cl2 (4ꢄ40 mL), dried over MgSO4 and evaporated in
vacuo. The residue was purified by flash chromatography (cyclohexane/
EtOAc 6:1) to afford (S)-5-pentyl-2-(5H)-furanone (992 mg, 92%):
[a]D =+91.0 (c=1.2 in CHCl3); 1H NMR (500 MHz, CDCl3; *=inter-
changeable): d=0.88–0.92 (m, 5’-H3), 1.29–1.35 (m, 3’-H2, 4’-H2), 1.38–
1.52 (m, 2’-H2), 1.63–1.70 (m, 1’-H1), 1.73–1.80 (m, 1’-H2), 5.04 (dddd, J5,1’-
ent-15: 1H NMR (500 MHz, CDCl3): d=0.90 (mc, 5’’-H3), 1.27–1.50 (m,
2’’-H2, 3’’-H2, 4’’-H2), 1.58–1.76 (m, 1’-H2), superimposed with 1.59 (s, 1’-
H3), 2.29 (ddd, J3a,3-H(A) =7.5, J3a,4 =5.5, J3a,3-H(B) =2.0 Hz, 3a-H), 3.78 (ddd,
4
4
H(1) =7.3*, J5,1’-H(2) =5.4*, J5,4 ꢁ J5,3 ꢁ1.7 Hz, 5-H), 6.10 (dd, J3,4 =5.7, J3,5
=
J
4,1’’-H(1) =7.5, J4,1’’-H(2) =J4,3a =5.5 Hz, 4-H), AB signal (dA =4.71, dB =4.82,
2.0 Hz, 3-H), 7.45 (dd, J4,3 =5.8, J4,5 =1.5 Hz, 4-H) ppm; tr(S)=34.50 min,
tr(R)=33.18 min (1008C, 100 kPa); 94% ee; elemental analysis calcd (%)
for C9H14O2 (154.2): C 70.01, H 9.15; found: C 70.01, H 9.18.
JAB =18.5 Hz, A part in addition split by JA,3a =7.5 Hz, B part in addition
split by JB,3a =2.0 Hz, 3-H2) ppm.
(5S)-4-Hydroxy-3,5-dimethyl-5-pentyl-2-(3H)-furanone ((S)-18): a) At
ꢀ788C, n-BuLi (2.27m in THF, 2.47 mL, 5.60 mmol, 2.8 equiv) was added
to a solution of diisopropylamine (0.79 mL, 0.57 g, 5.6 mmol, 2.8 equiv)
in THF (8 mL). After the mixture had been stirred for 30 min, a solution
of (4R,5S)-10 (370 mg, 2.00 mmol, 84% ee) in THF (3 mL) was added
b) At 08C, diazomethane (0.45m in diethyl ether, 43 mL, 19.5 mmol,
5.0 equiv) was added to
a solution of (S)-5-pentyl-2-(5H)-furanone
(600 mg, 3.89 mmol, 94% ee) in diethyl ether (6 mL). The solution was
allowed to reach room temperature and was stirred for 15 h. After evapo-
ration in vacuo, the residue was purified by flash chromatography (cyclo-
hexane/EtOAc 5:1) to afford the title compound (730 mg, 96%): IR
(film): n˜ =2960, 2935, 2865, 1770, 1355, 1225, 1205, 1185, 1025, 1000, 945,
905, 765, 755, 730, 720, 695, 655 cmꢀ1; elemental analysis calcd (%) for
C10H16N2O2 (196.3): C 61.20, H 8.23, N 14.27; found: C 61.27, H 8.08 N
14.09.
and the mixture was stirred for 1 h.
A solution of methyl iodide
(0.22 mL, 0.51 g, 3.6 mmol, 1.8 equiv) in DMPU (5.4 mL) and THF
(7.1 mL) was added to this mixture during 90 min. It was then warmed to
ꢀ408C and stirred overnight at this temperature. Aqueous HCl (2%,
30 mL) was added and the mixture was allowed to reach room tempera-
ture. After extraction with EtOAc (3ꢄ30 mL), the combined organic ex-
tracts were washed with aq. NaCl (2ꢄ30 mL) and dried over MgSO4.
Evaporation in vacuo followed by flash chromatography (cyclohexane/
EtOAc 3:1) afforded (3R,4R,5S)-4,5-dihydro-4-hydroxy-3,5-dimethyl-5-
pentyl-2-(3H)-furanone (295 mg, 74%): [a]D =ꢀ5.0 (c=0.3 in CHCl3);
tr(3R,4R,5S)=30.70 min, tr(3S,4S,5R)=28.51 min (1408C, 100 kPa); 86%
ee; elemental analysis calcd (%) for C11H20O3 (200.3): C 65.97, H 10.07;
found: C 65.85, H 9.87.
(3aS,4R,6aR)-3,3a,4,6a-Tetrahydro-4-pentylfuro[3,R4c]pyrazol-6-one
(ent-13): a) (R)-5-Pentyl-2-(5H)-furanone (852 mg, 95%) was prepared
from (R,R)-4 (1.00 g, 5.80 mmol) by an analogous procedure to that de-
scribed for 13 (part a): [a]D =ꢀ94.8 (c=0.9 in CHCl3); IR (film): n˜ =
3090, 2955, 2930, 2860, 1750, 1600, 1465, 1330, 1165, 1115, 1100, 1030,
1000, 960, 920, 900, 815 cmꢀ1; tr(R)=29.75 min, tr(S)=33.80 min (1408C,
100 kPa); 97% ee.
b) The title compound (219 mg, 86%) was prepared from (R)-5-pentyl-2-
(5H)-furanone (200 mg, 1.30 mmol, 97% ee) by an analogous procedure
to that described for 13 (part b): 1H NMR (500 MHz, CDCl3): d=0.90
(mc, 5’-H3), 1.27–1.49 (m, 2’-H2, 3’-H2, 4’-H2), 1.63–1.78 (m, 1’-H2), 2.67
(dddd, J3a,6a =9.0, J3a,3-H(A) =7.9, J3a,4 =5.2, J3a,3-H(B) =2.8 Hz, 3a-H), 3.92
(dt, J4,1’-H(1) =7.5, J4,3a =J4,1’-H(2) =5.3 Hz, 4-H), AB signal (dA =4.75, dB =
4.83, JAB =18.5 Hz, A part in addition split by JA,3a =8.2, 5JA,6a =2.0 Hz, B
part in addition split by JB,3a =5JB,6a =2.6 Hz, 3-H2), 5.52 (dt, J6a,3a =9.1,
5J6a,3-H(A) =5J6a,3-H(B) =2.2 Hz, 6a-H) ppm.
b) At ꢀ788C, trifluoroacetic anhydride (0.33 mL, 0.49 g, 2.3 mmol,
2.0 equiv) was added to a solution of DMSO (0.29 mL, 0.32 g, 4.1 mmol,
3.5 equiv) in CH2Cl2 (6 mL). The resulting mixture was stirred for
30 min. After addition of a solution of (3R,4R,5S)-4,5-dihydro-4-hydroxy-
3,5-dimethyl-5-pentyl-2-(3H)-furanone (232 mg, 1.16 mmol, 86% ee) in
CH2Cl2 (6 mL), the mixture was stirred for 2 h at ꢀ788C. Triethylamine
(0.65 mL, 0.47 g, 4.6 mmol, 4.0 equiv) was then added and the mixture
was stirred for 14 h. After addition of H2O (15 mL) the solution was al-
lowed to reach room temperature and was extracted with CH2Cl2 (5ꢄ
20 mL). Drying over MgSO4 and evaporation in vacuo followed by flash
chromatography (cyclohexane/EtOAc 3:1) afforded the title compound
(229 mg, 99%): [a]D =+0.6 (c=1.1 in CHCl3); IR (film): n˜ =2955, 2930,
2870, 2865, 1720, 1650, 1460, 1405, 1370, 1335, 1310, 1265, 1170, 1105,
1050 cmꢀ1; tr(S)=15.58 min, tr(R)=12.69 min (1408C, 100 kPa); 85% ee;
elemental analysis calcd (%) for C11H18O3 (198.2): C 66.64, H 9.15;
found: C 66.42, H 9.34.
(3aS,4S,6aS)-1,3a,4,6a-Tetrahydro-6a-methyl-4-pentylfuro[3,4c]pyrazol-6-
one (14) and (3aR,4S,6aS)-3,3a,4,6a-tetrahydro-6a-methyl-4-pentylfur-
o[3,4c]pyrazol-6-one (15): At ꢀ788C, nBuLi (2.05m in hexane, 0.84 mL,
1.73 mmol, 1.7 equiv) was added to
a solution of diisopropylamine
(0.242 mL, 175 mg, 1.73 mmol, 1.7 equiv) in THF (1.7 mL). After the
mixture had been stirred for 30 min, a solution of 13 (200 mg, 1.02 mmol)
in THF (1.5 mL) was added and the mixture was stirred for 30 min at
ꢀ788C. Methyl iodide (0.13 mL, 0.29 g, 2.0 mmol, 2.0 equiv) was added.
The solution was allowed to warm to ꢀ408C and stirred for 18 h. After
addition of H2O the mixture was allowed to reach room temperature, ex-
tracted with EtOAc (4ꢄ20 mL), and dried over MgSO4. Evaporation in
vacuo followed by flash chromatography (cyclohexane/EtOAc 6:1) af-
forded the separated title compounds in a 79:21 ratio (14: 138 mg, 65%;
15: 33 mg, 15%).
(5R)-4-Hydroxy-3,5-dimethyl-5-pentyl-2-(3H)-furanone
((R)-18):
a) (3S,4S,5R)-4,5-Dihydro-4-hydroxy-3,5-dimethyl-5-pentyl-2-(3H)-fura-
none (471 mg, 72%) was prepared from (4S,5R)-10 (611 mg, 3.28 mmol,
80% ee) by an analogous procedure to that described for (S)-18 (part a):
[a]D =+4.3 (c=0.6 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.90 (t,
J
5’,4’ =7.0 Hz, 5’-H), 1.25–1.46 (m, 2’-H2, 3’-H2, 4’-H2), superimposed with
1.30 (d, J3-Me,3 =7.1 Hz, 3-CH3) and 1.33 (s, 5-CH3), 1.63–1.75 (m, 1’-H2),
2.44 (brd, J4-OH,4 =5.2 Hz, 4-OH), 2.66 (dq, J3,4 =9.8, J3,3-Me =7.1 Hz, 3-H),
3.86 (dd, J4,3 =9.9, J4,4-OH =5.2 Hz, 4-H) ppm; IR (film): n˜ =3445, 2955,
2935, 2875, 1755, 1750, 1460, 1385, 1350, 1310, 1255, 1245, 1200, 1125,
1110, 1075, 1040, 945, 620 cmꢀ1; tr(3S,4S,5R)=27.13 min, tr(3R,4R,5S)=
30.08 min (1408C, 100 kPa); 78% ee.
14: IR (film): n˜ =3030, 2960, 2935, 2860, 1770, 1380, 1235, 1230, 1215,
1210, 1200, 1190, 1145, 1115, 1100, 800 cmꢀ1; HRMS: m/z calcd for
C11H18N2O2: 210.137130; found 210.136828; elemental analysis calcd (%)
for C11H18N2O2 (210.3): C 62.84, H 8.63, N 13.32; found: C 62.78, H 8.82,
N 13.19.
2160
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2154 – 2162

g-Chiral Butenolides
FULL PAPER
b) The title compound (278 mg, 99%) was prepared from (3S,4S,5R)-4,5-
(mc, 5’-H3), 1.23–1.46 (m, 2’-H2, 3’-H2, 4’-H2), 1.61 (dddd, Jgem =14.5,
5
dihydro-4-hydroxy-3,5-dimethyl-5-pentyl-2-(3H)-furanone
(248 mg,
J
1’-H(1),2’-H(1) =9.8, J1’-H(1),5 =7.8, J1’-H(1),2’-H(2) =5.2 Hz, 1’-H1), 1.73 (d, J3-Me,5
=
=
=
1.42 mmol, 80% ee) by an analogous procedure to that described for (S)-
18 (part b): [a]D =ꢀ1.0 (c=1.0 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=0.86 (mc, 5’-H3), 1.13–1.35 (m, 2’-H2, 3’-H2, 4’-H2), 1.47 (s, 5-CH3),
1.71–1.86 (m, 1’-H2), superimposed with 1.73 (s, 3-CH3), 10.07 (brs, 4-
OH) ppm; tr(R)=13.88 min, tr(S)=16.81 min (1408C, 100 kPa); 82% ee.
1.2 Hz, 3-CH3), 1.98 (dddd, Jgem =14.1, J1’-H(2),2’-H(1) =9.6*, J1’-H(2),2’-H(2)
6.1*, J1’-H(2),5 =3.6 Hz, 1’-H2), 4.76 (incompletely resolved ddq, J5,1’-H(1)
7.7**, J5,1’-H(2) =3.4**, 5J5,3-Me =1.2 Hz, 5-H), 10.71 (brs, 4-OH) ppm; IR
(KBr): n˜ =2970, 2955, 2925, 2875, 2855, 1710, 1645, 1270, 1230, 1220,
1100, 1080 cmꢀ1; elemental analysis calcd (%) for C10H16O3 (184.2): C
65.20, H 8.76; found: C 65.20, H 8.90.
(5S)-2-Methoxy-3,5-dimethyl-5-pentyl-4-(5H)-furanone
((S)-19):
At
ꢀ
room temperature, Me3O+·BF4 (199 mg, 1.35 mmol, 3.0 equiv) was
added to a solution of (S)-18 (89 mg, 0.45 mmol) in CH2Cl2 (7 mL). After
the mixture had been stirred for 28 h, aq. NaHCO3 (9 mL) was added.
The solution was extracted with CH2Cl2 (5ꢄ10 mL) and dried over
MgSO4. After evaporation in vacuo the residue was purified by flash
chromatography (cyclohexane/EtOAc 3:1) to afford the title compound
(81 mg, 85%): [a]D =ꢀ54.5 (c=0.5 in CHCl3); tr(S)=11.14 min, tr(R)=
11.68 min (1208C, 100 kPa), 87% ee; IR (film): n˜ =3000, 2960, 2930,
2875, 2865, 1595, 1480, 1455, 1400, 1375, 1195, 1125, 980, 800, 785, 765,
760, 750, 745, 730, 725, 715, 710, 675, 665 cmꢀ1; elemental analysis calcd
(%) for C12H20O3 (212.3): C 67.95, H 9.43; found: C 68.04, H 9.73.
Acknowledgements
This work was financially supported by the Fonds der Chemischen Indus-
trie. We are indebted to Valentina Morgel for her skillful technical assis-
tance and we express our gratitude to Dr. Manfred Keller (Institut fꢀr
Organische Chemie und Biochemie, Universitꢁt Freiburg) for performing
the X-ray analyses and to Melanie Junge (Universitꢁt Hamburg) for pre-
paring the GLC column for the analysis, the results of which are shown
in Figure 1.
(5R)-2-Methoxy-3,5-dimethyl-5-pentyl-4-(5H)-furanone ((R)-19): The
title compound (173 mg, 87%) was prepared from (R)-18 (185 mg,
0.933 mmol) by an analogous procedure to that described for (S)-19:
[a]D =+50.6 (c=0.7 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.86
(mc, 5’-H3), 1.17–1.34 (m, 2’-H2, 3’-H2, 4’-H2), 1.39 (s, 5-CH3), 1.59 (s, 3-
CH3), 1.69–1.80 (m, 1’-H2), 4.01 (s, 2-OCH3); tr(R)=11.58 min, tr(S)=
11.17 min (1208C, 100 kPa); 81% ee.
[1] Recent reviews on the chemistry of D2-butenolides: a) A. Hashem,
E. Kleinpeter, Adv. Heterocycl. Chem. 2001, 81, 107–165; b) N. B.
Carter, A. E. Nadany, J. B. Sweeney, J. Chem. Soc. Perkin Trans. 1
2002, 2324–2342.
[2] Y. Saritas, M. Mekem Sonwa, H. Iznaguen, W. A. Kçnig, H. Muhle,
R. Mues, Phytochemistry 2001, 57, 443–457.
[3] a) M. Junge, W. A. Kçnig, J. Sep. Sci. 2003, 26, 1607–1614; b) V.
Schurig, J. Chromatogr. A 2001, 906, 275–299; c) W. A. Kçnig, Gas
Chromatographic Enantiomer Separation with Modified Cyclodex-
trins, Hꢀthig, Heidelberg, 1992.
[4] Circular dichroism measurements have been used for determining
the absolute configuration of differently substituted D2-butenolides:
A. Gypser, C. Bꢀlow, H.-D. Scharf, Tetrahedron 1995, 51, 1921–
1930; J. K. Gawronski, A. v. Oeveren, H. v. d. Deen, C. W. Leung,
B. L. Feringa, J. Org. Chem. 1996, 61, 1513–1515; V. J. R. V. Mukku,
M. Speitling, H. Laatsch, E. Helmke, J. Nat. Prod. 2000, 63, 1570–
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Lee, J. H. Jung, J. Nat. Prod. 2004, 67, 721–724; T. Murakami, Y.
Morikawa, M. Hashimoto, T. Okuno, Y. Harada, Org. Lett. 2004, 6,
157–160; ref. [9i].
(3R,4R,5R)-4,5-Dihydro-4-hydroxy-3-methyl-5-pentyl-2-(3H)-furanone
(20): At ꢀ788C, n-BuLi was added to a solution of diisopropylamine
(1.41 mL, 1.02 g, 10.1 mmol, 5.0 equiv) in THF (7 mL). After the mixture
had been stirred for 30 min, a solution of (R,R)-4 (347 mg, 2.02 mmol,
97% ee) in THF (2 mL) was added. The solution was stirred for 1 h at
ꢀ788C, then a solution of methyl iodide (1.25 mL, 2.86 g, 20.2 mmol,
10.0 equiv) in THF (7 mL) was added. After the mixture had been stirred
for 2 h, a solution of glacial acetic acid (1.7 mL) in THF (7 mL) was
added and the mixture was allowed to reach room temperature. Aqueous
NaHCO3 (35 mL) was added and the aqueous phase was extracted with
EtOAc (4ꢄ30 mL). The combined organic extracts were dried over
MgSO4 and evaporated in vacuo. The residue was purified by flash chro-
matography (cyclohexane/EtOAc 4:1) to afford the title compound
(311 mg, 83%): [a]D =+78.3 (c=1.2 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.90 (mc, 5’-H3), 1.26–1.46 (m, 2’-H1, 3’-H2, 4’-H2), superim-
posed with 1.30 (d, J3-Me,3 =7.7 Hz, 3-CH3), 1.48–1.58 (m, 2’-H2), 1.69–1.80
[5] We are unaware of a method allowing the assignment of absolute
configurations to a,b,g-trisubstituted or a,b,g,g-tetrasubstituted D2-
butenolides based on 1H NMR shift differences observed upon the
addition of enantiopure lanthanide shift reagents.
(m, 1’-H2), 2.42 (d, J4-OH,4 =4.9 Hz, 4-OH), 2.61 (qd, J3,3-Me =7.6, J3,4
=
3.8 Hz, 3-H), 4.14 (ddd, J4,4-OH =J4,5 =4.9, J4,3 =3.9 Hz, 4-H), 4.46 (mc, 5-
H) ppm; IR (film): n˜ =3450, 2955, 2930, 2875, 2860, 1760, 1460, 1380,
1355, 1330, 1235, 1205, 1130, 1085, 1045, 1025, 1000, 955 cmꢀ1
.
[6] Reviews: a) B. B. Lohray, Tetrahedron: Asymmetry 1992, 3, 1317–
1349; b) R. A. Johnson, K. B. Sharpless, Asymmetric Catalysis in Or-
ganic Synthesis (Ed.: I. Ojima), VCH, New York, 1993, 227–272;
c) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483–2547; d) G. Poli, C. Scolastico, Methoden Org. Chem.
(Houben-Weyl) 4th ed. 1952–, Vol. E21e (Eds.: G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995,
pp. 4547–4598; e) R. A. Johnson, K. B. Sharpless, Catalytic Asym-
metric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, New York,
2000, 357–389; f) C. Bolm, J. P. Hildebrand, K. Muniz, Catalytic
Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, New
York, 2000, 399–428.
(3S,4S,5S)-4,5-Dihydro-4-hydroxy-3-methyl-5-pentyl-2-(3H)-furanone
(ent-20): The title compound (945 mg, 87%) was prepared from (S,S)-4
(1.0 g, 5.8 mmol, 94% ee) by an analogous procedure to that described
for 20: [a]D =ꢀ74.6 (c=1.5 in CHCl3); elemental analysis calcd (%) for
C10H18O3 (186.3): C 64.50, H 9.74; found: C 64.23, H 9.94.
(5R)-4-Hydroxy-3-methyl-5-pentyl-2-(3H)-furanone (21): At ꢀ788C, tri-
fluoroacetic anhydride (0.47 mL, 0.70 g, 3.3 mmol, 2.0 equiv) was added
to a solution of DMSO (0.41 mL, 0.45 g, 5.8 mmol, 3.5 equiv) in CH2Cl2
(9 mL). After the mixture had been stirred for 30 min, a solution of 20
(309 mg, 1.66 mmol) in CH2Cl2 (9 mL) was added and the mixture was
stirred for 1 h at ꢀ788C. After addition of triethylamine (0.93 mL,
0.67 mg, 6.6 mmol, 4.0 equiv) and stirring for 45 min, H2O (20 mL) was
added and the solution was allowed to reach room temperature. After
the mixture had been stirred for 30 min, the aqueous phase was extracted
with CH2Cl2 (4ꢄ30 mL) and the combined organic extracts were dried
over MgSO4. Evaporation in vacuo followed by flash chromatography
(cyclohexane/EtOAc 2:1) afforded the title compound (281 mg, 92%):
[a]D =+15.6 (c=1.0 in CHCl3).
[7] C. Harcken, R. Brꢀckner, Angew. Chem. 1997, 109, 2866–2868;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2750–2752.
[8] Recent syntheses of enantiomerically pure butanolides include the
following: W. Wang, Y. Zhong, G. Lin, Tetrahedron Lett. 2003, 44,
4613–4616; P. M. Donate, D. Frederico, R. da Silva, M. G. Constan-
tino, G. Del Ponte, P. S. Bonatto, Tetrahedron: Asymmetry 2003, 14,
3253–3256; S. Koul, B. Singh, S. C. Taneja, G. N. Qazi, Tetrahedron
2003, 59, 3487–3491; K. Suzuki, K. Inomata, Y. Endo, Heterocycles
2003, 60, 2743–2748; R. B. Chhor, B. Nosse, S. Sçrgel, C. Bçhm, M.
Seitz, O. Reiser, Chem. Eur. J. 2003, 9, 260–270; H. Miyabe, M.
Ueda, K. Fujii, A. Nishimura, T. Naito, J. Org. Chem. 2003, 68,
(5S)-4-Hydroxy-3-methyl-5-pentyl-2-(3H)-furanone (ent-21): The title
compound (776 mg, 94%) was prepared from ent-20 (831 mg, 4.46 mmol)
by an analogous procedure to that described for 20: [a]D =ꢀ14.5 (c=1.0
in CHCl3); 1H NMR (500 MHz, CDCl3; *,**=interchangeable): d=0.87
Chem. Eur. J. 2005, 11, 2154 – 2162
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2161

R. Brꢀckner, W. A. Kçnig et al.
5618–5626; A. Samarat, H. Amri, Y. Landais, Tetrahedron 2004, 60,
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bonded to dimethylpolysiloxane as a stationary phase.
[14] CCDC-249458 and CCDC-249459 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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[18] Acid (Z)-7 was obtained in isomerically pure form by conjugate ad-
dition (same procedure as in ref. [17]) of Me2CuLi to 2-octynoic
Received: November 10, 2004
Published online: February 15, 2005
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