Bioactive butenolides from Streptomyces antibioticus Tü 99: Absolute configurations and synthesis of analogs

Article abstract of DOI:10.1016/S0040-4020(03)00483-6

The four furanones (butenolides) 1-4, which had been isolated from the fermentation broth of Streptomyces antibioticus Tü 99 and in preliminary tests had been shown to be biologically active, were synthesized by reaction of the readily available furanones 9 or 16 with 2-methylpropanal or 2-methylbutanal. In addition, a series of analogs was prepared in a similar way from 16 using different aldehydes. The hitherto unknown absolute configurations of the natural products 1-4 as well as those of all the analogs prepared were determined with Mosher's NMR method and/or X-ray crystallography. Some of the compounds synthesized proved to be active in the quorum sensing system of Chromobacterium violaceum.

Full text of DOI:10.1016/S0040-4020(03)00483-6

Tetrahedron 59 (2003) 3237–3251
¨
Bioactive butenolides from Streptomyces antibioticus TU 99:
absolute configurations and synthesis of analogs
ˆ
Gilles Grossmann, Marc Poncioni, Marc Bornand, Benoıt Jolivet, Markus Neuburger
*
´
and Urs Sequin
¨
Departement Chemie der Universitat Basel, St Johanns-Ring 19, CH-4056 Basel, Switzerland
Received 18 November 2002; revised 17 February 2003; accepted 15 March 2003
¨
Abstract—The four furanones (butenolides) 1–4, which had been isolated from the fermentation broth of Streptomyces antibioticus TU 99
and in preliminary tests had been shown to be biologically active, were synthesized by reaction of the readily available furanones 9 or 16 with
2-methylpropanal or 2-methylbutanal. In addition, a series of analogs was prepared in a similar way from 16 using different aldehydes. The
hitherto unknown absolute configurations of the natural products 1–4 as well as those of all the analogs prepared were determined with
Mosher’s NMR method and/or X-ray crystallography. Some of the compounds synthesized proved to be active in the quorum sensing system
of Chromobacterium violaceum. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
¨
In the 1960s, the strain Streptomyces antibioticus TU 99 was
characterized with respect to the metabolites produced and
was shown to yield chlorothricin and bromothricin,1 the
juglomycins A and B, ketomycin,2 the nikkomycins Z and
J,1 as well as nocardamine. Later, the strain was reinvesti-
gated using HPLC with photoconductivity detection,3 which
led to the discovery of four new metabolites, the substituted
butenolides 1–4. These butenolides (furanones) showed in
preliminary tests an antibiotic activity against Pseudomonas
as well as a weak inhibition of the chitinase from Serratia
marcescens. However, only small amounts could be isolated
which did neither allow a determination of the absolute
configurations nor permit a more detailed investigation of
the biological properties. Therefore, synthetic routes to this
class of molecules were sought.4
2.1. Syntheses
The synthetic pathway sought not only should yield the
natural metabolites 1–4 but should allow the introduction of
different side chains at C(3). Deliberately, a non-stereo-
selective approach was used, since stereoisomers of
biologically active natural products often allow interesting
conclusions with respect to structure-activity relationships.
The hemiacetalic compounds 1 and 3 epimerize in solution
to mixtures of stereoisomers, which makes their isolation
and characterization tedious; therefore, the first synthetic
targets were compounds 2 and 4, which lack the C(5) OH
group.
Cycloaddition of diazomethane to the commercially
Keywords: butenolides; 2(5H)-furanones; Streptomyces antibioticus; Mosher esters; quorum sensing.
*
Corresponding author. Tel.: þ41-61-2671110; fax: þ41-61-2671103; e-mail: urs.sequin@unibas.ch
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00483-6

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G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
Scheme 1. (a) Et2O, diazomethane, rt, 90%. (b) Dioxane, 1308C, 87%. (c) CH2Cl2, Br2, 408C, 87%. (d) CH2Cl2, sym-collidine, rt, 92%. (e) THF/pentane/Et2O,
tert-BuLi, 2-methylpropanal for 10a/(S)-2-methylbutanal for 10b, 21208C, 57–60%.
available 2(5H)-furanone (5) followed by elimination of
nitrogen gave the methylated furanone 7 (Scheme 1), which
was then transformed to 8 and subsequently to 9 by a
bromination–dehydrobromination process. Halogen-metal
exchange with tert-butyllithium gave a nucleophile,
which now could be added to suitable aldehydes. Reaction
with 2-methylpropanal or (S)-2-methylbutanal gave the
racemate 10a and the pair of diastereomers 10b,
respectively.
mixture of diastereomers, direct separation by HPLC
could be achieved to give natural product 4 and its 10-
epimer 15.
To alleviate the problem of epimerization, the synthesis of
compounds 1 and 3 was started with the menthyl ether 16
(Scheme 3) which is easily accessible in optically pure
form5 from the condensation product of propanal with
glyoxylic acid and (2)-menthol, and where the hemiacetalic
OH group is blocked. Ether 16 was treated with LDA,
which, aided by the large protecting menthyl group, led to
abstraction of H–C(3) rather than of the more activated
H–C(5); the nucleophile thus obtained was reacted with a
variety of aldehydes to give the diastereomeric mixtures
Racemate 10a was esterified with (R)-Mosher acid
chloride (11) to give 12 and 13 (Scheme 2), which could
be separated by HPLC. Saponification then yielded the
natural product 2 and its enantiomer 14. Since 10b was a
Scheme 2. (a) Pyridine, CCl4, rt. (b) HPLC RP-C18, water/MeOH 3:7. (c) Dioxane, 1.2 M NaOH in water, 808C, 1 h. (d) HPLC RP-C18, water/THF 87:13.

G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
3239
Scheme 3. (a) THF, LDA (1.1 equiv.), 2788C, 30 min. (b) Aldehyde, 2788C, 30 min. (c) Flash chromatography SiO2. (d) CH2Cl2, BBr3, 2788C. (e) MeOH,
NaBH4, 08C.
17a–e, which were separated by flash chromatography into
the epimers 18a–e and 19a–e. After removal of the
menthyl group with boron tribromide,6 compounds 1, 3,
20c–e and 21a–e were obtained, respectively; their
reduction with NaBH4 gave eventually 2, 4, 22c–e, 14,
15, and 23c–e, respectively. The synthetic products 1–4
were identical with the natural products originally isolated
from the fermentation broth.
methylbutanal and with (RS)-2-methylbutanal, respectively.
The natural product 4 showed the same retention time as one
of the products obtained from (S)-2-methylbutanal. There-
fore, the C(20) configuration of 4 had to be (S). The same had
to be true for 3, since this compound could be obtained from
4 by reduction with sodium borohydride.
The absolute configurations at C(10) were determined with
Mosher’s empirical NMR method for secondary alcohols.7
Whereas derivatives 12 and 13, which were used in the
resolution of the racemate 10a, were directly suited for the
NMR analysis, compound 4 had to be esterified once with
(R)-Mosher acid chloride (11) and once with (S)-Mosher
acid chloride (24) to give 25 and 26, respectively
(Scheme 4).
2.2. Determination of the configurations
The absolute configuration at C(20) of metabolites 3 and 4
was determined at an early stage of the project by GC
comparison of the natural product 4 with the two product
mixtures obtained from the bromofuranone 9 with (S)-2-

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G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
Scheme 4.
According to Mosher7 the preferred conformation for esters
of a-methoxy-a-trifluoromethylphenylacetic acid (MTPA,
Mosher’s acid) is such that all the bonds between the CF3
group and the hydrogen at the OH bearing carbon of the
alcohol part lie more or less in one plane (the ‘MTPA
plane’8). In this arrangement (Fig. 1), the phenyl group of
the MTPA part shields the protons of that alcohol part which
is in an eclipsed position to it. Thus, a comparison of the
chemical shifts of 12 with the corresponding values for 13
will reveal the absolute configurations. The chemical shift
differences Dd¼d122d13 are compiled in Table 1. They are
negative for the protons of the isopropyl group and positive
for the protons of the furanone part. This is a proof for the
(S)-configuration at C(10) of 12; the same must hold for the
synthetic product 2. In a similar way, chemical shift
comparison of 25 and 26 (Table 1) led to the conclusion
that 25 had the (S) configuration at C(10), which then must
also be the configuration of the synthe0tic compound 4. In
both pairs of isomers, the proton at C(2 ) shows an unusual
behavior. The chemical shift differences observed are
opposite to what is expected. Preliminary calculations
suggested that the furanone ring adopts different orien-
tations in 12 and 13, which might lead to different shieldings
of H–C(20) by the furanone carbonyl group in the two
isomers.9
The correlation between the synthetic products 1–4 and the
metabolites originally isolated was made by comparison of
the NMR spectra and the specific rotations. Since metabolite
2 had been isolated in such a small quantity that the specific
rotation could not be determined, a tiny amount of the
natural product was esterified with (R)-Mosher’s acid
chloride (11); the derivative obtained was identical to 12
1
by 600 MHz H NMR and HPLC.
The configurations in the pairs 18a/19a and 18b/19b were
determined again with Mosher’s method: compounds 19a
and 19b were each derivatized once with (R)-Mosher’s acid
chloride (11) and once with (S)-Mosher’s acid chloride (24)
(Scheme 5). The resulting pairs of esters 27a/28a and 27b/
28b were subjected to NMR analysis as described above
(see chemical shifts in Section 4), which led to the absolute
configurations shown in the schemes.
Finally, compounds 13, 18c,e, 19d, 25, 27a, and 27b gave
crystals that were suitable for X-ray structure determi-
nations. For 18c,e, and 19d these crystal structures were the
anchoring points for the absolute configurations in the
corresponding series of compounds, whereas in the cases of
13, 25, 27a,b corroboration of the configurational assign-
ments made from the NMR measurements was obtained. In
addition, the crystal structures of the MTPA esters
confirmed that the preferred solution conformation (Fig. 1),
which is the basis of Mosher’s method for the determination
of absolute configurations, is also present in the crystal,
although the ‘MTPA plane’ is in some cases somewhat
distorted. The structure of 13 (Fig. 2) is shown as an
example. To our knowledge, the ‘MTPA plane’ has so
far only rarely been visualized by X-ray structure
determinations.8
Figure 1. Preferred conformations for the Mosher esters 12 and 13 (the
torsion angles shown around the bonds leading to the furanone and to the
isopropyl group, respectively, are arbitrary).
Table 1. Chemical shifts and chemical shift differences for selected protons
of the Mosher esters 12, 13, 25, and 26
d of 12 d of 13
(ppm)
Dd
(ppm)
d of 25 d of 26
(ppm)
Dd
(ppm)
(ppm)
(ppm)
Ha–C(5)
Hb–C(5)
CH3–C(4) 2.21
4.92
4.65
4.61
4.57
1.89
þ0.08
þ0.08
þ0.32
20.06
20.17
þ0.07
4.60
4.56
1.90
4.69
4.65
2.11
20.09
20.09
20.21
CH3–C(20) 0.81
CH3–C(20) 0.85
H–C(20)
Ha–C(30)
Hb–C(30)
H–C(40)
0.87
1.02
2.42
0.83
0.77
þ0.06
2.49
2.24
1.63
1.20
0.90
2.33
1.43
1.03
0.80
20.10
þ0.20
þ0.17
þ0.10
2.3. Biological activity
A selection of the compounds prepared were tested for their

G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
3241
Scheme 5.
Figure 2. Crystal structure of 13, stereo view.
biological properties. The weak antimicrobial activity
detected in preliminary tests3 with the natural products
1–4 could not be confirmed; none of the compounds tested
with the agar diffusion method at a concentration of
1 mg/ml showed any activity against a variety of micro-
organisms (6 Gram positive bacteria, 3 Gram negative
bacteria, and 6 fungi).10 However, some of the compounds
proved to interfere with the quorum sensing system of the
Chromobacterium violaceum mutant CV026.11 Furanones
21c,d,e were found to inhibit violacein production when
administered together with an optimal concentration of
N-hexanoylhomoserine lactone (29), the natural signaling
compound of C. violaceum. In contrast, the natural
metabolites 3 and 4 and their diastereoisomers 21b and 15
proved to be activators: they showed a synergistic effect
when administered together with a suboptimal concen-
tration of N-hexanoylhomoserine lactone.12
and to their analogs and stereoisomers. Unfortunately, the
antimicrobial activity observed earlier3 for the natural
products 1–4 could not be confirmed. However, the
interesting behavior in the quorum sensing system of
Chromobacterium violaceum displayed by some of the
furanones described makes this class of compounds a
valuable target for further investigations.
4. Experimental
4.1. General information
Chemicals were bought from Fluka AG, Merck GmbH,
Acros Organics, and Aldrich Chemical Company, Inc. Flash
chromatography: silica gel 60 (0.040–0.063 mm) from
Merck and from Macherey–Nagel. All solvents for flash
chromatography were distilled solvents of a technical
quality. THF was freshly distilled over Na under Ar before
use. The removal of solvents was done under vacuum in a
rotary evaporater. Mp: Bu¨chi 535 apparatus or Kofler hot
stage, uncorrected. Optical rotations: Perkin–Elmer 141
(10 cm cell) and Perkin–Elmer 341 (10 cm cell) at 208C.
NMR Spectra: Varian Gemini 300 (1H: 300 MHz, 13C:
75 MHz), Varian VXR 400 (1H: 400 MHz, 13C: 100 MHz)
Bruker VRX 500 (1H: 500 MHz, 13C 125 MHz); chemical
shifts (d) in ppm downfield from TMS (d¼0.0) as internal
standard; coupling constants J in Hz; in 13C NMR spectra of
Mosher esters, the resonances of the CF3 and of the 48
3. Conclusion
An easy access was found to the natural butenolides 1–4

3242
G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
carbon next to it were not always clearly observed due to the
splitting by JCF and long relaxation times. MS: VG 70–250
(EI, 70 eV) spectrometer and Finnigan MAT 312 (FAB-MS,
matrix: 3-nitrobenzyl alcohol (NBA)). Elemental analyses
were performed by the Microanalytical Laboratory of the
3H, H3C–C(4)). 13C NMR (75 MHz, CDCl3): 174.2; 166.2;
116.4; 74.0; 14.1. EI-MS: 98 (45, Mþ), 84 (10), 70 (10), 69
(100), 68 (20), 41 (59), 40 (34), 39 (41), 38 (14).
4.3.3. 3,4-Dibromo-4,5-dihydro-4-methylfuran-2(3H)-
one 8. To a solution of 7 (3.14 g, 32.0 mmol) in CH2Cl2
(15 ml), a solution of bromine (3.50 ml, 10.9 g, 68.1 mmol)
in CHCl3 (5 ml) was added over 30 min at rt under
protection from light with an aluminum sheet. The resulting
mixture was refluxed for 24 h. After cooling, the excess of
bromine was removed by bubbling argon through the
solution. After the addition of saturated NaHCO3 solution
(20 ml), the aqueous phase was extracted three times with
CH2Cl2. The combined organic phases were dried over
Na2SO4, filtered, and the solvent was evaporated. Flash
chromatography (gradient hexane/CH2Cl2 1:1 B 1:3 B
CH2Cl2) afforded 8 (7.18 g, 27.8 mmol, 87%) as a colorless
liquid. 1H NMR (300 MHz, CDCl3): 4.68 (s, 1H, H–C(3));
4.59 (d, J¼10.9 Hz, 1H, Ha–C(5)); 4.44 (d, J¼10.9 Hz, 1H,
Hb–C(5)); 2.06 (s, 3H, H3C–C(4)). 13C NMR (75 MHz,
CDCl3): 170.5; 78.0; 61.8; 47.9; 25.3. EI-MS: 260 (1), 258
(2), 256 (1, Mþ), 135 (63), 133 (66), 121 (13), 119 (12), 81
(12), 79 (12), 69 (28), 53 (100), 51 (11), 50 (11), 41 (52).
¨
Departement Chemie, Universitat Basel. MPLC: System
Bu¨chi B680 with B687 gradient former, B688 pump and
B684 fraction collector; detection: Knauer variable wave-
length ultraviolet light detector. Preparative HPLC: System
Waters 600 with a pump model 510 (250 ml pump head), a
Photodiode Array Detector 991, and Millenium V 2.01
software from Waters. All solvents were HPLC quality.
4.2. X-Ray structure determinations
Crystals of the compounds under investigation were
mounted on a Nonius KappaCCD or CAD4 diffractometer.
Data collection and integration of the data sets were carried
out using the Nonius collect suite.13 The structures were
solved using direct methods using the program SIR92.14
Least squares refinement was carried out using the program
CRYSTALS.15 Plots were produced using Ortep3 for
Windows.16 Chebychev polynomial weights17 were used
to complete the refinement. Crystallographic data (exclud-
ing structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Center as supplementary publication. CCDC-numbers: 13:
187135; 18c: 187134; 18e: 187132; 19d: 187133; 25:
187136; 27a: 187130; 27b: 187131. Copies of the data can
be obtained, free of charge, on application to the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: þ44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.3.4. 3-Bromo-4-methylfuran-2(5H)-one 9. 2,4,6-Tri-
methylpyridine (9.20 ml, 8.43 g, 69.6 mmol) was added to
a solution of 8 (5.98 g, 23.2 mmol) in CH2Cl2 (250 ml).
After stirring for 1.5 h at rt, the reaction mixture was
successively washed two times with 10% H2SO4 solution
(100 ml), two times with saturated NaHCO3 solution
(100 ml) and once with brine (100 ml). The combined
organic phase was dried over Na2SO4, filtered and the
solvent evaporated. Flash chromatography with a gradient
4.3. Syntheses
hexane/CH2Cl2 1:4 B CH2Cl2 afforded 9 (3.78 g,
21.4 mmol, 92%) as yellow prisms. Mp 65–668C. (Lit.,20
64–658C). 1H NMR (300 MHz, CDCl3): 4.76 (q, J¼0.9 Hz,
2H, H–C(5)); 2.13 (t, J¼0.9 Hz, 3H, H3C–C(4)). 13C NMR
(75 MHz, CDCl3): 169.2; 160.6; 108.9; 73.4; 13.9. EI-MS:
178 (33), 176 (34, Mþ), 149 (94), 147 (100), 121 (62), 119
(80), 117 (16), 97 (20), 93 (12), 81 (19), 79 (20), 68 (10), 67
(63), 66 (18), 53 (45), 52 (12), 51 (33), 50 (41), 49 (15), 41
(22). Anal. calcd for C5H5BrO2 (177.00): C 33.93, H 2.85, O
18.08; found: C 33.75, H 2.95, O 18.14.
4.3.1. 3,3a,4,6a-Tetrahydrofuro[3,4,-c]pyrazol-6-one 6.
A solution of diazomethane (3.00 g, 71.0 mmol) in Et2O
(300 ml) was added with careful stirring to (5H)-furan-2-
one (4.79 g, 57.0 mmol). The reaction mixture was left
overnight at rt. Then, the excess diazomethane was
destroyed with a 5% solution of benzoic acid in Et2O. The
precipitated product was filtered off, washed with Et2O,
dried and recrystallized from warm THF to yield 6 (6.48 g,
51.4 mmol, 90%) as colorless prisms. Mp 109.5–110.58C
(Lit.,18 110.0–110.58C). 1H NMR (400 MHz, CDCl3): 5.58
(ddd, J¼9.3, 2.2, 2.0 Hz, 1H, H–C(6a)); 4.88 (ddd, J¼18.6,
8.0, 2.0 Hz, 1H, Ha–C(3)); 4.83 (ddd, J¼18.6, 3.7, 2.2 Hz,
1H, Hb–C(3)); 4.58 (dd, J¼9.8, 8.7 Hz, 1H, Ha–C(4)); 3.87
(dd, J¼9.8, 4.8 Hz, 1H, Hb–C(4)); 3.14 (m, 1H, H–C(3a)).
13C NMR (75 MHz, CDCl3): 168.7; 93.2; 86.4; 73.0; 31.0.
EI-MS: 70 (12), 69 (100), 68 (80), 55 (16), 54 (14), 53 (13),
42 (58), 41 (81), 40 (67), 39 (82), 39 (14).
4.3.5. 3-[(RS)-1-Hydroxy-2-methylpropyl]-4-methyl-
furan-2(5H)-one 10a.
A
solution of
9
(710 mg,
4.01 mmol) in a mixture of absolute THF (60 ml), pentane
(15 ml) and absolute Et2O (15 ml) under argon was cooled
to 21208C (EtOH/N2). Under vigorous stirring, a 1.3 M
solution of tert-butyllithium in hexane (3.09 ml, 4.01 mmol)
was quickly added. After 1 min, 2-methylpropanal (366 ml,
289 mg, 4.01 mmol) was added. The reaction mixture was
allowed to warm up to 2108C over 3 h, and the reaction was
quenched with a saturated (NH4)2SO4 solution (30 ml). The
two-phase system was acidified with conc. HCl to pH 2–3.
The aqueous phase was separated and extracted two times
with CH2Cl2, and the combined organic phases were dried
over Na2SO4, filtered and the solvent evaporated. A first
purification with MPLC (LiChroPrep 25–40; eluent A, 95%
water/5% MeOH, eluant B, MeOH; gradient 0 min (100:0),
10 min (100:0), 60 min (0:100); tR¼38–40 min) followed
by HPLC (Eurospher 100-7 RP-C18; water/THF (85:15),
tR¼19–22 min) afforded 10a (387 mg, 2.27 mmol, 57%) as
4.3.2. 4-Methylfuran-2(5H)-one 7. A solution of 6 (2.50 g,
19.8 mmol) in dioxane (25 ml) was heated for 1 h at 708C.
The temperature of the oil bath was incrementally raised by
208C/h up to 1308C. Then, the reaction was refluxed for
48 h. After cooling down, the solvent was distilled off under
reduced pressure; vacuum distillation of the crude product
gave 7 (1.69 g, 17.2 mmol, 87%) as a colorless, hygroscopic
liquid. Bp 101–1038C [12 mbar] (Lit.,19 105–1078C
1
[15 mbar]). H NMR (300 MHz, CDCl3): 5.86–5.83 (m,
1H, H–C(3)); 4.74–4.72 (m, 2H, H–C(5)); 2.15–2.13 (m,

G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
3243
1
a colorless, viscous oil. H NMR (300 MHz, CDCl3): 4.70
57 (14), 55 (10), 43 (17), 41 (10). Anal. calcd for
C19H21F3O5 (386.37): C 59.06, H 5.48, O 20.71; found: C
59.05, H 5.55, O 20.70. Crystal data: crystallized from
hexane/CH2Cl2; Mr: 386.37 g/mol; crystal system: ortho-
(d, J¼17.3 Hz, 1H, Ha–C(5)); 4.67 (d, J¼17.3 Hz, 1H,
Hb–C(5)); 4.14 (d, J¼8.0 Hz, 1H, H–C(10)); 3.13 (br, 1H,
HO–C(10)); 2.09 (s, 3H, H3C–C(4)); 2.08–1.97 (m, 1H,
H–C(20)); 1.05 (d, J¼6.7 Hz, 3H, H–C(30)); 0.84 (d,
J¼6.8 Hz, 3H, H3C–C(20)). 13C NMR (75 MHz, CDCl3):
174.3; 158.5; 127.4; 72.8; 72.4; 33.9; 18.8; 18.5; 12.5. FAB-
MS (NBA): 172 (10), 171 (100, [MþH]þ), 153 (62), 71
(10), 57 (25), 55 (16), 43 (30), 41 (13). Anal. calcd for
C9H14O3 (170.21): C 63.51, H 8.29, O 28.20; found: C
63.11, H 8.11, O 28.31.
˚
rhombic; space group: P212121; a: 9.402(1) A; b:
˚
˚
10.634(2) A; c: 19.152(4) A; a: 908; b: 908; g: 908; V:
3
1914.9(5) A ; Z: 4; F(000): 808; density: 1.34 g/cm23; m:
˚
0.11 mm21; crystal size: 0.30£0.50£0.70 mm3; tempera-
ture: 293 K; radiation type: Mo Ka wavelength: 0.71073 l;
instrument: CAD4; umax: 30.448; no. of measured reflec-
tions: 2795; no. of independent reflections: 2782; no. of
reflections in refinement: 2100; no. of variables: 245; final
R: 0.0385; final Rw: 0.0424; weighting scheme: Chebychev
polynomial; last max/min in difference map:
4.3.6. (1S)-1-(4-Methyl-2-oxo-2,5-dihydrofuran-3-yl)-2-
methylpropyl (2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate 12 and (1R)-1-(4-methyl-2-oxo-2,5-dihydro-
furan-3-yl)-2-methylpropyl (2S)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate 13. (2R)-3,3,3-Trifluoro-2-
methoxy-2-phenylpropanoyl chloride ((R)-Mosher’s acid
chloride, 11) (100 mg, 0.396 mmol) was dissolved at rt in
abs. pyridine (1 ml) under argon. A solution of 10a
(48.2 mg, 0.283 mmol) in abs. CCl4 (1 ml) was added at rt
and the resulting mixture was stirred at this temperature for
24 h. Then, 3-dimethylamino-1-propylamine (84.0 ml,
68.5 mg, 0.671 mmol) was added and the resulting solution
was stirred for further 15 min. After the addition of Et2O
(5 ml), the solution was washed with cold 1N HCl, saturated
NaHCO3 solution, and brine. The combined organic phases
were dried over Na2SO4, filtered, and the solvent was
evaporated. Purification and separation of the diastereo-
isomers with HPLC (Eurospher 100-7 RP-C18; water/
MeOH 30:70; tR 12¼16.5–20.0 min, tR 13¼20.5–
21.5 min) gave 12 (34.6 mg, 0.090 mmol, 32%) and 13
(37.4 mg, 0.097 mmol, 34%) as cubes.
0.21/20.22 eA23; CCDC-number; 187135.
˚
4.3.7. 3-[(1S)-1-Hydroxy-2-methylpropyl]-4-methyl-
furan-2(5H)-one 2. Compound 12 (35 mg, 0.091 mmol)
was dissolved in a mixture of dioxane (12 ml) and 1.2 M
NaOH in water (12 ml). The solution was heated at 808C for
1 h. After cooling, the mixture was acidified (pH ,3) with
diluted HCl and extracted 3£ with Et2O (60 ml). The
combined organic phases were dried over Na2SO4, filtered,
and the solvent was evaporated. Purification with HPLC
(Eurospher 100-7 RP-C18; eluent: water/MeOH gradient
0 min (50:50) 30 min (0:100); tR 2¼9.4 min) gave 2
(8.00 mg, 0.047 mmol, 52%) as a colorless oil. [a]2D0¼
216.5 (c¼1.00, MeOH). 1H NMR (500 MHz, CDCl3): 4.71
(d, J¼17.3 Hz, 1H, Ha–C(5)); 4.66 (d, J¼17.3 Hz, 1H,
Hb–C(5)); 4.14 (d, J¼7.9 Hz, 1H, H–C(10)); 3.13 (br, 1H,
HO–C(10)); 2.09 (s, 3H, H3C–C(4)); 2.08–1.98 (m, 1H,
H–C(20)); 1.04 (d, J¼6.7 Hz, 3H, (H3C)2–C(20)); 0.84 (d,
J¼6.7 Hz, 3H, (H3C)2–C(20)). 13C NMR (125 MHz,
CDCl3): 174.2; 158.5; 127.3; 72.7; 72.3; 33.7; 18.7; 18.3;
12.4. EI-MS: 152 (10), 128 (23), 127 (100), 110 (36), 109
(12), 99 (24), 82 (32), 53 (14), 43 (29), 41 (17), 39 (15).
Anal. calcd for C9H14O3 (170.21): C 63.51, H 8.29, O 28.20;
found: C 63.22, H 8.33, O 28.27.
Data of (1S)-1-(4-Methyl-2-oxo-2,5-dihydrofuran-3-yl)-2-
methylpropyl (2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate (12). Mp 85.7–88.28C. [a]2D0¼260.0 (c¼1.04,
1
MeOH). H NMR (300 MHz, CDCl3): 7.53–7.37 (m, 5H,
phenyl); 5.35 (d, J¼9.2 Hz, 1H, H–C(10)); 4.69 (d,
J¼17.3 Hz, 1H, Ha –C(5)); 4.65 (d, J¼17.3 Hz, 1H,
Hb–C(5)); 3.52 (s, 3H, H3CO–C(200)); 2.53–2.44 (m, 1H,
H–C(20)); 2.21 (s, 3H, H3C–C(4)); 0.85 (d, J¼6.6 Hz, 3H,
H–C(30)); 0.81 (d, J¼6.8 Hz, 3H, H3C–C(20)). 13C NMR
(75 MHz, CDCl3): 171.9; 166.2; 162.9; 131.9; 129.7; 128.4;
4.3.8. 3-[(1R)-1-Hydroxy-2-methylpropyl]-4-methyl-
furan-2(5H)-one 14. Same procedure as for 2. Compound
13 (42.0 mg, 0.109 mmol) afforded 14 (10.0 mg,
0.059 mmol, 54%) as a colorless oil. [a]2D0¼þ17.0
1
(c¼1.00, MeOH). H NMR (500 MHz, CDCl3): 4.71 (d,
1
2
127.3; 123.8; 123.3 (q, JCF¼287 Hz); 84.5 (q, JCF
¼
J¼17.3 Hz, 1H, Ha–C(5)); 4.66 (d, J¼17.3 Hz, 1H,
Hb–C(5)); 4.14 (t, J¼8.7 Hz, 1H, H–C(10)); 3.10 (d,
J¼9.4 Hz, 1H, HO–C(10)); 2.08 (s, 3H, H3C–C(4));
2.08–2.00 (m, 1H, H–C(20)); 1.05 (d, J¼6.7 Hz, 3H,
28 Hz); 75.6; 72.5; 55.6; 29.9; 18.7; 18.4; 12.7. FAB-MS
(NBA): 387 (10, [MþH]þ), 189 (12), 153 (100), 57 (22), 55
(15), 43 (24), 41 (13). Anal. calcd for C19H21F3O5 (386.37):
C 59.06, H 5.48, O 20.71; found: C 58.85, H 5.71, O 20.70.
(H3C)2–C(20)); 0.84 (d, J¼6.7 Hz, 3H, (H3C)2–C(20)). 13
C
NMR (125 MHz, CDCl3): 174.2; 158.3; 127.4; 72.7; 72.4;
33.8; 18.8; 18.4; 12.4. EI-MS: 152 (12), 128 (23), 127 (100),
110 (36), 109 (13), 99 (24), 82 (31), 53 (14), 43 (29), 41
(18), 39 (15). Anal. calcd for C9H14O3 (170.21): C 63.51, H
8.29, O 28.20; found: C 63.21, H 8.38, O 28.60.
Data of (1R)-1-(4-Methyl-2-oxo-2,5-dihydrofuran-3-yl)-2-
methylpropyl (2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate (13). Mp 87.2–90.48C. [a]2D0¼22.9 (c¼2.18,
1
MeOH). H NMR (300 MHz, CDCl3): 7.47–7.37 (m, 5H,
phenyl); 5.41 (d, J¼9.0 Hz, 1H, H–C(10)); 4.61 (d,
J¼17.3 Hz, 1H, Ha –C(5)); 4.57 (d, J¼17.3 Hz, 1H,
Hb–C(5)); 3.55 (s, 3H, H3CO–C(200)); 2.49–2.34 (m, 1H,
H–C(20)); 1.89 (s, 3H, H3C–C(4)); 1.02 (d, J¼6.6 Hz, 3H,
H–C(30)); 0.87 (d, J¼6.8 Hz, 3H, H3C–C(20)). 13C NMR
(75 MHz, CDCl3): 172.0; 166.1; 162.0; 131.8; 129.7; 128.4;
4.3.9. Mixture 10b: 3-[(1S,2S)-1-hydroxy-2-methyl-
butyl]-4-methylfuran-2(5H)-one 4 and 3-[(1R,2S)-1-
hydroxy-2-methylbutyl]-4-methylfuran-2(5H)-one 15.
Compound 9 (400 mg, 2.26 mmol) was coupled with (S)-
2-methylbutanal21 (237 ml, 195 mg, 2.26 mmol) using the
procedure given for 10a to yield mixture 10b. A first
purification with MPLC (LiChroPrep 25–40; eluent A, 95%
water/5% MeOH, eluant B, MeOH; gradient 0 min (100:0),
1
127.3; 124.0; 123.2 (q, JCF¼287 Hz); 84.6 (q,
2JCF¼28 Hz); 75.8; 72.4; 55.7; 30.5; 18.9; 18.5; 12.5.
FAB-MS (NBA): 387 (10, [MþH]þ), 189 (13), 153 (100),

3244
G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
10 min (100:0), 60 min (0:100); tR 10b¼44–46 min)
followed by a separation with HPLC (Eurospher 100-7
RP-C18; water/THF (87:13), tR 4¼18.0–19.5 min and
tR 15¼19.5–22.0 min) afforded 4 (182 mg, 0.998 mmol,
44%) and 15 (74.2 mg, 0.403 mmol, 18%) as colorless
oils.
Data of (5R)-3-[(1R)-1-hydroxy-2-methylpropyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one (18a). Mp 82.0 – 83.58C.
[a]2D0¼2130.5 (c¼1.00, CHCl3, stab. 1% EtOH). 1H
NMR (500 MHz, CDCl3): 5.75 (s, 1H, H–C(5)); 4.13 (t,
J¼8.4 H0z0 , 1H, H–C(100)); 2.89 (d, J¼9.1 Hz, 1H,
HO–C(1 )); 2.05–1.97 (m, 1H, H–C(200)); 1.99 (s, 3H,
H3C–C(4)); 1.04 (d, J¼6.6 Hz, 3H, (H3C)2–C(200)); 0.84 (d,
J¼6.9 Hz, 3H, (H3C)2–C(200)). Menthyl resonances: 3.63;
2.16–2.12; 2.12–2.08; 1.72–1.67; 1.67–1.63; 1.36; 1.29–
1.22; 1.07–0.99; 1.03–0.98; 0.96; 0.91–0.82; 0.88; 0.80.
13C NMR (125 MHz, CDCl3): 171.6; 156.4; 129.9; 100.6;
72.4; 33.9; 18.8; 18.3; 11.7. Menthyl resonances: 79.4; 47.7;
40.4; 34.2; 31.4; 25.2; 23.1; 22.2; 20.8; 15.7. EI-MS: 281
(10), 168 (15), 152 (64), 144 (17), 143 (38), 141 (27), 140
(12), 139 (77), 138 (11), 137 (12), 127 (71), 126 (56), 123
(11), 97 (28), 95 (27), 83 (100), 81 (36), 71 (20), 69 (65), 67
(15), 57 (33), 55 (59), 43 (64), 41 (52), 39 (11). Anal. calcd
for C19H32O4 (324.46): C 70.33, H 9.94, O 19.72; found: C
70.54, H 10.04, O 19.48.
Data of 3-[(1S,2S)-1-hydroxy-2-methylbutyl]-4-methyl-
furan-2(5H)-one (4). [a]2D0¼234.0 (c¼1.35, MeOH) (nat.
prod.3: [a]2D3¼210.4 (c¼0.31, MeOH)). 1H NMR
(500 MHz, CDCl3): 4.71 (d, J¼17.3 Hz, 1H, Ha–C(5));
4.66 (d, J¼17.3 Hz, 1H, Hb–C(5)); 4.21 (t, J¼8.3 Hz, 1H,
H–C(10)); 2.09 (s, 3H, H3C–C(4)); 1.88–1.81 (m, 1H,
H–C(20)); 1.80–1.73 (m, 1H, Ha–C(30)); 1.25–1.15 (m,
1H, Hb–C(30)); 0.93 (t, J¼7.5 Hz, 3H, H–C(40)); 0.79 (d,
J¼6.8 Hz, 3H, H3C–C(20)). 13C NMR (125 MHz, CDCl3):
174.3; 158.5; 127.4; 72.7; 70.9; 39.9; 24.6; 14.9; 12.4; 10.7.
EI-MS: 128 (31), 127 (100), 110 (65), 99 (21), 82 (42), 53
(13), 43 (15), 41 (21), 39 (14). Anal. calcd for C10H16O3
(184.24): C 65.19, H 8.75, O 26.05; found: C 65.17, H 8.79,
O 26.10.
Data of (5R)-3-[(1S)-1-hydroxy-2-methylpropyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one (19a). Mp 51.5 – 53.08C.
[a]2D0¼2111.0 (c¼1.00, CHCl3, stab. 1% EtOH). 1H
NMR (500 MHz, CDCl3): 5.70 (s, 1H, H–C(5)); 4.09 (dd,
J¼9.7 Hz, 8.1, 1H, H–C(100)); 2.97 (d, J¼9.7 Hz, 1H,
HO–C(100)); 2.05–1.98 (m, 1H, H–C(200)); 1.96 (s, 3H,
H3C–C(4)); 1.04 (d, J¼6.6 Hz, 3H, (H3C)2–C(200)) 0.84 (d,
J¼6.9 Hz, 3H, (H3C)2–C(200)). Menthyl resonances: 3.62;
2.14–2.08; 2.08–2.05; 1.77–1.66; 1.66–1.63; 1.46–1.36;
1.28–1.21; 1.07–0.94; 1.03–0.98; 0.95; 0.91–0.82; 0.80.
13C NMR (125 MHz, CDCl3): 171.7; 156.3; 129.7; 100.8;
72.6; 34.1; 18.8; 18.5; 11.8. Menthyl resonances: 79.4; 47.7;
40.4; 34.2; 31.4; 25.5; 23.3; 22.2; 20.8; 16.0. EI-MS: 281
(11), 168 (11), 152 (59), 144 (11), 143 (44), 141 (25), 140
(12), 139 (85), 137 (11), 127 (66), 126 (43), 123 (12), 97
(28), 95 (24), 83 (100), 81 (34), 71 (19), 69 (62), 67 (14), 57
(33), 55 (54), 43 (59), 41 (49). Anal. calcd for C19H32O4
(324.46): C 70.33, H 9.94, O 19.72; found: C 70.56, H 9.86,
O 19.68.
Data of 3-[(1R,2S)-1-hydroxy-2-methylbutyl]-4-methyl-
1
furan-2(5H)-one (15) [a]2D0¼þ17.0 (c¼1.00, MeOH). H
NMR (500 MHz, CDCl3): 4.70 (d, J¼17.3 Hz, 1H,
Ha–C(5)); 4.65 (d, J¼17.3 Hz, 1H, Hb–C(5)); 4.29 (t,
J¼8.5 Hz, 1H, H–C(10)); 3.06 (d, J¼9.2 Hz, 1H,
HO–C(10)); 2.08 (s, 3H, H3C–C(4)); 1.80–1.71 (m, 1H,
H–C(20)); 1.43–1.34 (m, 1H, Ha–C(30)); 1.30–1.10 (m,
1H, Hb–C(30)); 1.00 (d, J¼6.7 Hz, 3H, H3C–C(20)); 0.91 (t,
J¼7.4 Hz, 3H, H–C(40)). 13C NMR (125 MHz, CDCl3):
174.3; 158.1; 127.5; 72.7; 71.0; 40.4; 25.6; 14.6; 12.5; 11.5.
EI-MS: 128 (40), 127 (100), 110 (67), 99 (23), 82 (47), 53
(15), 43 (19), 41 (24), 39 (15). Anal. calcd for C10H16O3
(184.24): C 65.19, H 8.75, O 26.05; found: C 65.21, H 8.80,
O 26.32.
4.3.10. Mixture 17a: (5R)-3-[(1R)-1-hydroxy-2-methyl-
propyl]-5-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-
oxy}-4-methylfuran-2(5H)-one 18a and (5R)-3-[(1S)-1-
hydroxy-2-methylpropyl]-5-{[(1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl]oxy}-4-methylfuran-2(5H)-one 19a. A
solution of freshly distilled diisopropylamine (1.83 ml,
1.30 g, 12.8 ml) in freshly distilled THF (90 ml) was cooled
to 08C under argon. n-BuLi in hexane (8.60 ml, 12.8 mmol)
was added dropwise over 30 min and the resulting solution
was stirred for 30 min at 08C. Then, the mixture was cooled
to 2788C and a solution of 165 (2.70 g, 10.7 mmol) in THF
(5 ml) was added dropwise during 30 min and the resulting
solution was stirred for 30 min with the apparition of an
orange color. Freshly distilled 2-methylpropanal (1.07 ml,
0.85 g, 11.8 mmol) was added dropwise during 30 min and
the solution was stirred for further 30 min. After warm-up to
2208C, the reaction was quenched with saturated NH4Cl
solution (50 ml) and the mixture was extracted three times
with CH2Cl2 (150 ml), washed with saturated NaHCO3
solution, brine and water, dried over MgSO4, filtered and the
solvent evaporated. Flash chromatography with CH2Cl2
afforded 2.70 g (8.33 mmol, 78%) of the mixture 17a. A
second flash chromatography with AcOEt/hexane 1:5 as
eluent afforded 18a (1.43 g, 4.41 mmol, 41%) as colorless
plates and 19a (1.27 g, 3.92 mmol, 37%) as colorless plates,
too.
4.3.11. Mixture 17b: (5R)-3-[(1S,2S)-1-hydroxy-2-
methylbutyl]-5-{[(1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyl]oxy}-4-methylfuran-2(5H)-one 18b and (5R)-3-
[(1R,2S)-1-hydroxy-2-methylbutyl]-5-{[(1R,2S,5R)-2-iso-
propyl-5-methylcyclohexyl]oxy}-4-methylfuran-2(5H)-
one 19b. Same procedure as for 17a. 16 (15.0 g, 59.6 mmol)
was coupled with (S)-methylbutanal21 (4.73 g, 65.4 mmol).
The second flash chromatography was performed with a
mixture of tert-butyl methyl ether/hexane 1:4 as eluant and
afforded 18b (3.80 g, 11.2 mmol, 19%) as colorless star-
shaped crystals and 19b (4.60 g, 13.6 mmol, 23%) as
colorless star-shaped crystals, too.
Data of (5R)-3-[(1S,2S)-1-hydroxy-2-methylbutyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one (18b). Mp 61.5 – 63.58C.
[a]2D0¼2153.5 (c¼1.00, CHCl3, stab. 1% EtOH). 1H
NMR (500 MHz, CDCl3): 5.75 (s, 1H, H–C(5)); 4.18 (t,
J¼8.5 H0z0 , 1H, H–C(100)); 2.81 (d, J¼9.2 Hz, 1H,
HO–C(1 )); 1.98 (s, 3H, H3C–C(4)); 1.86–1.74 (m, 2H,
H–C(200), Ha–C(300)); 1.29–1.23 (m, 1H, Hb–C(300)); 0.93

G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
3245
(t, J¼7.3 0H0 z, 3H, H–C(400)); 0.79 (d, J¼7.0 Hz, 3H,
H3C–C(2 )). Menthyl resonances: 3.63; 2.16–2.12;
2.12–2.08; 1.72–1.67; 1.67–1.62; 1.46–1.37; 1.23–1.15;
1.09–1.00; 1.00–0.96; 0.96; 0.91–0.82; 0.88; 0.80. 13C
NMR (125 MHz, CDCl3): 171.7; 156.3; 130.0; 100.6; 71.2;
40.1; 24.7; 15.0; 11.7; 11.0. Menthyl resonances: 79.4; 47.7;
40.4; 34.2; 31.4; 25.2; 23.1; 22.2; 20.8; 15.8. EI-MS: 281
(12), 182 (11), 166 (21), 144 (30), 143 (34), 139 (73), 137
(11), 127 (48), 126 (53), 110 (16), 97 (25), 95 (17), 83 (100),
81 (26), 71 (11), 69 (51), 67 (11), 57 (48), 55 (44), 43 (26),
41 (38). Anal. calcd for C20H34O4 (338.49): C 70.97, H
10.12, O 18.91; found: C 70.92, H 10.23, O 18.92.
Data of (5R)-3-[(1R)-1-hydroxyethyl]-5-{[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl]oxy}-4-methylfuran-2(5H)-
one (19c). Mp 86.9–87.38C. [a]2D0¼2118.5 (c¼1.00,
CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3):
5.69 (s, 1H, H–C(5)); 4.68 (dq, J¼8.1 H0z0 , 6.8, 1H,
H–C(100)); 2.92 (d, J¼6.7 Hz, 1H, HO–C(1 00)); 2.00 (s,
3H, H3C–C(4)); 1.48 (d, J¼6.7 Hz, 3H, H–C(2 )). Menthyl
resonances: 3.62; 2.16–2.08; 1.72–1.64; 1.46–1.37; 1.29–
1.21; 1.09–0.85; 0.96; 0.88; 0.81. 13C NMR (125 MHz,
CDCl3): 171.3; 154.6; 131.4; 101.0; 63.1; 22.8; 11.4.
Menthyl resonances: 79.7; 47.7; 40.5; 34.2; 31.4; 25.1;
23.0; 22.2; 20.9; 15.7. EI-MS: 141 (25), 140 (11), 139 (14),
138 (23), 137 (20), 124 (100), 113 (12), 99 (33), 95 (26), 83
(42), 81 (48), 69 (33), 67 (15), 57 (18), 55 (31), 43 (43), 41
(26). Anal. calcd for C17H28O4 (296.41): C 68.89, H 9.52, O
21.59; found: C 68.87, H 9.57, O 21.63.
Data of (5R)-3-[(1R,2S)-1-hydroxy-2-methylbutyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one (19b). Mp 51.0 – 52.58C.
[a]2D0¼2117.5 (c¼1.00, CHCl3, stab. 1% EtOH). 1H
NMR (500 MHz, CDCl3): 5.70 (s, 1H, H–C(5)); 4.26 (t,
J¼7.3 Hz, 1H, H–C(100)); 3.01 (d, J¼9.1 Hz, 1H,
HO – C(100)); 2.15 – 2.09 1.98 (s, 3H, H3C – C(4));
1.79–1.72 (m, 2H, H–C(200), Ha–C(300)); 1.46–1.36 (m,
1H, Hb–C(300)); 0.99 (d, J¼6.7 Hz, 3H, H3C–C(200)); 0.90
(t, J¼7.4 Hz, 3H, H–C(400)). Menthyl resonances: 3.63;
2.15–2.09; 2.08–2.05; 1.77–1.71; 1.71–1.64; 1.46–1.36;
1.29–1.22; 1.11–1.05; 1.05–1.00; 0.96; 0.91–0.82; 0.88;
0.81. 13C NMR (125 MHz, CDCl3): 171.7; 156.1; 129.9;
100.8; 71.1; 40.6; 25.4; 14.4; 11.7; 11.5. Menthyl
resonances: 79.4; 47.6; 40.4; 43.2; 31.4; 25.5; 23.3; 22.2;
20.7; 15.9. EI-MS: 281 (12), 182 (12), 166 (18), 144 (19),
143 (34), 139 (71), 127 (40), 126 (40), 110 (13), 97 (26), 95
(17), 83 (100), 81 (25), 71 (10), 69 (50), 67 (11), 57 (47), 55
(44), 43 (25), 41 (37). Anal. calcd for C20H34O4 (338.49): C
70.97, H 10.12, O 18.91; found: C 70.92, H 10.28, O 18.91.
4.3.13. Mixture 17d: (5R)-3-[(1S)-hydroxypropyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one 18d and (5R)-3-[(1R)-hydroxy-
propyl]-5-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-
oxy}-4-methylfuran-2(5H)-one 19d. Same procedure as
for 17a. 16 (15.0 g, 59.6 mmol) was coupled with
propionaldehyde (6.10 ml, 83.3 mmol). Two flash chroma-
tographies were performed with a mixture of tert-butyl
methyl ether/AcOEt/hexane 1:4:15 as eluent and afforded
18d (2.20 g, 7.10 mmol, 12%) as colorless cubes and 19d
(2.60, g 8.38 mmol, 14%) as colorless cubes, too.
Data of (5R)-3-[(1S)-1-hydroxypropyl]-5-{[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl]oxy}-4-methylfuran-2(5H)-
one (18d). Mp 116.3–116.58C. [a]2D0¼2156.0 (c¼1.00,
CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3): 5.72
(s, 1H, H–C(5)); 4.41 (td, J¼8.30H0 z, 7.2, 1H, H–C(100));
2.81 (d, J¼8.8 Hz, 1H, HO–C(1 )); 1.99 (s, 3H, H3C–
C(4)); 1.89–1.80 (m, 1H, Ha–C(200)); 1.76–1.69 (m, 1H,
Hb–C(200)); 0.94 (t, J¼7.4 Hz, 3H, H–C(300)). Menthyl
resonances: 3.62; 2.16–2.08; 1.69–1.62; 1.47–1.37; 1.29–
1.22; 1.08–0.93; 0.96; 0.87; 0.80. 13C NMR (125 MHz,
CDCl3): 171.4; 155.7; 130.4; 100.7; 68.3; 29.6; 11.4; 9.9.
Menthyl resonances: 79.5; 47.7; 40.4; 34.2; 31.4; 25.1; 23.0;
22.2; 20.9; 15.7. EI-MS: 281 (14), 155 (25), 154 (15), 143
(30), 139 (55), 138 (100), 127 (30), 126 (11), 97 (14), 95
(26), 95 (26), 83 (63), 81 (48), 69 (40), 67 (11), 57 (48), 57
(48), 55 (43), 43 (26), 41 (42). Anal. calcd for C18H30O4
(310.44): C 69.64, H 9.74, O 20.62; found: C 69.51, H 9.56,
O 20.50.
4.3.12. Mixture 17c: (5R)-3-[(1S)-1-hydroxyethyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one 18c and (5R)-3-[(1R)-1-hydro-
xyethyl]-5-{[(1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyl]oxy}-4-methylfuran-2(5H)-one
19c.
Same
procedure as for 17a. 16 (15.0 g, 59.6 mmol) was coupled
with acetaldehyde (4.70 ml, 83.3 mmol). Two flash
chromatographies were performed with a mixture of tert-
butyl methyl ether/AcOEt/hexane 1:4:15 as eluent and
afforded 18c (4.00 g, 13.5 mmol, 23%) as colorless cubes
and 19c (3.20 g, 10.8 mmol, 18%) as colorless cubes, too.
Data of (5R)-3-[(1S)-1-hydroxyethyl]-5-{[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl]oxy}-4-methylfuran-2(5H)-
one (18c). Mp 101.0–101.68C. [a]2D0¼2162.0 (c¼1.00,
CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3): 5.69
(s, 1H, H–C(5)); 4.70 (dq, J¼7.2 Hz, 006.8, 1H, H–C(100));
2.87 (d, J¼8.0 Hz, 1H, HO–C(1 )); 2.000 1 (s, 3H,
H3C–C(4)); 1.47 (d, J¼6.7 Hz, 3H, H–C(2 )). Menthyl
resonances: 3.62; 2.17–2.08; 1.72–1.64; 1.46–1.37;
1.29–1.21; 1.08–0.85; 0.96; 0.88; 0.80. 13C NMR
(125 MHz, CDCl3): 171.4; 154.7; 131.6; 100.8; 63.0;
22.6; 11.4. Menthyl resonances: 79.5; 47.7; 40.4; 34.2;
31.4; 25.1; 23.0; 22.2; 20.9; 15.7. EI-MS: 141 (27), 140
(11), 139 (14), 138 (24), 137 (23), 124 (100), 113 (14),
99 (33), 95 (29), 83 (36), 81 (52), 69 (31), 67 (15), 57 (17),
55 (31), 43 (53), 41 (25). Anal. calcd for C17H28O4 (296.41):
C 68.89, H 9.52, O 21.59; found: C 68.96, H 9.27, O
21.70.
Data of (5R)-3-[(1R)-1-hydroxypropyl]-5-{[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl]oxy}-4-methylfuran-2(5H)-
one (19d). Mp 91.6–91.98C. [a]2D0¼2121.0 (c¼1.00,
CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3):
5.70 (s, 1H, H–C(5)); 4.40 (td, J¼9.2, 7.1 Hz, 1H,
H–C(100)); 2.91 (d, J¼9.3 Hz, 1H, HO–C(100)); 1.98 (s,
3H, H3C–C(4)); 1.90–1.81 (m, 1H, Ha–C(200)); 1.78–1.71
(m, 1H, Hb–C(200)); 0.94 (t, J¼7.3 Hz, 3H, H–C(300)).
Menthyl resonances: 3.63; 2.14–2.08; 1.71–1.62;
1.47–1.37; 1.29–1.22; 1.07–0.92; 0.96; 0.88; 0.81. 13C
NMR (125 MHz, CDCl3): 171.5; 155.7; 130.3; 100.9; 68.4;
29.8; 11.5; 9.8. Menthyl resonances: 79.6; 47.7; 40.4; 34.2;
31.4; 25.3; 23.2; 22.2; 20.8; 15.8. EI-MS: 281 (11), 155
(24), 154 (13), 143 (37), 139 (64), 138 (100), 137 (19), 127
(32), 97 (15), 95 (27), 83 (77), 81 (52), 69 (41), 67 (11), 57

3246
G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
(49), 55 (42), 43 (20), 41 (35). Anal. calcd for C18H30O4
(310.44): C 69.64, H 9.74, O 20.62; found: C 69.40, H 9.69,
O 20.64.
solvent was evaporated. Flash chromatography with AcOEt/
hexane 1:1 afforded 1 (1.80 g, 9.68 mmol, 79%) as colorless
amorphous solid. This amorphous product was crystallized
from AcOEt/hexane to afford 1 (1.60 g, 8.60 mmol, 70%,
mixture of epimers) as colorless plates. Mp 103.5–105.08C.
[a]D20¼216.0 (c¼1.00, MeOH) (nat. prod.3: [a]2D3¼214.6
(c¼0.31, MeOH)). 1H NMR (500 MHz, CDCl3): 5.90–5.85
(m, 2£1H, H–C(51 and 2)); 5.25 (d, J¼9.3 Hz, 1H, HO–
C(551 or 2)); 5.05 (d, J¼9.3 Hz, 1H, HO–C(52 or 1));
4.15–4.05 (m, 2£1H, H–C(101 and 2)0); 3.33 (br, 1H, HO–
C(101 or 2)); 3.09 (br, 1H, HO–C(1 2 or 1)); 2.08 (s, 3H,
H3C–C(41 or 2)); 2.06 (s, 3H, H3C–C(42 or 1)); 2.05–1.95
(m, 02£1H, H–C(201 and 2)); 1.04 (d, J¼6.6 Hz, 3H, (H3C)2–
C(2 1 or 2)); 1.03 (d, J¼6.6 Hz, 3H, (H3C)2–C(202 or 1));
0.85 (d, J¼6.8 Hz, 3H, (H3C)2–C(201 or 2)); 0.83 (d,
J¼6.8 Hz, 3H, (H3C)2–C(202 or 1)). 13C NMR (125 MHz,
CDCl3): 172.1; 172.0; 158.5; 129.7; 129.2; 98.9; 98.8; 72.3;
72.2; 33.9; 33.5; 18.7; 18.5; 18.4; 11.9; 11.6. EI-MS: 168
(12), 153 (32), 143 (23), 135 (20), 126 (38), 125 (17), 109
(10), 99 (21), 98 (18), 97 (27), 71 (40), 70 (10), 69 (30), 67
(11), 55 (13), 53 (10), 44 (43), 43 (100), 42 (11), 41 (54), 39
(30). Anal. calcd for C9H14O4 (186.21): C 58.05, H 7.58, O
34.37; found: C 58.06, H 7.58, O 34.40.
4.3.14. Mixture 17e: (5R)-3-[(1S)-hydroxy-2,2-dimethyl-
propyl]-5-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-
oxy}-4-methylfuran-2(5H)-one 18e and (5R)-3-[(1R)-
hydroxy-2,2-dimethylpropyl]-5-{[(1R,2S,5R)-2-isopro-
pyl-5-methylcyclohexyl]oxy}-4-methylfuran-2(5H)-one
19e. Similar procedure as for 17a. 16 (15.1 g, 59.0 mmol)
was coupled with 2,2-dimethylpropanal (8.50 ml,
77.0 mmol) at 21108C (diethyl ether/hexane 1:4, liquid
N2. The second flash chromatography was performed with a
mixture of AcOEt/hexane 1:9 as eluent and afforded 18e
(4.0 g, 12 mmol, 20%) as colorless needles and 19e (4.0 g,
12 mmol, 20%) as colorless needles, too.
Data of (5R)-3-[(1S)-hydroxy-2,2-dimethylpropyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one (18e). Mp 112.7 – 113.68C.
[a]2D0¼2153.5 (c¼1.00, CHCl3, stab. 1% EtOH). 1H
NMR (500 MHz, CDCl3): 5.75 (s, 1H, H–C(5)); 4.18 (s,
J¼8.7 Hz, 1H, H–C(100)); 3.36 (d, J¼8.6 Hz, 1H,
HO–C(100)); 1.99 (s, 3H, H3C–C(4)); 0.95 (s, 9H,
(H3C)3 –C(200)). Menthyl resonances: 3.62; 2.10–2.06;
1.72–1.63; 1.48–1.35; 1.30–1.21; 1.12–0.85; 0.95; 0.88;
0.80. 13C NMR (125 MHz, CDCl3): 172.6; 158.0; 129.3;
100.9; 75.7; 38.2; 26.4; 13.0. Menthyl resonances: 79.8;
48.2; 40.8; 34.6; 31.9; 25.7; 23.6; 22.6; 21.2; 16.2. EI-MS:
282 (16), 281 (13), 166 (16), 144 (82), 143 (31), 139 (72),
127 (47), 126 (100), 97 (18), 95 (14), 83 (85), 81 (21), 69
(36), 57 (65), 55 (38), 43 (21), 41 (36). Anal. calcd for
C20H34O4 (338.49): C 70.97, H 10.12, O 18.91; found: C
71.01, H 10.04, O 18.77.
4.3.16. 5-Hydroxy-3-[(1S,2S)-1-hydroxy-2-methylbutyl]-
4-methylfuran-2(5H)-one 3. Same procedure as for 1. 18b
(2.00 g, 5.92 mmol) was treated with boron tribromide
(1.90 ml, 17.8 mmol). The resulting mixture was stirred for
2 h. Then, additional boron tribromide (1.90 ml, 17.8 mmol)
was added and the mixture was stirred for another 2 h. The
flash chromatography afforded 3 (970 mg, 4.85 mmol, 82%,
mixture of epimers) as
a colorless yellowish oil.
[a]D20¼221.0 (c¼0.51, MeOH) (nat. prod.3: [a]2D4¼221.9
(c¼0.45, MeOH)). 1H NMR (500 MHz, CDCl3): 6.70–6.30
(br, 2£1H, HO–C(51 and 2)); 5.90 (s, 1H, H–C(51 or 2));
5.88 (s, 1H, H–C(52 or 1)); 4.22 (d, J¼8.3 Hz, 1H, H–
C(101 or 2)); 4.17 (d, J¼8.7 Hz, 1H, H–C(102 or 1));
3.70–3.30 (br, 2£1H, HO–C(101 and 2)); 2.07 (s, 3H,
H3C–C(41 or 2)); 2.05 (s, 3H, H3C–C(42 or 1)); 1.90–1.80
(m, 2£1H, H–C(201 and 2)); 1.80–1.70 (m, 1H, Ha–
C((301 and 2)); 1.22–1.14 (m, 1H, Hb–C(301 and 2)); 0.92 (t,
J¼7.3 Hz, 3H, H–C(401 or 2)); 0.92 (t, J¼7.4 Hz, 3H, H–
C(402 or 1)); 0.79 (d, J¼6.8 Hz, 3H, H3C–C(201 or 2));
0.75 (d, J¼6.8 Hz, 3H, H3C–C(202 or 1)). 13C NMR
(125 MHz, CDCl3): 172.4; 172.0; 159.3; 159.2; 129.4;
129.2; 98.8; 98.7; 70.7; 70.5; 39.6; 39.0; 24.8; 24.7; 14.8;
14.7; 11.8; 11.6; 10.8; 10.7. EI-MS: 144 (11), 143 (61),
127 (10), 126 (100), 125 (28), 98 (12), 97 (30), 69 (27),
57 (13), 41 (29), 39 (13). Anal. calcd for C10H16O4 (200.24):
C 59.98, H 8.05, O 31.96; found: C 60.04, H 8.14, O
31.95.
Data of (5R)-3-[(1R)-hydroxy-2,2-dimethylpropyl]-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-4-
methylfuran-2(5H)-one (19e). Mp 85.5 – 86.88C.
[a]2D0¼2108.5 (c¼1.00, MeOH). 1H NMR (500 MHz,
CDCl3): 5.68 (s, 1H, H–C(5)); 4.17 (s, J¼9.5 Hz, 1H,
H–C(100)); 3.53 (d, J¼9.5 Hz, 1H, HO–C(100)); 1.97 (s, 3H,
H3C–C(4)); 0.95 (s, 9H, (H3C)3 –C(200)). Menthyl
resonances: 3.64; 2.15–2.03; 1.72–1.63; 1.47–1.37;
1.29–1.23; 1.09–0.85; 0.96; 0.88; 0.81. 13C NMR
(125 MHz, CDCl3): 172.2; 157.2; 128.7; 100.6; 75.4;
37.7; 26.0; 12.7. Menthyl resonances: 79.4; 47.8; 40.4;
34.4; 31.5; 25.8; 23.7; 22.2; 20.7; 16.2. EI-MS: 282 (17),
281 (13), 166 (13), 144 (89), 143 (31), 139 (70), 127 (45),
126 (100), 97 (19), 95 (17), 83 (92), 81 (23), 69 (40), 57
(69), 55 (42), 43 (22), 41 (40). Anal. calcd for C20H34O4
(338.49): C 70.97, H 10.12, O 18.91; found: C 70.93, H
10.06, O 18.88.
4.3.17. 5-Hydroxy-3-[(1S)-1-hydroxyethyl]-4-methyl-
furan-2(5H)-one 20c. Same procedure as for 1. 18c
(1.00 g, 3.38 mmol) was treated with boron tribromide
(0.974 ml, 10.1 mmol). The resulting mixture was stirred for
2 h. Then, additional boron tribromide (0.974 ml,
10.1 mmol) was added and the mixture was stirred for
another 2 h. The flash chromatography afforded 20c
(330 mg, 1.90 mmol, 62%, mixture of epimers). Colorless
cubes (Et2O/hexane). Mp 101.0–102.58C. [a]2D0¼210.3
4.3.15. 5-Hydroxy-3-[(1S)-1-hydroxy-2-methylpropyl]-4-
methylfuran-2(5H)-one 1. 18a (4.00 g, 12.3 mmol) was
dissolved in absolute CH2Cl2 (200 ml) under argon. The
solution was cooled to 2788C and boron tribromide
(6.00 ml, 61.7 mmol) was added over 30 min, and the
resulting mixture was stirred for 2 h at this temperature. The
solution was allowed to warm up to 2258C and saturated
NaHCO3 solution (100 ml) was added. After warming up to
rt, the mixture was extracted with AcOEt. The combined
organic phases were dried over MgSO4, filtered, and the
1
(c¼1.00, MeOH). H NMR (500 MHz, d6-DMSO): 7.68
(2s, 2£1H, HO–C(51 and 2)); 5.80 (m, 2£1H,

G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
3247
H–C(51 and 2)); 5.11–5.07 (m, 1H, H–C(101 or 2));
4.55–4.49 (m, 1H, H–C(102 or 1)); 3.37–3.37 (m, 2£1H,
HO–C(101 and 2)); 2.04 (2s, 2£3H, H3C–C(41 and 2)); 1.27
(2d, J¼6.6 Hz, 2£3H, H–C(201 and 2)). 13C NMR
(125 MHz, d6-DMSO): 170.6; 157.6; 131.0; 98.0; 97.9;
61.3; 22.2; 11.4. EI-MS: 143 (25), 140 (19), 125 (18), 124
(11), 112 (11), 97 (35), 71 (20), 69 (50), 67 (32), 66 (10), 53
(17), 45 (13), 44 (49), 43 (100), 41 (59), 40 (13), 39 (46).
Anal. calcd for C7H10O4 (158.15): C 53.16, H 6.37, O 40.47;
found: C 53.30, H 6.32, O 40.53.
afforded 21a (1.90 g, 10.2 mmol, 83%) as colorless
amorphous solid. This amorphous product was crystallized
from AcOEt/hexane to afford 21a (1.70 g, 9.14 mmol, 75%,
mixture of epimers) as colorless plates. Mp 105.0–106.58C.
[a]2D0¼þ16.0 (c¼1.00, MeOH). 1H NMR (500 MHz,
CDCl3): 5.90–5.85 (m, 2£1H, H–C(51 and 2)); 5.23 (d,
J¼8.9 Hz, 1H, HO–C(51 or 2)); 5.01 (d, J¼7.4 Hz, 1H,
HO–C(52 or 1)); 4.15–4.08 (m, 2£1H, H–C(101 and 2)); 3.33
(d, J¼9.2 Hz, 1H, HO–C(101 or 2)); 3.08 (d, J¼8.4 Hz, 1H,
HO–C(102 or 1)); 2.08 (s, 3H, H3C–C(41 or 2)); 2.06 (s, 3H,
H3C–C(42 or 1)); 2.05–1.95 (m, 2£1H, H–C(201 and 2));
1.04 (d, J¼6.6 Hz, 3H, (H3C)2–C(201 or 2)); 1.03 (d,
J¼6.6 Hz, 3H, (H3C)2–C(202 or 1)); 0.85 (d, J¼6.8 Hz, 3H,
(H3C)2–C(201 or 2)); 0.83 (d, J¼6.8 Hz, 3H, (H3C)2–
C(202 or 1)). 13C NMR (125 MHz, CDCl3): 172.1; 172.0;
158.5; 158.5; 129.8; 129.2; 98.9; 98.8; 72.3; 72.2; 33.9;
33.6; 18.7; 18.5; 18.4; 11.9; 11.6. EI-MS: 168 (17), 153
(44), 143 (20), 135 (29), 126 (33), 125 (15), 110 (10), 99
(23), 98 (18), 97 (34), 71 (38), 69 (30), 67 (11), 55 (13), 53
(11), 44 (40), 43 (100), 42 (11), 41 (54), 39 (31). Anal. calcd
for C9H14O4 (186.21): C 58.05, H 7.58, O 34.37; found: C
58.09, H 7.62, O 34.37.
4.3.18. 5-Hydroxy-3-[(1S)-1-hydroxypropyl]-4-methyl-
furan-2(5H)-one 20d. Same procedure as for 1. 18d
(1.00 g, 3.38 mmol) was treated with boron tribromide
(0.930 ml, 9.68 mmol). The resulting mixture was stirred for
2 h. Then, additional boron tribromide (0.930 ml,
9.68 mmol) was added and the mixture was stirred for
another 2 h. The flash chromatography afforded 20d
(350 mg, 2.03 mmol, 63%). Colorless cubes (Et2O/hexane).
Mp 77.0–78.58C. [a]D20¼218.7 (c¼1.00, MeOH). 1H NMR
(500 MHz, d6-DMSO): 7.68 (m, 2£1H, HO–C(51 and 2));
5.86–50.77 (m, 2£1H, H–C(51 and 2)); 5.08–5.04 (m, 1H,
H–C(1 1 or 2)); 4.32–4.24 (m, 1H, H–C(102 or 1)); 3.36 (s,
1H, HO–C(101 or 2)); 3.35 (s, 1H, HO–C(102 or 1)); 2.02 (2s,
2£3H, H3C–C(41 and 2)); 1.61 (2q, J¼7.1 Hz, 2£2H,
H–C(201 and 2)); 0.82 (2t, J¼7.4 Hz, 2£3H, H–C(301 and 2)).
13C NMR (125 MHz, d6-DMSO): 170.7; 158.6, 130.0; 98.0;
97.9; 66.4; 66.3; 28.5; 11.5; 9.7. EI-MS: 154 (25), 143 (67),
139 (40), 125 (74), 115 (14), 111 (13), 97 (100), 95 (10), 83
(17), 81 (13), 79 (15), 71 (14), 69 (68), 67 (20), 57 (40), 53
(20), 51 (12), 44 (28), 43 (29), 41 (79), 39 (53). Anal. calcd
for C8H12O4 (172.18): C 55.81, H 7.03, O 37.17; found: C
55.80, H 6.89, O 37.26.
4.3.21. 5-Hydroxy-3-[(1R,2S)-1-hydroxy-2-methylbutyl]-
4-methylfuran-2(5H)-one 21b. Same procedure as for 1.
19b (2.00 g, 5.92 mmol) was treated with boron tribromide
(1.90 ml, 17.8 mmol). The resulting mixture was stirred for
2 h. Then, additional boron tribromide (1.90 ml, 17.8 mmol)
was added and the mixture was stirred for another 2 h. The
flash chromatography afforded 21b (950 mg, 4.50 mmol,
76%, mixture of epimers) as colorless yellowish needles.
1
Mp 79.5–81.08C. [a]2D0¼þ5.0 (c¼1.00, MeOH). H NMR
(500 MHz, CDCl3): 6.00–5.85 (m, 2£1H, H–C(51 and 2));
4.30 (d, J¼6.09 Hz, 1H, H–C(101 or 2)); 4.24 (d, J¼7.4 Hz,
1H,0 H–C(1 2 or 1)); 3.70–3.30 (2br, 2£1H, HO–
C(1 1 and 2)); 3.00–2.50 (br, 2£1H, HO–C(51 and 2)); 2.08
(s, 3H, H3C–C(41 or 2)); 2.06 (s, 3H, H3C–C(42 or 1));
1.81–1.70 (m, 2£1H, H–C((201 and 2)); 1.42–1.30 (m,
2£1H, Ha–C(301 and 2)); 1.12–1.00 (m, 2£1H, Hb–
C(301 and 2)); 0.99 (d, J¼6.7 Hz, 3H, H3C–C(201 or 2));
0.97 (d, J¼6.7 Hz, 3H, H3C–C(202 or 1)); 0.90 (t,
J¼7.3 Hz, 3H, H–C(401 or 2)); 0.89 (t, J¼7.3 Hz, 3H,
H–C(402 or 1)). 13C NMR (125 MHz, CDCl3): 172.4;
172.2; 158.9; 129.6; 129.3; 98.9; 98.8; 70.7; 40.0; 39.7;
25.4; 14.4; 14.3; 11.9; 11.6; 11.4; 11.3. EI-MS: 153 (10),
144 (11), 143 (56), 127 (10), 126 (100), 125 (28), 98 (13), 97
(31), 69 (30), 57 (16), 41 (33), 39 (16). Anal. calcd for
C10H16O4 (200.24): C 59.98, H 8.05, O 31.96; found: C
60.06, H 8.03, O 32.19.
4.3.19. 5-Hydroxy-3-[(1S)-1-hydroxy-2,2-dimethylpro-
pyl]-4-methylfuran-2(5H)-one 20e. Same procedure as
for 1. 18e (1.00 g, 2.96 mmol) reacted with boron
tribromide (0.860 ml, 8.86 mmol). The resulting mixture
was stirred for 2 h. Then, additional boron tribromide
(0.860 ml, 8.86 mmol) was added and the mixture was
stirred for another 2 h. Flash chromatography with AcOEt/
hexane 1:2 afforded 20e (482 mg, 2.41 mmol, 81%).
Colorless
cubes
(EtOH).
Mp
162.3–162.78C.
1
[a]2D0¼241.5 (c¼1.00, MeOH). H NMR (500 MHz, d6-
DMSO): 7.75 (d, J¼7.5 Hz, 1H, HO–C(51)); 7.66 (d,
J¼8.5 Hz, 1H, HO–C(52)); 5.93 (d, J¼7.5 Hz, 1H,
H–C(51 or 2)); 5.80 (d, J¼8.5 Hz, 1H, H–C(52 or 1)); 5.12
(d, J¼4.9 Hz, 1H, HO–C(101 and 2)); 4.14 (d, J¼0 4.7 Hz; 1H,
H–C(101 or 2)); 4.11 (d, J¼4.5 Hz, 1H, H–C(1 2 or 1)); 2.09
(s, 3H, H3C–C(41 and 2)); 0.90 (s, 9H, (H3C)3–C(201 or 2));
0.89 (s, 9H, (H3C)3–C(202 or 1)). 13C NMR (125 MHz,
d6-DMSO): 172.7; 172.4; 161.1; 160.4; 130.2; 98.9;
98.8; 73.8; 73.7; 38.1; 38.0; 26.9; 13.9; 13.7. EI-MS: 167
(32), 149 (43), 144 (11), 127 (10), 126 (100), 98 (17),
97 (15), 70 (12), 69 (26), 57 (85), 55 (11), 44 (12), 43
(19), 41 (68), 39 (34). Anal calcd for C10H16O4 (200.23):
C 59.98, H 8.05, O 31.96; found: C 60.08, H 7.98, O
32.04.
4.3.22. 5-Hydroxy-3-[(1R)-1-hydroxyethyl]-4-methyl-
furan-2(5H)-one 21c. Same procedure as for 1. 19c
(1.00 g, 3.38 mmol) was treated with boron tribromide
(0.974 ml, 10.1 mmol). The resulting mixture was stirred for
2 h. Then, additional boron tribromide (0.974 ml,
10.1 mmol) was added and the mixture was stirred for
another 2 h. The flash chromatography afforded 21c
(300 mg, 1.90 mmol, 56%, mixture of epimers). Colorless
cubes (Et2O/hexane). Mp 103.0–104.58C. [a]2D0¼þ7.6
1
4.3.20. 5-Hydroxy-3-[(1R)-1-hydroxy-2-methylpropyl]-
4-methylfuran-2(5H)-one 21a. Same procedure as for 1.
19a (4.00 g, 12.3 mmol) was treated with boron tribromide
(6.00 ml, 61.7 mmol), and the flash chromatography
(c¼1.00, MeOH). H NMR (500 MHz, d6-DMSO): 7.68
(d, J¼8.1 Hz, 1H, HO–C(51)); 7.68 (d, J¼7.9 Hz, 1H, HO–
C(52)); 5.81 (d, J¼7.9 Hz, 1H, H–C(51 or 2)); 5.79 (d,
J¼8.1 Hz, 1H, H–C(52 or 1)); 5.10–5.08 (m, 1H,

3248
G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
H–C(101 or 2)); 4.55–4.49 (m, 1H, H–C(102 or 1)); 3.36 (2s,
2£1H, HO–C(101 and 2)); 2.04 (s, 3H, H3C–C(41 or 2)); 2.03
(s, 3H, H3C–C(42 or 1)); 1.27 (d, J¼6.6 H0z, 3H, H–
C(201 or 2)); 1.26 (d, J¼6.6 Hz, 3H, H–C(2 2 or 1)). 13C
NMR (125 MHz, d6-DMSO): 170.6; 170.5; 157.6; 131.1;
131.0; 98.0; 97.9; 61.3; 61.2; 22.3; 22.2; 11.4. EI-MS:
143 (55), 140 (22), 125 (39), 114 (11), 112 (13), 111 (10),
98 (19), 97 (66), 95 (10), 83 (11), 71 (19), 69 (72), 68
(10), 67 (33), 66 (12), 53 (16), 45 (26), 44 (33), 43 (100), 41
(72), 40 (15), 39 (53), 38 (10). Anal. calcd for C7H10O4
(158.15): C 53.16, H 6.37, O 40.47; found: C 53.19, H 6.23,
O 40.32.
4.3.25. 3-[(1S)-1-Hydroxy-2-methylpropyl]-4-methyl-
furan-2(5H)-one 2. 1 (750 mg, 4.03 mmol) was dissolved
in absolute MeOH (20 ml) under argon and the solution was
cooled to 08C. Sodium borohydride (620 mg, 16.1 mmol)
was added in portions, and the mixture was stirred for
45 min at rt. The reaction was quenched with water and
extracted three times with AcOEt. The combined organic
phases were dried over MgSO4, filtered, and the solvent was
evaporated. Flash chromatography with tert-butyl methyl
ether afforded 2 (400 mg, 2.35 mmol, 58%) as a colorless
liquid. For the characterization, see above.
4.3.26. 3-[(1S,2S)-1-Hydroxy-2-methylbutyl]-4-methyl-
furan-2(5H)-one 4. Same procedure as for 2. 3 (1.00 g,
5.00 mmol) was reduced with sodium borohydride (720 mg,
20.0 mmol). Purification afforded 4 (500 mg, 2.72 mmol,
54%) as a colorless oil. For the characterization, see
above.
4.3.23. 5-Hydroxy-3-[(1R)-1-hydroxypropyl]-4-methyl-
furan-2(5H)-one 21d. Same procedure as for 1. 19d
(1.00 g, 3.38 mmol) was treated with boron tribromide
(0.930 ml, 9.68 mmol). The resulting mixture was stirred for
2 h. Then, additional boron tribromide (0.930 ml,
9.68 mmol) was added and the mixture was stirred for
another 2 h. The flash chromatography afforded 21d
(350 mg, 2.03 mmol, 63%). Colorless cubes (Et2O/hexane).
Mp 79.5–81.08C. [a]D20¼þ15.6 (c¼1.00, MeOH). 1H NMR
(500 MHz, d6-DMSO): 7.69 (d, J¼7.9 Hz, 1H, HO–C(51));
7.68 (d, J¼8.1 Hz, 1H, HO–C(52)); 5.84 (d, J¼7.8 Hz, 1H,
H–C(51 or 2)); 5.80 (d, J¼8.1 Hz, 1H, H–C(52 or 1)); 5.09–
5.03 (m, 1H, H–C(101 or 2)); 4.32–4.24 (m, 1H,
H–C(102 or 1)); 3.36 (2s, 2£1H, HO–C(101 and 2)); 2.03 (s,
3H, H3C–C(41 or 2)); 2.02 (s, 3H, H3C–C(42 or 1)); 1.61
(2qd, J¼6.8, 3.1 Hz, 2£2H, H–C(201 and 2)); 0.82 (t,
J¼7.3 Hz, 3H Hz, H–C(301 or 2)); 0.81 (t, J¼7.3 Hz, 3H,
H–C(302 or 1)). 13C NMR (125 MHz, d6-DMSO): 170.8;
170.7; 158.6; 158.5; 130; 129.9; 98.0; 97.9; 66.4; 66.3;
28.5; 28.4; 11.6; 11.5; 9.8; 9.7. EI-MS: 154 (30), 143
(66), 139 (47), 126 (10), 125 (72), 115 (13), 111 (14), 98
(11), 97 (100), 95 (12), 83 (19), 81 (14), 79 (17), 71 (15),
69 (69), 67 (23), 57 (43), 55 (13), 53 (22), 51 (13), 44
(32), 43 (30), 41 (82), 39 (57). Anal. calcd for C8H12O4
(172.18): C 55.81, H 7.03, O 37.17; found: C 55.97, H 6.84,
O 37.22.
4.3.27. 3-[(1S)-1-Hydroxyethyl]-4-methylfuran-2(5H)-
one 22c. Same procedure as for 2. 20c (200 mg,
1.27 mmol) was reduced with sodium boron hydride
(192 mg, 5.06 mmol). Purification afforded 22c (120 mg,
0.845 mmol, 66%) as an oil. [a]2D0¼230.2 (c¼1.00, CHCl3,
stab. 1% EtOH). 1H NMR (500 MHz, CDCl3): 4.72 (q,
J¼6.3 Hz, 1H, H–C(10)); 4.65 (s, 2H, H–C(5)); 3.31 (s, 1H,
HO–C(10)); 2.12 (s, 3H, H3C–C(4)); 1.46 (d, J¼6.6 Hz, 3H,
H–C(20)). 13C NMR (125 MHz, CDCl3): 174.0; 157.3;
128.7; 72.6; 62.7; 22.4; 12.1. EI-MS: 127 (100), 124 (16),
99 (58), 96 (15), 95 (13), 71 (12), 69 (13), 67 (27), 53 (24),
45 (14), 43 (51), 41 (30), 39 (26). Anal. calcd for C7H10O3
(142.16): C 59.14, H 7.09, O 33.77; found: C 58.80, H 6.89,
O 33.84.
4.3.28. 3-[(1S)-1-Hydroxypropyl]-4-methylfuran-2(5H)-
one 22d. Same procedure as for 2. 20d (200 mg, 1.16 mmol)
was reduced with sodium borohydride (177 mg,
4.65 mmol). The purification afforded 22d (150 mg,
0.961 mmol, 83%) as an oil. [a]2D0¼240.5 (c¼1.00,
CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3):
4.68–40.64 (m, 2H, H–C(5)); 4.44 (t, J¼6.6 Hz, 1H,
H–C(1 )); 3.31 (s, 1H, HO–C(10)); 2.11 (s, 3H, H3C-(4));
1.84 (dquin., J¼13.8 Hz, 7.4, 1H, Ha–C(20)); 1.73 (ddq,
J¼13.8 Hz, 7.4, 6.6, 1H, Hb–C(20)); 0.93 (t, J¼7.4 Hz, 3H,
H–C(30)). 13C NMR (125 MHz, CDCl3): 174.0; 158.2;
127.7; 72.6; 67.9; 29.2; 12.1; 9.7. EI-MS: 138 (11), 127
(100), 99 (41), 71 (10), 53 (19), 43 (22), 41 (16), 39 (14).
Anal. calcd for C8H12O3 (156.18): C 61.52, H 7.74, O 30.73;
found: C 61.30, H 7.73, O 31.28.
4.3.24. 5-Hydroxy-3-[(1R)-1-hydroxy-2,2-dimethylpro-
pyl]-4-methylfuran-2(5H)-one 21e. Same procedure as
for 1. 19e (1.00 g, 2.96 mmol) was treated with boron
tribromide (0.860 ml, 8.86 mmol). The resulting mixture
was stirred for 2 h. Then, additional boron tribromide
(0.860 ml, 8.86 mmol) was added and the mixture was
stirred for another 2 h. Flash chromatography with AcOEt/
hexane 1:2 afforded 21e (330 mg, 1.65 mmol, 66%).
Colorless cubes (EtOH). Mp 162.0–162.78C. [a]2D0¼
1
þ39.0 (c¼1.00, MeOH). H NMR (500 MHz, d6-DMSO):
7.71 (d, J¼7.5 Hz, 1H, HO–C(51)); 7.62 (d, J¼8.6 Hz, 1H,
HO–C(52)); 5.90 (dd, J¼7.5 Hz, 0.6, 1H, H–C(51 or 2));
5.76 (dd, J¼8.5 Hz, 0.2, 1H, H–C(52 or 1)); 5.08 (d,
J¼4.8 Hz, 1H, HO–C(101 and 2)); 4.11 (d, J¼04.6 Hz; 1H,
H–C(101 or 2)); 4.07 (d, J¼4.3 Hz, 1H, H–C(1 2 or 1)); 2.06
(s, 3H, H3C–C(41 or 2)); 2.05 (s, 3H, H3C–C(42 or 1)); 0.86
(s, 9H, (H3C)3–C(201 or 2)); 0.85 (s, 9H, (H3C)3–C(202 or 1)).
13C NMR (125 MHz, d6-DMSO): 172.7; 172.4; 161.1;
160.0; 130.2; 98.9; 98.8; 73.8; 73.7; 38.1; 38.0; 26.9;
13.9; 13.7. EI-MS: 144 (14), 126 (100), 97 (11), 69 (16),
57 (50), 41 (29), 39 (12). Anal. calcd for C10H16O4 (200.23):
C 59.98, H 8.05, O 31.96; found: C 60.20, H 7.89, O
31.71.
4.3.29. 3-[(1S)-1-Hydroxy-2,2-dimethylpropyl]-4-
methylfuran-2(5H)-one 22e. Same procedure as for 2.
20e (200 mg, 1.00 mmol) was reduced with sodium
borohydride (200 mg, 5.28 mmol). The purification
afforded 22e (134 mg, 73%) as a colorless solid. Mp 77–
788C. [a]2D0¼228.4 (c¼1.00, CH2Cl2). 1H NMR (500 MHz,
CDCl3): 4.73 (d, J¼17.5 Hz, 1H, Ha–C(5)); 4.65 (d,
J¼17.5 Hz, 1H, Hb–C(5)); 4.20 (d, J¼9.5 Hz, 1H,
H–C(10)); 3.66 (d, J¼9.5 Hz, 1H, HO–C(10)); 2.08 (s, 3H,
CH3–C(4)); 0.96 (s, 9H, (CH3)3–C(20)). 13C NMR
(125 MHz, CDCl3): 174.8; 159.3; 126.3; 75.2; 72.8; 37.8;
25.9; 13.3. EI-MS (70 eV): 151 (13), 128 (80), 127 (64), 110
(100), 99 (12), 82 (65), 57 (49), 53 (13), 43 (18), 41 (35), 39,

G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
3249
(19). FAB-MS (NBA): 186 (10), 185 (100), 167 (82), 137
(14), 136 (10), 127 (14), 77 (14), 57 (12), 41 (12), 39 (13).
FAB-MS (NBAþKCl): 223 (46), 186 (10), 185 (100), 167
(91), 137 (10), 127 (16), 57 (16), 43 (13), 41 (13), 39 (30).
Anal. calcd for C10H16O3 (184.24): C 65.19, H 8.75, O
26.05; found: C 64.97, H 8.78, O 26.12.
CHCl3, stab. 1% EtOH). 1H NMR (500 MHz, CDCl3):
4.68–40.64 (m, 2H, H–C(5)); 4.44 (t, J¼6.6 Hz, 1H,
H–C(1 )); 3.21 (s, 1H, HO–C(10)); 2.11 (s, 3H, H3C-(4));
1.85 (dquin., J¼13.8, 7.4 Hz, 1H, Ha–C(20)); 1.73 (ddq,
J¼13.8, 7.4, 6.6 Hz, 1H, Hb–C(20)); 0.93 (t, J¼7.4 Hz, 3H,
H–C(30)). 13C NMR (125 MHz, CDCl3): 174.0; 158.1;
127.7; 72.6; 68.0; 29.3; 12.1; 9.7. EI-MS: 138 (11), 127
(100), 99 (41), 71 (10), 53 (20), 43 (23), 41 (17), 39 (15).
Anal. calcd for C8H12O3 (156.18): C 61.52, H 7.74, O 30.73;
found: C 61.37, H 7.74, O 31.19.
4.3.30. 3-[(1R)-1-Hydroxy-2-methylpropyl]-4-methyl-
furan-2(5H)-one 14. Same procedure as for 2. 21a
(750 mg, 4.03 mmol) was reduced with sodium borohydride
(620 mg, 16.1 mmol). Purification afforded 14 (400 mg,
2.35 mmol, 58%) as colorless needles. Mp 42.5–43.08C.
[a]2D0¼þ17.0 (c¼1.00, MeOH). 1H NMR (500 MHz,
CDCl3): 4.71 (d, J¼17.3 Hz, 1H, Ha–C(5)); 4.66 (d,
J¼17.3 Hz, 1H, Hb–C(5)); 4.14 (t, J¼8.7 Hz, 1H,
H–C(10)); 3.10 (d, J¼9.4 Hz, 1H, HO–C(10)); 2.08 (s, 3H,
H3C–C(4)); 2.08–2.00 (m, 1H, H–C(20)); 1.05 (d,
J¼6.7 Hz, 3H, (H3C)2–C(20)); 0.84 (d, J¼6.7 Hz, 3H,
(H3C)2–C(20)). 13C NMR (125 MHz, CDCl3): 174.2; 158.3;
127.4; 72.7; 72.4; 33.8; 18.8; 18.4; 12.4. EI-MS: 152 (12),
128 (23), 127 (100), 110 (36), 109 (13), 99 (24), 82 (31), 53
(14), 43 (29), 41 (18), 39 (15). Anal. calcd for C9H14O3
(170.21): C 63.51, H 8.29, O 28.20; found: C 63.21, H 8.38,
O 28.60.
4.3.34. 3-[(1R)-1-Hydroxy-2,2-dimethylpropyl]-4-
methylfuran-2(5H)-one 23e. Same procedure as for 2.
21e (200 mg, 1.00 mmol) was reduced with sodium
borohydride (200 mg, 5.28 mmol). The purification
afforded 23e (118 mg, 64%) as a colorless solid. Mp 77–
788C. [a]2D0¼þ27.0 (c¼1.00, CH2Cl2). 1H NMR (500 MHz,
CDCl3): 4.73 (d, J¼17.0 Hz, 1H, Ha–C(5)); 4.65 (d,
J¼17.5 Hz, 1H, Hb–C(5)); 4.20 (d, J¼9.5 Hz, 1H,
H–C(10)); 3.65 (d, J¼10 Hz, 1H, HO–C(10)); 2.08 (s, 3H,
CH3–C(4)); 0.96 (s, 9H, (CH3)3–C(20)). 13C NMR
(125 MHz, CDCl3): 174.8; 159.3; 126.3; 75.2; 72.8; 37.8;
25.9; 13.3. EI-MS (70 eV): 151 (13), 128 (81), 127 (65), 123
(11), 110 (100), 99 (12), 82 (64), 57 (49), 53 (13), 43 (17),
41 (35), 39, (18). FAB-MS (NBA): 185 (100), 167 (82), 137
(10), 127 (12), 57 (11), 41 (11), 39 (10). FAB-MS
(NBAþKCl): 223 (39), 185 (100), 167 (92),137 (14), 127
(15), 57 (17), 43 (11), 41 (13), 39 (13). Anal. calcd for
C10H16O3 (184.24): C 65.19, H 8.75, O 26.05; found: C
65.24, H 8.75, O 26.34.
4.3.31. 3-[(1R,2S)-1-Hydroxy-2-methylbutyl]-4-methyl-
furan-2(5H)-one (15). Same procedure as for 2. 21b
(1.00 mg, 5.00 mmol) was reduced with sodium boro-
hydride (720 mg, 20.0 mmol). Purification afforded 15
(530 mg, 2.88 mmol, 58%) as a colorless solid. Mp 91.0–
92.08C. [a]2D0¼þ17.0 (c¼1.00, MeOH). 1H NMR
(500 MHz, CDCl3): 4.70 (d, J¼17.3 Hz, 1H, Ha–C(5));
4.65 (d, J¼17.3 Hz, 1H, Hb–C(5)); 4.29 (t, J¼8.5 Hz, 1H,
H–C(10)); 3.06 (d, J¼9.2 Hz, 1H, HO–C(10)); 2.08 (s, 3H,
H3C–C(4)); 1.80–1.71 (m, 1H, H–C(20)); 1.43–1.34 (m,
1H, Ha–C(30)); 1.30–1.10 (m, 1H, Hb–C(30)); 1.00 (d,
J¼6.7 Hz, 3H, H3C–C(20)); 0.91 (t, J¼7.4 Hz, 3H,
H–C(40)). 13C NMR (125 MHz, CDCl3): 174.3; 158.1;
127.5; 72.7; 71.0; 40.4; 25.6; 14.6; 12.5; 11.5. EI-MS: 128
(40), 127 (100), 110 (67), 99 (23), 82 (47), 53 (15), 43 (19),
41 (24), 39 (15). Anal. calcd for C10H16O3 (184.24): C
65.19, H 8.75, O 26.05; found: C 65.21, H 8.80, O 26.32.
4.3.35. (1S,2S)-2-Methyl-1-(4-methyl-2-oxo-2,5-dihydro-
furan-3-yl)butyl (2S)-3,3,3-trifluoro-2-methoxy-2-phe-
nylpropanoate 25. Same procedure as for 12. (2R)-3,3,3-
trifluoro-2-methoxy-2-phenylpropanoyl chloride ((R)-
Mosher’s acid chloride, 11) (35 mg, 0.140 mmol) was
reacted with 4 (18.4 mg, 0.100 mmol). Purification by
HPLC (Eurospher 100-7 RP-C18; water/MeOH 25:75; tR
25¼13.5–15.0 min) afforded 25 (22.5 mg, 0.056 mmol,
56%) as colorless plates. Mp 84.3–85.28C. [a]2D0¼257.2
(c¼1.18, MeOH). 1H NMR (300 MHz, CDCl3): 7.55–7.34
(m, 5H, phenyl); 5.44 (d, J¼9.4 Hz, 1H, H–C(10)); 4.69 (d,
J¼17.3 Hz, 1H, Ha–C(5)); 4.65 (d, J¼17.3 Hz, 1H,
Hb–C(5)); 3.52 (s, 3H, H3CO–C(200)); 2.40–2.26 (m, 1H,
H–C(20)); 2.11 (s, 3H, H3C–C(4)); 1.49–1.36 (m, 1H,
Ha–C(30)); 1.10–0.950 (m, 1H, Hb–C(30)); 0.80 (t,
J¼7.4 Hz, 3H, H–C(4 )); 0.77 (d, J¼6.9 Hz, 3H, H3C–
C(20)). 13C NMR (75 MHz, CDCl3): 172.0; 166.2; 162.9;
132.0; 129.6; 128.4; 127.3; 123.8; 123.3 (q, 1JCF¼287 Hz);
4.3.32. 3-[(1R)-1-Hydroxyethyl]-4-methylfuran-2(5H)-
one 23c. Same procedure as for 2. 21c (200 mg,
1.27 mmol) was reduced with sodium borohydride
(192 mg, 5.06 mmol). Purification afforded 23c (120 mg,
0.845 mmol, 66%) as an oil. [a]2D0¼þ29.7 (c¼1.00, CHCl3,
1
stab. 1% EtOH). H NMR (500 MHz, CDCl3): 4.72 (q,
J¼6.6 Hz, 1H, H–C(10)); 4.65 (s, 2H, H–C(5)); 3.26 (s, 1H,
HO–C(10)); 2.12 (s, 3H, H3C–C(4)); 1.47 (d, J¼6.6 Hz, 3H,
H–C(20)). 13C NMR (125 MHz, CDCl3): 174.0; 157.2;
128.8; 72.6; 62.7; 22.4; 12.1. EI-MS: 127 (100), 124 (27),
99 (56), 81 (10), 71 (12), 69 (14), 67 (39), 53 (27), 45
(13), 43 (50), 41 (36), 39 (30). Anal. calcd for C7H10O3
(142.16): C 59.14, H 7.09, O 33.77; found: C 58.86, H 6.99,
O 33.90.
84.5 (q, JCF¼27 Hz); 74.0; 72.4; 55.6; 35.6; 24.6; 14.5;
2
12.7; 10.2. FAB-MS (NBA): 401 (8, [MþH]þ), 189 (12),
168 (10), 167 (100), 43 (13). Anal. calcd for C20H23F3O5
(400.40): C 60.00, H 5.79, O 19.98; found: C 59.98, H 5.84,
O 20.12.
4.3.36. (1S,2S)-2-Methyl-1-(4-methyl-2-oxo-2,5-dihydro-
furan-3-yl)butyl (2R)-3,3,3-trifluoro-2-methoxy-2-phe-
nylpropanoate 26. Same procedure as for 12 (2S)-3,3,3-
trifluoro-2-methoxy-2-phenylpropanoyl chloride ((S)-
Mosher’s acid chloride, 24) (35 mg, 0.140 mmol) was
reacted with 4 (18.4 mg, 0.100 mmol). Purification by
HPLC (Eurospher 100-7 RP-C18; water/MeOH 25:75; tR
26¼12.0–14.0 min) afforded 26 (25.2 mg, 0.063 mmol,
4.3.33. 3-[(1R)-1-Hydroxypropyl]-4-methylfuran-2(5H)-
one 23d. Same procedure as for 2. 21d (200 mg, 1.16 mmol)
was reduced with sodium borohydride (177 mg,
4.65 mmol). Purification afforded 23d (140 mg,
0.897 mmol, 77%) as an oil. [a]2D0¼þ41.7 (c¼1.00,

3250
G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
63%) as colorless plates. Mp 86.2–88.68C. [a]2D0¼212.8
(16), 57 (12), 55 (15). Anal. calcd for C30H41F3O6 (554.65):
C 64.97, H 7.45, O 17.31; found: C 65.04, H 7.59, O
17.03.
1
(c¼1.43, MeOH). H NMR (300 MHz, CDCl3): 7.47–7.35
(m, 5H, phenyl); 5.50 (d, J¼9.1 Hz, 1H, H–C(10)); 4.60 (d,
J¼17.3 Hz, 1H, Ha–C(5)); 4.56 (d, J¼17.3 Hz, 1H,
Hb–C(5)); 3.54 (s, 3H, H3CO–C(200)); 2.28–2.19 (m, 1H,
H–C(20)); 1.90 (s, 3H, H3C–C(4)); 1.70–1.56 (m, 1H,
Ha–C(30)); 1.28–1.120 (m, 1H, Hb–C(30)); 0.90 (t,
J¼7.4 Hz, 3H, H–C(4 )); 0.83 (d, J¼6.9 Hz, 3H, H3C–
C(20)). 13C NMR (75 MHz, CDCl3): 172.0; 166.1; 162.1;
131.8; 129.7; 128.4; 127.3; 124.0; 123.2 (q, 1JCF¼287 Hz);
4.3.39. (1R)-1-[(5R)-5-{[(1R,2S,5R)-2-Isopropyl-5-
methylcyclohexyl]oxy}-4-methyl-2-oxo-2,5-dihydro-
furan-3-yl]-2-methylpropyl (2R)-3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate 28a. Same procedure as for 12.
19a (143 mg, 0.441 mmol) was esterified with 24 (200 mg,
0.794 mmol). Flash chromatography with AcOEt/hexane
1:5 afforded 28a (190 mg, 0.352 mmol, 80%) as a pale
yellow oil. [a]2D0¼222.5 (c¼1.00, CHCl3, stab. 1% EtOH).
1H NMR (500 MHz, CDCl3): 7.50–7.35 (m, 5H, phenyl);
5.74 (s, 1H, H–C(5)); 5.35 (d, J¼9.4 Hz, 1H, H–C(100));
3.51 (s, 3H, H–C(300)); 2.48–2.39 (m, 1H, H–C(200)); 2.02
(s, 3H, H3C–C(4)); 0.85 (d, J¼6.6 Hz, 3H, (H3C)2–C(200));
0.84 (d, J¼7.0 Hz, 3H, (H3C)2–C(200)). Menthyl reson-
ances: 3.64; 2.14–2.09; 2.11–2.05; 1.72–1.66; 1.68–1.63;
1.46–1.36; 1.29–1.22; 1.07–0.99; 1.03–0.93; 0.95; 0.91–
0.82; 0.88; 0.81. 13C NMR (125 MHz, CDCl3): 169.4;
166.2; 161.2; 132.0; 129.6; 128.4; 127.3; 126.2; 123.1 (q,
1JCF¼289 Hz); 100.1; 75.4; 55.5; 30.3; 18.7; 18.3; 12.0.
Menthyl resonances: 79.2; 47.7; 40.3; 34.2; 31.4; 25.5; 23.3;
22.2; 20.7; 15.9. EI-MS: 190 (12), 189 (100), 169 (24), 152
(19), 151 (24), 123 (11), 105 (13), 83 (32), 77 (10), 69 (18),
55 (18), 43 (12), 41 (11). Anal. calcd for C29H39F3O6
(540.63): C 64.43, H 7.27, O 17.76; found: C 64.51, H 7.37,
O 17.79.
2
84.4 (q, JCF¼27 Hz); 74.3; 72.4; 55.6; 36.3; 24.6; 14.6;
12.5; 10.5. FAB-MS (NBA): 401 (8, [MþH]þ), 189 (12),
168 (11), 167 (100), 57 (16), 55 (11), 43 (19), 41 (12). Anal.
calcd for C20H23F3O5 (400.40): C 60.00, H 5.79, O 19.98;
found: C 59.69, H 6.03, O 20.37.
4.3.37. (1R)-1-[(5R)-5-{[(1R,2S,5R)-2-Isopropyl-5-
methylcyclohexyl]oxy}-4-methyl-2-oxo-2,5-dihydro-
furan-3-yl]-2-methylpropyl (2S)-3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate 27a. Same procedure as for 12.
19a (143 mg, 0.441 mmol) was esterified with 11 (200 mg,
0.794 mmol). Flash chromatography with AcOEt/hexane
1:5 afforded 27a (190 mg, 0.352 mmol, 80%). Colorless
prisms (AcOEt/hexane). Mp 103.5–105.08C. [a]2D0¼284.0
(c¼1.00, CHCl3, stab. 1% EtOH). 1H NMR (500 MHz,
CDCl3): 7.50–7.34 (m, 5H, phenyl); 5.69 (s, 1H, H–C(5));
5.37 (d, J¼9.1 Hz, 1H, H0–0 C(100)); 3.55 (s, 3H, H–C(300));
2.44–2.35 (m, 1H, H–C(2 )); 1.82 (s, 3H, H3C–C(4)); 1.03
(d, J¼6.6 Hz, 3H, (H3C)2–C(200)); 0.87 (d, J¼6.7 Hz, 3H,
(H3C)2–C(200)). Menthyl resonances: 3.62; 2.13–2.09;
2.11–2.06; 1.72–1.67; 1.68–1.63; 1.46–1.36; 1.29–1.22;
1.07–0.99; 1.03–0.93; 0.95; 0.91–0.82; 0.88;0.80. 13C
NMR (125 MHz, CDCl3): 169.4; 166.1; 160.2; 131.8;
4.3.40. (1R,2S)-1-[(5R)-5-{[(1R,2S,5R)-2-Isopropyl-5-
methylcyclohexyl]oxy}-4-methyl-2-oxo-2,5-dihydro-
furan-3-yl]-2-methylbutyl (2R)-3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate 28b. Same procedure as for 12.
19b (150 mg, 0.444 mmol) was esterified with 24 (200 mg,
0.794 mmol). Flash chromatography with AcOEt/hexane
1:5 afforded 28b (140 mg, 0.253 mmol, 57%) as a colorless
oil. [a]2D0¼223.0 (c¼1.00, CHCl3, stab. 1% EtOH). 1H
NMR (500 MHz, CDCl3): 7.50–7.47 (m, 5H, phenyl); 5.73
(s, 1H, H–C(5)); 5.48 (d, J¼8.8 Hz, 1H, H–C(100)); 3.51 (s,
3H, H–C(300)); 2.24–2.16 (m, 1H, H–C(200)); 2.00 (s, 3H,
H3C–C(4)); 1.35–1.28 (m, 1H, Ha–C(300)); 1.05–1.00 (m,
1H, Hb–C(300)); 0.87 (t, J¼7.4 Hz, 3H, H–C(400)); 0.83 (d,
J¼6.6 Hz, 3H, H3C–C(200)). Menthyl resonances: 3.63;
2.14–2.09; 2.08–2.04; 1.72–1.63; 1.46–1.36; 1.28–1.23;
1.09–1.00; 1.05–1.00; 0.95; 0.91–0.82; 0.88; 0.81. 13C
NMR (125 MHz, CDCl3): 169.5; 166.1; 160.9; 131.9;
1
129.6; 128.4; 127.3; 126.4; 123.1 (q, JCF¼288 Hz);
100.0; 75.6; 55.7; 30.5; 19.0; 18.4; 11.9. Menthyl
resonances: 79.1; 47.8; 40.3; 34.2; 31.4; 25.4; 23.3; 22.3;
20.8; 15.9. EI-MS: 190 (12), 189 (100), 169 (26), 152 (19),
151 (22), 83 (30), 69 (17), 55 (16), 43 (12), 41 (10). Anal.
calcd for C29H39F3O6 (540.63): C 64.43, H 7.27, O 17.76;
found: C 64.19, H 7.28, O 17.88.
4.3.38. (1R,2S)-1-[(5R)-5-{[(1R,2S,5R)-2-Isopropyl-5-
methylcyclohexyl]oxy}-4-methyl-2-oxo-2,5-dihydro-
furan-3-yl]-2-methylbutyl (2S)-3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoate 27b. Same procedure as for 12.
19b (150 mg, 0.444 mmol) was esterified with 11 (200 mg,
0.794 mmol). Flash chromatography with AcOEt/hexane
1:5 afforded 27b (130 mg, 0.234 mmol, 53%) as colorless
cubes. Mp 117.0–118.08C. [a]2D0¼286.0 (c¼1.00, CHCl3,
1
129.6; 128.4; 127.3; 126.3; 123.3 (q, JCF¼289 Hz);
100.1; 84.4 (q); 74.4; 55.5; 36.6; 25.0; 14.8; 12.1; 10.9.
Menthyl resonances: 79.2; 47.7; 40.4; 34.2; 31.4; 25.5; 23.3;
22.2; 20.7; 16.0. EI-MS: 190 (12), 189 (100), 183 (43), 166
(16), 165 (24), 110 (12), 83 (40), 69 (18), 57 (13), 55 (18),
41 (11). Anal. calcd for C30H41F3O6 (554.65): C 64.97, H
7.45, O 17.31; found: C 65.10, H 7.68, O 17.29.
1
stab. 1% EtOH). H NMR (500 MHz, CDCl3): 7.46–7.33
(m, 5H, phenyl); 5.67 (s, 1H, H–C(5)); 5.51 (d, J¼8.4 Hz,
1H, H–C(100)); 3.54 (s, 3H, H–C(300)); 2.19–2.10 (m, 1H,
H–C(200)); 1.79 (s, 3H, H3C–C(4)); 1.38–1.30 (m, 1H,
Ha–C(300)); 1.12–0.90 (m, 1H, Hb–C(300)); 0.99 (d,
J¼6.6 Hz, 3H, H3C–C(200)); 0.90 (t, J¼7.4 Hz, 3H,
H–C(400)). Menthyl resonances: 3.61; 2.12–2.05;
1.73–1.64; 1.46–1.36; 1.28–1.22; 1.12–0.90; 0.95;
0.91–0.82; 0.88; 0.80. 13C NMR (125 MHz, CDCl3):
169.5; 166.1; 160.0; 131.8; 129.5; 128.4; 127.3; 126.5;
123.1 (q, 1JCF¼288 Hz); 100.0; 74.5; 55.7; 36.9; 25.2; 15.1;
11.9; 11.0. Menthyl resonances: 79.1; 47.8; 40.3; 34.2; 31.4;
25.4; 23.3; 22.2; 20.8; 15.9. EI-MS: 190 (13), 189
(100), 183 (47), 166 (15), 165 (24), 110 (12), 83 (33), 69
4.4. Determination of the C(20) configuration of 4
Furanone 9 was reacted once with (S)-2-methylbutanal21
and once with (RS)-2-methylbutanal according to the
procedure given for 10b. The product mixture was subjected
to GC: Carlo Erba HRGC 5000, permethylated b-cyclo-
dextrin column 25 m£0.22 mm (Chrompack), He, Split
50:1, isothermal 1388C. Retention times (min) and, in
parentheses, peak areas (%):

G. Grossmann et al. / Tetrahedron 59 (2003) 3237–3251
3251
Products from 9 and (RS)-2-methylbutanal
Products from 9 and (S)-2-methylbutanal
Metabolite 4
29.8 (31)
–
–
30.2 (19)
30.2 (38)
30.2 (100)
30.7 (19)
–
–
32.5 (31)
32.5 (62)
–
8. Kusumi, T.; Ohtani, I. O. In The Biology–Chemistry Interface;
Cooper, R., Snyder, J. K., Eds.; Marcel Dekker: New York,
1999; pp 103–137.
Acknowledgements
This work was supported by the Swiss National Science
Foundation (Project No. 20-63344.00). We thank Professor
¨
9. Spichty, M. Universitat Basel, personal communication.
¨
¨
¨
Dr H.-P. Fiedler, Universitat Tubingen, for the investigation
of the antimicrobial activity of our compounds,
¨
Dr M. Spichty, Universitat Basel, for calculations, and
Dr D. Martinelli, Professor Dr R. Bachofen, and PD Dr
¨
10. Fiedler, H. -P. Universitat Tubingen, personal communication.
11. McClean, K. H.; Winson, M. K.; Fish, L.; Taylor, A.; Chhabra,
S. R.; Camara, M.; Daykin, M.; Lamb, J. H.; Swift, S.; Bycroft,
B. W.; Stewart, G. S. A. B.; Williams, P. Microbiology 1997,
143, 3703–3711.
¨
H. Brandl, Universitat Zurich, for testing our substances
with respect to quorum sensing.
¨
¨
¨
12. Martinelli, D.; Bachofen, R.; Brandl, H. Universitat Zurich,
personal communication.
13. COLLECT Software, Nonius BV; 1997–2001.
14. Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr.
1994, 27, 435.
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