Total synthesis of the mushroom metabolite (+)-calopin

Article abstract of DOI:10.1016/S0040-4020(02)01451-5

A synthesis of (+)-calopin (1a) was achieved employing a highly stereoselective ene reaction between 8-phenylmenthyl glyoxylate (3) and the β,β-dimethylstyrene 4c. Transesterification of the resulting homoallylic alcohol 5c, followed by allylic oxidation and hydrogenation yielded the δ-lactone 13 which was deprotected to the natural product 1a.

Full text of DOI:10.1016/S0040-4020(02)01451-5

Tetrahedron 59 (2003) 123–129
Total synthesis of the mushroom metabolite (1)-calopin
*
¨
Heiner Ebel, Sebastian Knor and Wolfgang Steglich
¨ ¨ ¨
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13 (F), 81377 Munchen, Germany
Received 24 September 2002; accepted 4 November 2002
Abstract—A synthesis of (þ)-calopin (1a) was achieved employing a highly stereoselective ene reaction between 8-phenylmenthyl
glyoxylate (3) and the b,b-dimethylstyrene 4c. Transesterification of the resulting homoallylic alcohol 5c, followed by allylic oxidation and
hydrogenation yielded the d-lactone 13 which was deprotected to the natural product 1a. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
and a suitably protected 3-methyl-6-(2-methylpropenyl)-
catechol 4, which should deliver the homoallylic alcohols 5
exclusively with the desired configuration at C-2 and C-3
(Scheme 1).2–4
The calopins and cyclocalopins constitute a new class of
mushroom metabolites, which are in part responsible for the
¨
¨
bitter taste of Boletus calopus (German: Schonfussrohrling)
and related mushrooms.1 Common to all compounds is a
d-lactone ring with three contiguous stereogenic centres. In
addition, calopin (1a) and its O-acetyl derivative 1b contain
a 3-methylcatechol unit, a structural motif rarely encoun-
tered in natural products. The absolute configuration of
these compounds was determined by the synthesis of (þ)-
(2S,3R,4S)-9-demethyl-7,8-dideoxycalopin (2) and com-
parison of its CD spectra and Mosher esters with those of
natural 1a.2 In this communication we report on the
asymmetric synthesis of (þ)-calopin (1a).
To prepare building block 4, 3-methylcatechol (6) was
transformed into the MOM ether 7,5 which after ortho-
lithiation6 and subsequent treatment with dimethyl
formamide afforded aldehyde 8 (Scheme 2). Wittig reaction
of 8 with i-PrP(Ph)3I gave the styrene derivative 4a in
excellent overall yield. As expected, the MOM groups did
not survive the Lewis acidic conditions of the ene reaction
and had therefore to be replaced by a less acid-labile
protecting group. After unsuccessful experiments with
benzyl, isopropyl and methylene residues, the problem
was finally solved with the 3,4-dichlorobenzyl group.7–10
To prepare the desired derivative, the MOM acetals in 4a
were cleaved quantitatively with a saturated solution of HCl
in EtOAc to yield the free catechol 4b,11 which was then
converted into the bis-3,4-dichlorobenzyl ether 4c.
The styrene derivative 4c was subjected to the ene reaction
with glyoxylate 33,4 in the presence of SnCl4 to afford the
d-hydroxy ester 5c as a single diastereomer in 81% yield
(Scheme 3). In order to prevent cleavage of the protecting
2. Results and discussion
The synthesis of (þ)-calopin (1a) employed a similar
approach to that used in preparing analogue 2.2 It relies on
the ene reaction between 8-phenylmenthyl glyoxylate (3)3,4
Keywords: natural product synthesis; calopin; lactones; asymmetric
synthesis; ene reaction.
*
Corresponding author. Tel.: þ49-89-2180-7757; fax: þ49-89-2180-7756;
Scheme 1. Stereoselective formation of the crucial intermediate 5 by an ene
reaction.
e-mail: wos@cup.uni-muenchen.de
0040–4020/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01451-5

124
H. Ebel et al. / Tetrahedron 59 (2003) 123–129
Scheme 2. Reagents and conditions: (a) MOMCl, NaH, K2CO3, DMF, 08C (90%); (b) n-BuLi, THF, 08C!rt, then DMF (96%); (c) n-BuLi, i-PrP(Ph)3I, THF,
08C!rt (87%); (d) HCl, EtOAc (99%); (e) 3,4-dichlorobenzyl chloride, K2CO3, KI, DMF, reflux (67%). MOM¼methoxymethyl; Bn(Cl)2¼3,4-
dichlorobenzyl.
ation, the sterically demanding phenylmenthyl group had to
be removed by alkaline hydrolysis (Scheme 3). The
resulting acid 9 was then converted into ethyl ester 10 the
carbinol group of which was protected with TBS-triflate. In
accord with prior experience,2 hydroboration of the TBS
ether 11 yielded only the undesired (4R)-alcohol 14. To
circumvent this problem, a sequence of allylic oxidation and
subsequent hydrogenation of the resulting allylic alcohol
was applied. Thus, allylic oxidation of 11 with stoichio-
metric amounts of SeO2 delivered the desired alcohol 12
(Scheme 4),12 although in maximising the yield (29% at
47% conversion) the reaction had to be stopped at ,50%
Scheme 3. Reagents and conditions: (a) SnCl4, CH2Cl2, 2788C, then 4c,
278!2478C (81%); (b) KOH, EtOH, DME, H2O, 658C (81%); (c) SOCl2,
conversion because of over oxidation to the corresponding
aldehyde (4%). Reduction of the unstable aldehyde yielded
some additional alcohol 12. In this manner, the allylic
alcohol 12 could be obtained in 32% yield from 11 (61%
related to recovered 11).
DMF, EtOH (83%); (d) TBSOTf, 2,6-lutidine, CH2Cl2 (90%). DME¼
dimethoxyethane; DMF¼N,N-dimethylformamide; Rp¼(2)-8-phenyl-
menthyl; TBS¼t-butyldimethylsilyl; Bn(Cl)2¼3,4-dichlorobenzyl.
groups, the styrene derivative was added to the reaction
Hydrogenation of 12 with Wilkinson’s catalyst and hydro-
gen (15 bar) in the presence of Hu¨nig’s base,13 afforded two
diastereomeric alcohols that could be easily separated due to
their different tendency towards lactonization.2 Treatment
of the crude product with TFA yielded the desired d-lactone
13 (52% yield) and the epimeric alcohol 14 (14%) that were
readily separated by flash chromatography. The stereo-
chemistry of the newly generated stereogenic centres of 13
(4S) and 14 (4R) was determined by NOESY experiments,
mixture after coordination of SnCl4 to the glyoxylate. In
analogy to the stereochemical outcome of the ene reaction
with b,b-dimethylstyrene,2 the absolute configuration of 5c
was assigned as (2S, 3R).
With the optically pure alcohol 5c to hand, the introduction
of the third stereocentre by conversion of the terminal
isopropenyl residue into the desired (S)-HOCH2CH(CH3)–
moiety was addressed. As a prerequisite for this transform-
Scheme 4. Reagents and conditions: (a) SeO2, t-BuO2H, CH2Cl2, then Me2S (32%); (b) (Ph3P)3RhCl, H2 (15 bar), benzene, then TFA, CHCl3, separation of 13
(52%) and 14 (14%); (c) TFA, CH2Cl2 (79%); (d) 5% HF–CH3CN (92%); (e) 10% Pd–C, H2 (40 bar), MeOH (68%). TFA¼trifluoroacetic acid; Bn(Cl)2¼3,4-
dichlorobenzyl.

H. Ebel et al. / Tetrahedron 59 (2003) 123–129
125
in the latter case after conversion to the corresponding
lactone 15. Attempts to avoid the formation of the undesired
(4R)-epimer by varying the conditions for the hydrogen-
ation failed.
6.90–7.00 (m, 2H). 13C NMR (75 MHz, CDCl3, TMS) d
16.6, 56.2, 57.4, 95.2, 98.9, 114.3, 124.1, 124.4, 132.6,
145.4, 149.8. EI MS m/z (%) 212 (10) [M]þ, 149 (5), 136
(100), 45 (78). HRMS calcd for C11H16O4 [M]þ 212.1049;
found 212.1043. Anal. calcd for C11H16O4 C 62.25, H 7.60;
found C 62.11, H 7.82.
The silyl ether 13 was deprotected with HF to yield alcohol
16.14,15 Deblocking of the catechol groups in 16 was
accomplished by hydrogenolysis with palladium on
charcoal and hydrogen (40 bar) in dry MeOH to afford
(þ)-calopin (1a) in 68% yield. The physical and spectro-
scopic properties of the synthetic compound were identical
with those of authentic (þ)-calopin (1a).1
3.1.2. 2,3-Bis(methoxymethoxy)-4-methylbenzaldehyde
(8). To a solution of 7 (4.59 g, 21.63 mmol) in dry THF
(80 mL) was added n-butyllithium (2.5 M solution in
hexane, 9.5 mL, 23.75 mmol) at 08C, and the mixture was
stirred for 2 h. Dry DMF (5.0 mL, 64.84 mmol) was then
added, and the mixture was stirred for additional 1 h. The
reaction was quenched with aqueous KHSO4 (1.1 M,
30 mL), the resulting mixture diluted with saturated
aqueous NH4Cl (200 mL) and extracted with EtOAc
(3£200 mL). The combined organic layers were washed
with water (3£300 mL) and brine (1£100 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure.
Flash chromatography on silica gel (EtOAc/petroleum
ether, 1:4) yielded 8 (5.00 g, 96%) as a colourless solid,
mp 55–568C. Rf¼0.25 (EtOAc/petroleum ether, 1:4). UV
(CH3CN) lmax 1 215 (20890), 261 (12660), 303 nm (2780).
Overall, the synthesis of (þ)-calopin was accomplished
from 3-methylcatechol (6) in 14 steps and 3% yield.
3. Experimental
3.1. General
Silica gel 60 (40–63 mm, Merck) and RP 18 (Lichroprepw)
were used for column chromatography. Rf values were
measured on silica gel 60 F254 TLC plates (Merck). Melting
points (uncorrected) were determined on a Bu¨chi SMP 535.
Optical rotations were determined on a Perkin–Elmer 241
polarimeter. UV/VIS spectra were recorded on a Perkin–
Elmer Lambda 16 instrument. CD spectra were measured on
a S. A. Jobin Yvon CD-6-Dichrograph. FT IR spectra were
determined on a Perkin–Elmer Spectrum 1000 spec-
trometer. 1H and 13C NMR spectra were recorded on
Bruker ARX 300, Varian VXR 400S and Bruker AMX 600
instruments. 1H and 13C chemical shifts are given with
respect to the solvent or TMS as internal standard. Mass
spectra were measured with a Finnigan MAT 90 or Finnigan
MAT 95Q sector mass spectrometer. Elemental analyses
were carried out by the Microanalytical Laboratory of the
IR (KBr) n 3435 (w), 2910 (m), 1688 (s), 1598 (m), 1487
˜
(m), 1458 (m), 1429 (m), 1380 (s), 1254 (s), 1195 (m), 1159
(s), 1078 (s), 1046 (s), 957 (s), 917 (s), 891 (s), 813 (w), 775
1
(m), 602 (w), 547 (w), 487 (w), 436 cm21 (w). H NMR
(300 MHz, CDCl3, TMS) d 2.37 (s, 3H), 3.56 (s, 3H), 3.59
(s, 3H), 5.11 (s, 2H), 5.20 (s, 2H), 7.06 (d, J¼8.0 Hz, 1H),
7.53 (d, J¼8.0 Hz, 1H), 10.34 (s, 1H). 13C NMR (75 MHz,
CDCl3, TMS) d 17.3, 57.8, 58.1, 99.3, 100.2, 123.5, 126.9,
129.3, 140.7, 148.8, 152.8, 189.8 (CHO). EI MS m/z (%)
240 (1) [M]þ, 208 (4), 195 (23), 164 (37), 45 (100). HRMS
calcd for C12H16O5 [M]þ 240.0998; found 240.0995. Anal.
calcd for C12H16O5 C 59.99, H 6.71; found C 59.97, H 6.83.
3.1.3. 2,3-Bis(methoxymethoxy)-4-(2-methylpropenyl)-
toluene (4a). To a suspension of isopropyltriphenyl-
phosphonium iodide (58.24 g, 134.73 mmol) in dry THF
(340 mL), was added n-butyllithium (2.5 M solution in
hexane, 53.4 mL, 133.50 mmol) at 08C, and the mixture was
stirred for 1 h. A solution of 8 (24.90 g, 103.64 mmol) in dry
THF (2£22 mL) was then added via syringe and the stirring
was continued for 30 min. The reaction mixture was poured
into petroleum ether (450 mL) and water (450 mL). The
separated aqueous phase was extracted with petroleum ether
(3£300 mL) and the combined organic layers then dried
(Na2SO4), filtered and concentrated under reduced pressure.
Flash chromatography on silica gel (EtOAc/petroleum
ether, 1:25) yielded 4a (24.10 g, 87%) as a colourless
liquid. Rf¼0.44 (EtOAc/petroleum ether 1:4). UV (CH3CN)
¨
¨
Chemistry Department at the Universitat Munchen. All
solvents were destilled before use. For chromatography
petroleum ether 40–608 was used. (2)-8-Phenylmenthol
was purchased from Aldrich.
3.1.1. 2,3-Bis(methoxymethoxy)toluene (7). To a solution
of 3-methylcatechol (6) (8.00 g, 64.44 mmol) in dry DMF
(64 mL) were added, at 08C, NaH (2£1.63 g, 135.83 mmol)
and further MOMCl (6 M solution in MeOH, 2£12 mL,
144.00 mmol). After addition of K2CO3 (26.7 g) and
MOMCl (6 M solution in MeOH, 18 mL, 108.00 mmol),
the mixture was stirred for 30 min, then poured into ice-cold
aqueous ammonia, diluted with EtOAc (400 mL) and
washed with aqueous ammonia (3£200 mL), water
(3£200 mL) and brine (1£200 mL). The organic layer was
dried (Na2SO4), filtered and concentrated under reduced
pressure. Flash chromatography on silica gel (EtOAc/
petroleum ether, 1:15) yielded 7 (12.28 g, 90%) as a
colourless liquid. Rf¼0.13 (EtOAc/petroleum ether, 1:15).
UV (CH3CN) lmax 1 216 (sh, 7610), 270 nm (570). IR
lmax 1 214 (23170), 247 nm (10580). IR (KBr) n 3522 (w),
˜
2956 (s), 2931 (s), 1658 (w), 1605 (w), 1566 (w), 1488 (w),
1453 (m), 1425 (m), 1390 (m), 1277 (m), 1201 (w), 1159 (s),
1084 (m), 1040 (s), 977 (s), 926 (s), 824 (w), 806 (w),
791 cm21 (w). 1H NMR (300 MHz, CDCl3 TMS) d 1.77 (s,
3H), 1.90 (s, 3H), 2.30 (s, 3H), 3.53 (s, 3H), 3.58 (s, 3H),
5.00 (s, 2H), 5.10 (s, 2H), 6.29 (s, 1H), 6.85 (d, J¼8.1 Hz,
1H), 6.88 (d, J¼8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) d
16.5, 19.5, 26.4, 57.4, 57.5, 98.9, 99.2, 120.9, 125.6, 125.6,
130.7, 131.3, 135.8, 147.5, 148.6. FAB MS m/z (%) 266 (26)
[M]þ, 235 (27), 221 (15), 190 (100). ESI MS m/z (%) 289
[MþNa]þ. HRMS (ESI) calcd for C15H22O4Na [MþNa]þ
(KBr) n 2956 (m), 2931 (m), 2901 (m), 2826 (m), 1604 (w),
˜
1586 (w), 1483 (s), 1440 (m), 1401 (w), 1310 (w), 1265 (s),
1223 (w), 1206 (m), 1187 (m), 1155 (s), 1076 (s), 1044 (s),
976 (s), 924 (m), 774 (m), 749 (w), 693 cm21 (w). 1H NMR
(300 MHz, CDCl3, TMS) d 2.32 (s, 3H), 3.49 (s, 3H), 3.60
(s, 3H), 5.11 (s, 2H), 5.18 (s, 2H), 6.83 (d, J¼7.1 Hz, 1H),

126
H. Ebel et al. / Tetrahedron 59 (2003) 123–129
289.1416; found 289.1430. Anal. calcd for C15H22O4
67.65, H 8.33; found C 67.95, H 8.64.
C
the corresponding acrylate) in dry CH2Cl2 (70 mL) was
added SnCl4 (4.27 mL, 36.40 mmol) at 2788C, and the
mixture was stirred for 10 min. Then, a solution of 4c
(5.00 g, 10.10 mmol) in dry CH2Cl2 (28 mL) was added via
syringe. The mixture was stirred for 22 h at 2478C, then
quenched with saturated aqueous NaHCO3 (0.8 L) and
diluted with Et2O (0.8 L). The organic layer was washed
with saturated aqueous NaHCO3 (3£400 mL) and brine
(1£300 mL), then dried (Na2SO4), filtered and concentrated
under reduced pressure. Flash chromatography on silica gel
(EtOAc/petroleum ether, 1:15) yielded 5c (6.42 g, 81%) as a
colourless oil. Rf¼0.45 (EtOAc/petroleum ether, 1:4).
[a]2D3¼þ32.2 (c 0.007, CHCl3). UV (CH3CN) lmax 1 202
3.1.4. 3-Methyl-6-(2-methylpropenyl)benzene-1,2-diol
(4b). 4a (504 mg, 1.892 mmol) was dissolved in a saturated
solution of HCl in EtOAc (10 mL) and stirred for 45 min.
The solvent was removed under reduced pressure, and the
crude product was purified by flash chromatography on RP
18 with MeOH/water (3:2) to yield 4b (334 mg, 99%) as a
colourless solid, mp 75–768C. UV (CH3CN) lmax 1 215
(26360), 247 (9980), 284 nm (1320). IR (KBr) n 3448 (s),
˜
3274 (s), 2979 (w), 2913 (w), 2859 (w), 1628 (w), 1573 (w),
1502 (w), 1464 (s), 1348 (m), 1322 (s), 1278 (s), 1250 (s),
1235 (s), 1192 (m), 1148 (m), 1072 (w), 1039 (s), 933 (m),
840 (w), 805 (w), 782 (w), 592 cm21 (w). 1H NMR
(300 MHz, CDCl3, TMS) d 1.68 (s, 3H), 1.92 (s, 3H), 2.24
(s, 3H), 5.01 (s, 1OH), 5.35 (s, 1OH), 6.10 (s, 1H), 6.52 (d,
J¼7.7 Hz, 1H), 6.65 (d, J¼7.7 Hz, 1H). 13C NMR (75 MHz,
CDCl3) d 15.4, 19.5, 25.8, 118.6, 120.2, 121.9, 122.5, 122.8,
139.7, 140.0, 142.0. EI MS m/z (%) 178 (100) [M]þ, 163
(42), 145 (25), 137 (14), 136 (12), 135 (11), 117 (13).
HRMS calcd for C11H14O2 [M]þ 178.0994; found
178.0998. Anal. calcd for C11H14O2 C 74.13, H 7.92;
found C 74.32, H 8.00.
(sh, 106450), 221 (sh, 36170), 271 nm (1570). IR (KBr) n
˜
3501 (w), 3058 (w), 2957 (s), 2870 (m), 1723 (s), 1643 (w),
1599 (w), 1564 (w), 1472 (s), 1455 (s), 1398 (m), 1368 (m),
1276 (s), 1215 (s), 1130 (m), 1110 (m), 1070 (m), 1031 (s),
983 (w), 954 (w), 903 (m), 874 (w), 816 (m), 762 (s),
700 cm21 (m). 1H NMR (300 MHz, CDCl3, TMS) d 0.60 (q,
J¼11.8 Hz, 1H), 0.83 (d, J¼6.4 Hz, 3H), 0.85–0.94 (m,
1H), 1.02–1.23 (m, 2H), 1.17 (s, 3H), 1.26 (s, 3H), 1.33–
1.47 (m, 1H), 1.56 (s, 3H), 1.60–1.70 (m, 1H), 1.72–1.82
(m, 1H), 1.89–2.00 (m, 1H), 2.26 (s, 3H), 2.62 (d,
J¼5.7 Hz, 1OH), 3.54 (dd, J¼5.7, 5.0 Hz, 1H), 3.85 (d,
J¼5.0 Hz, 1H), 4.77–4.92 (m, 7H), 6.89–7.02 (m, 3H),
7.12–7.24 (m, 6H), 7.36–7.50 (m, 4H). 13C NMR (75 MHz,
CDCl3) d 16.0, 21.8, 22.5, 23.7, 26.3, 28.8, 31.1, 34.3, 39.5,
41.1, 48.0, 50.4, 72.1, 73.0, 73.2, 75.6, 114.2, 125.0, 125.1,
125.3, 126.0, 126.7, 127.0, 127.9, 129.4, 129.7, 130.4,
130.4, 131.1, 131.8, 132.0, 132.1, 132.6, 137.6, 137.9,
143.5, 149.4, 149.6, 151.5, 173.5 three signals obscured.
FAB MS m/z (%) 811 (0.2) [M(37Cl335Cl)þNa]þ, 809 (0.8)
[M(37Cl325Cl2)þNa]þ, 807 (1.5) [M(37Cl35Cl3)þNa]þ,
805 (1.1) [M(35Cl4)þNa]þ. HRMS (FAB) calcd for C43-
3.1.5. 2,3-Bis(3,4-dichlorobenzyloxy)-4-(2-methylpro-
penyl)toluene (4c). To a solution of freshly prepared
catechol 4b (5.15 g, 28.90 mmol) in dry DMF (280 mL)
were added 3,4-dichlorobenzyl chloride (10.00 mL,
72.25 mmol), anhydrous K2CO3 (24 g) and KI (960 mg,
5.70 mmol). The resulting mixture was heated under reflux
for 10 h, cooled to room temperature then concentrated
under reduced pressure. The residue was dissolved in
EtOAc (1 L) and washed with water (3£0.5 L), 2 M NaOH
(3£0.5 L) and brine (1£0.5 L). The organic layer was dried
(Na2SO4), filtered and concentrated under reduced pressure.
Flash chromatography on silica gel (EtOAc/petroleum
ether, 1:100) yielded 4c (9.61 g, 67%) as a colourless oil.
Rf¼0.33 (EtOAc/petroleum ether, 1:4). UV (CH3CN) lmax
1 202 (sh, 90400), 219 (sh, 42910), 248 nm (sh, 11620). IR
H Cl35Cl3O5Na [MþNa]þ 807.1975; found 807.2033.
37
46
3.1.7. (2S,3R)-3-[2,3-Bis(3,4-dichlorobenzyloxy)-4-
methylphenyl]-2-hydroxy-4-methylpent-4-enoic acid
(9). To a solution of 5c (2.72 g, 3.47 mmol) in DME
(18 mL) and EtOH (27 mL) were added water (2.6 mL) and
KOH (584 mg, 10.41 mmol). The mixture was stirred for
20 h at 658C, then cooled to room temperature and
concentrated under reduced pressure. The residue was
poured into a mixture of petroleum ether (100 mL) and
0.5 M NaOH (300 mL) and the aqueous layer washed with
petroleum ether (4£100 mL), acidified with concentrated
HCl (pH 1), then extracted with CHCl3 (4£100 mL). The
combined organic layers were dried (Na2SO4), filtered and
concentrated under reduced pressure. Flash chromatography
on silica gel (formic acid/EtOAc/petroleum ether, 1:10:30)
yielded 9 (1.60 g, 81%) as a colourless oil. Rf¼0.22 (formic
acid/EtOAc/petroleum ether, 1:1:10). [a]2D3¼þ35.0 (c
0.005, CHCl3). UV (CH3CN) lmax 1 221 (sh, 139150),
(KBr) n 3023 (w), 2967 (w), 2926 (m), 2860 (w), 1596 (w),
˜
1564 (w), 1472 (s), 1423 (m), 1397 (s), 1360 (m), 1278 (s),
1212 (s), 1181 (w), 1131 (m), 1082 (s), 1050 (m), 1032 (s),
898 (w), 824 (w), 720 (w), 687 cm21 (w). 1H NMR
(300 MHz, CDCl3, TMS) d 1.75 (s, 3H), 1.90 (s, 3H), 2.25
(s, 3H), 4.82 (s, 2H), 4.91 (s, 2H), 6.23 (s, 1H), 6.89 (s, 2H),
7.12 (dd, J¼8.2, 1.5 Hz, 1H), 7.19 (dd, J¼8.2, 1.5 Hz, 1H),
7.35–7.43 (m, 2H), 7.45 (d, J¼1.4 Hz, 1H), 7.49 (d,
J¼1.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 16.1, 19.6,
26.5, 73.3, 73.7, 120.2, 125.7, 125.8, 127.1, 127.3, 129.8,
130.2, 130.3, 130.4, 130.6, 131.4, 132.0, 132.5, 132.6,
136.4, 137.8, 137.9, 149.4, 149.9 one signal obscured. EI
MS m/z (%) 500 (0.1) [M(37Cl335Cl)]þ, 498 (0.3)
[M(37Cl235Cl2)]þ, 496 (0.6) [M(37Cl35Cl3)]þ, 494 (0.4)
[M(35Cl4)]þ, 339 (2), 337 (12), 335 (17), 163 (9), 161
271 nm (4560). IR (KBr) n 3436 (s), 2924 (m), 1718 (m),
˜
1647 (m), 1595 (s), 1472 (m), 1398 (m), 1363 (m), 1275
(m), 1212 (m), 1130 (m), 1066 (m), 1031 (m), 899 (s), 873
(61), 159 (100). HRMS calcd for C25H Cl35Cl3O2 [M]þ
37
22
1
496.0291; found 496.0298. Anal. calcd for C25H22Cl4O2 C
60.51, H 4.47, Cl 28.58; found C 60.71, H 4.42, Cl 28.51.
(s), 812 (m), 701 (s), 592 cm21 (s). H NMR (300 MHz,
CDCl3) d 1.59 (s, 3H), 2.23 (s, 3H), 4.27 (d, J¼4.0 Hz, 1H),
4.51 (d, J¼4.0 Hz, 1H), 4.76–5.02 (m, 6H), 6.91 (d,
J¼8.3 Hz, 1H), 7.12 (d, J¼8.3 Hz, 1H), 7.31–7.41 (m, 6H).
13C NMR (75 MHz, CDCl3) d 16.0, 23.3, 48.5, 72.0, 73.0,
73.5, 114.6, 124.9, 126.2, 126.8, 127.4, 130.1, 130.1, 130.8,
130.8, 131.8, 132.0, 132.0, 132.1, 132.6, 137.3, 131.4,
3.1.6. (2)-8-Phenylmenthyl (2S,3R)-3-[2,3-bis(3,4-
dichlorobenzyloxy)-4-methylphenyl]-2-hydroxy-4-
methylpent-4-enoate (5c). To a solution of freshly prepared
glyoxylate 33,4 (prepared by ozonolysis of 12.12 mmol of

H. Ebel et al. / Tetrahedron 59 (2003) 123–129
127
143.3, 144.2, 149.8, 150.1, 177.7. EI MS m/z (%) 574 (0.02)
[M(37Cl335Cl)]þ, 572 (0.1) [M(37Cl235Cl2)]þ, 570 (0.3)
[M(37Cl35Cl3)]þ, 568 (0.3) [M(35Cl4)]þ, 500 (0.1), 498
(0.6), 496 (1.2), 494 (1), 411 (0.1), 409 (0.4), 163 (9), 161
4.07–4.22 (m, 2H), 4.17 (d, J¼5.0 Hz, 1H), 4.49 (d,
J¼5.0 Hz, 1H), 4.76 (d, J¼11.4 Hz, 1H), 4.91 (d,
J¼11.3 Hz, 1H), 4.93 (d, J¼11.4 Hz, 1H), 5.00 (s, 1H),
5.04 (d, J¼11.3 Hz, 1H), 5.36 (s, 1H), 6.90 (d, J¼8.0 Hz,
1H), 7.01 (d, J¼8.0 Hz, 1H), 7.19 (dd, J¼8.2, 2.0 Hz, 1H),
7.25 (dd, J¼8.2 Hz, 2.0 Hz, 1H), 7.42 (d, J¼8.2 Hz, 1H),
7.42 (d, J¼8.2 Hz, 1H), 7.49 (d, J¼2.0 Hz, 1H), 7.51 (d,
J¼2.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 26.0, 25.2,
14.2, 16.0, 18.1, 23.5, 25.6, 48.6, 60.6, 73.1, 73.7, 74.2,
114.6, 125.9, 125.9, 127.1, 127.5, 129.8, 130.1, 130.5,
130.5, 131.2, 131.4, 132.1, 132.2, 132.6, 137.6, 137.7,
142.5, 142.5, 149.6, 149.8, 172.6. FAB MS m/z (%) 713
(0.03) [Mþ(37Cl235Cl2)2H], 711 (0.03) [Mþ(37Cl35Cl3)2H],
709 (0.02) [Mþ(35Cl4)2H], 699 (0.1), 697 (0.1), 695 (0.1),
659 (0.3), 657 (1.2), 655 (2.2), 653 (1.6), 611 (0.2), 609
(0.3), 607 (0.2), 163 (9), 161 (48), 159 (80), 73 (100). EI MS
m/z (%) 712 (,0.1) [M(37Cl335Cl)]þ, 701 (,0.1), 699 (0.1),
697 (0.2), 695 (0.1), 659 (3), 657 (11), 655 (20), 653 (15),
609 (2), 163 (10), 161 (68), 159 (100). HRMS (EI) calcd for
(59), 159 (100). HRMS calcd for C27H Cl35Cl3O5 [M]þ
37
24
570.0348; found 570.0320. Anal. calcd for C27H24Cl4O5 C
56.86, H 4.24, Cl 24.87; found C 56.98, H 4.24, Cl 24.94.
3.1.8. Ethyl (2S,3R)-3-[2,3-bis(3,4-dichlorobenzyloxy)-4-
methylphenyl]-2-hydroxy-4-methylpent-4-enoate (10).
To a solution of 9 (1.78 g, 3.12 mmol) in EtOH (40 mL)
were added DMF (0.10 mL) and SOCl2 (381 mL,
5.21 mmol). The mixture was stirred for 6 h at room
temperature and then concentrated under reduced pressure.
The residue was dissolved in toluene and the solvents were
evaporated again. The crude product was purified by flash
chromatography on silica gel (EtOAc/MeOH/petroleum
ether, 2:3:50) to yield 10 (1.55 g, 83%) as a colourless oil.
Rf¼0.34 (EtOAc/petroleum ether, 1:4). [a]2D3¼þ52.9 (c
0.001, CHCl3). UV (CH3CN) lmax 1 225 nm (sh, 24050). IR
C34H Cl35Cl3O5Si [M2CH3]þ 697.1291; found 697.1292.
37
39
(KBr) n 3500 (m), 3073 (w), 2980 (s), 2928 (s), 2872 (m),
Anal. calcd for C35H42Cl4O5Si C 58.99, H 5.94; found C
59.08, H 6.16.
˜
1898 (w), 1732 (s), 1647 (m), 1596 (m), 1565 (m), 1471 (s),
1398 (s), 1367 (s), 1275 (s), 1130 (s), 1068 (s), 1031 (s), 947
(m), 900 (s), 873 (s), 817 (s), 735 (m), 688 (m), 673 (w), 657
(m), 592 (w), 537 cm21 (w). 1H NMR (300 MHz, CDCl3) d
1.22 (t, J¼7.1 Hz, 3H), 1.64 (s, 3H), 2.26 (s, 3H), 2.86 (d,
J¼5.2 Hz, 1OH), 4.16–4.26 (m, 3H), 4.54 (dd, J¼5.2,
4.7 Hz, 1H), 4.81–5.03 (m, 6H), 6.96 (d, J¼8.0 Hz, 1H),
7.14–7.19 (m, 2H), 7.21 (d, J¼8.0 Hz, 1H), 7.39 (d,
J¼8.2 Hz, 1H), 7.41 (d, J¼8.2 Hz, 1H), 7.45 (d, J¼2.0 Hz,
1H), 7.48 (d, J¼2.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) d
14.1, 16.0, 23.1, 48.1, 61.8, 73.3, 73.4, 73.8, 114.8, 125.3,
126.7, 127.3, 127.5, 130.0, 130.2, 130.8, 130.8, 131.5,
131.8, 132.0, 132.1, 132.6, 132.6, 137.5, 137.7, 143.2,
149.6, 149.7, 173.9. EI MS m/z (%) 600 (0.3)
[M(37Cl235Cl2)]þ, 598 (0.6) [M(37Cl35Cl3)]þ, 596 (0.5)
[M(35Cl4)]þ, 497 (5), 495 (9), 493 (7), 441 (0.2), 439
3.1.10. Ethyl (2S, 3R)-3-[2,3-bis(3,4-dichlorobenzyloxy)-
4-methylphenyl]-2-(tert-butyldimethylsilyloxy)-4-
(hydroxymethyl)pent-4-enoate (12). To a stirred suspen-
sion of SeO2 (234 mg, 2.11 mmol) in CH2Cl2 (1.5 mL) was
added t-butyl hydroperoxide (5.5 M solution in nonane,
1.68 mL, 9.24 mmol) and the mixture was stirred for
30 min. Then, a solution of 11 (3.000 g, 4.22 mmol) in
CH2Cl2 (1.5 mL) was added and the stirring was continued
for 48 h. The reaction was quenched by addition of
dimethylsulfide (1.0 mL, 13.65 mmol). After 2 h, the
mixture was diluted with Et2O (250 mL) and washed with
2 M NaOH (4£200 mL) then brine (1£200 mL). The
organic layer was dried (Na2SO4), filtered and concentrated
under reduced pressure. The products were separated by
flash chromatography on silica gel with EtOAc/petroleum
ether (1:8) to yield the allylic alcohol 12 (900 mg, 29%) and
the corresponding aldehyde (123 mg, 4%; Rf¼0.35,
EtOAc/petroleum ether, 1:4) as colourless oils, together
with unreacted 11 (1.594 g, 53%).
(0.8), 437 (1.1), 163 (10), 161 (62), 159 (100). HRMS calcd
35
28
for C29H Cl4O5 [M]þ 596.0691; found 596.0694. Anal.
calcd for C29H28Cl4O5 C 58.21, H 4.72, Cl 23.70; found C
58.12, H 4.62, Cl 23.70.
3.1.9. Ethyl (2S,3R)-3-[2,3-bis(3,4-dichlorobenzyloxy)-4-
methylphenyl]-2-(tert-butyldimethylsilyloxy)-4-methyl-
pent-4-enoate (11). To 10 (902 mg, 1.507 mmol) in dry
CH2Cl2 (14 mL) were added 2,6-lutidine (530 mL,
4.522 mmol) and TBSOTf (690 mL, 3.015 mmol) at
2158C, and the solution was stirred for 30 min. After
additional stirring for 3 h at room temperature, the mixture
was diluted with EtOAc (100 mL) and washed with
saturated aqueous NaHCO3 (3£100 mL), then brine
(1£100 mL). The organic layer was dried (Na2SO4), filtered
and the solvent removed under reduced pressure. Flash
chromatography on silica gel (EtOAc/petroleum ether,
1:100) yielded 11 (968 mg, 90%) as a colourless oil.
Rf¼0.40 (EtOAc/petroleum ether, 1:10). [a]2D3¼21.1 (c
0.002, CHCl3). UV (CH3CN) lmax 1 222 (sh, 33700),
For the conversion of the undesired aldehyde into additional
alcohol 12, a solution of the aldehyde (123 mg, 134 mmol)
in dry MeOH (2 mL) was treated with NaBH4 (12.80 mg,
338 mmol) at 2158C. The mixture was stirred for 30 min at
this temperature, then quenched with water (2 mL) and 2 M
HCl (0.2 mL), diluted with Et2O (100 mL) and washed with
water (3£50 mL) and brine (1£50 mL). The organic layer
was dried (Na2SO4), filtered and concentrated under
reduced pressure. Flash chromatography on silica gel
(EtOAc/petroleum ether, 1:10) yielded 12 (97 mg) as a
colourless oil. Total yield of 12: 997 mg (32%). Rf¼0.28
(EtOAc/petroleum ether, 1:4). [a]2D3¼þ32.2 (c 0.003,
CHCl3). UV (CH3CN) lmax 1 223 (sh, 36630), 273 nm
(1630). IR (KBr) n 3488 (s), 2953 (s), 2929 (s), 2882 (m),
˜
274 nm (1440). IR (KBr) n 2929 (s), 2857 (s), 1753 (s), 1565
2857 (s), 1851 (m), 1731 (m), 1712 (m), 1643 (w), 1565 (w),
1472 (s), 1397 (m), 1367 (m), 1276 (s), 1250 (s), 1214 (s),
1141 (s), 1066 (s), 1032 (s), 1003 (m), 937 (w), 896 (m), 872
(w), 826 (s), 779 (s), 745 (w), 689 (w), 658 (w), 595 cm21
(w). 1H NMR (600 MHz, CDCl3) d 20.41 (s, 3H), 20.06 (s,
3H), 0.81 (s, 9H), 1.23 (t, J¼7.1 Hz, 3H), 2.25 (s, 3H), 3.86
˜
(w), 1472 (s), 1398 (m), 1362 (m), 1274 (s), 1251 (s), 1211
(s), 1144 (s), 1068 (m), 1031 (s), 939 (w), 899 (m), 875 (m),
838 (s), 778 (s), 733 (w), 687 cm21 (w). 1H NMR
(300 MHz, CDCl3) d 20.38 (s, 3H), 20.06 (s, 3H), 0.81
(s, 9H), 1.21 (t, J¼7.2 Hz, 3H), 1.56 (s, 3H), 2.25 (s, 3H),

128
H. Ebel et al. / Tetrahedron 59 (2003) 123–129
(d, J¼13.3 Hz, 1H), 3.89 (d, J¼13.3 Hz, 1H), 4.11–4.16
(m, 1H), 4.17–4.22 (m, 1H), 4.45 (d, J¼4.5 Hz, 1H), 4.53
(d, J¼4.5 Hz, 1H), 4.77 (d, J¼11.4 Hz, 1H), 4.92 (d,
J¼11.4 Hz, 1H), 4.94 (d, J¼11.4 Hz, 1H), 5.03 (d,
J¼11.4 Hz, 1H), 5.31 (s, 1H), 5.62 (s, 1H), 6.90 (d,
J¼7.9 Hz, 1H), 7.01 (d, J¼7.9 Hz, 1H), 7.21 (dd, J¼8.2,
2.0 Hz, 1H), 7.27 (dd, J¼8.2, 2.0 Hz, 1H), 7.43 (d,
J¼8.0 Hz, 2H), 7.50 (d, J¼1.8 Hz, 1H), 7.53 (d,
J¼1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 26.1,
25.3, 14.2, 16.0, 18.1, 25.7, 43.9, 60.9, 66.6, 73.2, 73.9,
74.6, 114.7, 126.0, 126.0, 127.1, 127.7, 129.8, 130.3, 130.5,
130.5, 131.1, 131.5, 132.1, 132.3, 132.6, 132.7, 137.4,
137.6, 146.4, 149.6, 150.0, 172.4. EI MS m/z (%) 673 (0.3)
[M(37Cl325Cl2)2C(CH3)3]þ, 671 (0.5) [M(37Cl35Cl3)2
C(CH3)3]þ, 669 (0.4) [M(35Cl4)2C(CH3)3]þ, 629 (0.5),
627 (2), 625 (4), 623 (3), 599 (0.2), 597 (0.5), 595 (0.5), 495
(4), 493 (7), 491 (5), 335 (6), 333 (9), 163 (10), 161 (64),
466 (4), 423 (3), 421 (3), 349 (4), 347 (5), 337 (4) 335 (7),
333 (2), 163 (11), 161 (63), 159 (100). HRMS calcd for
C29H29Cl4O5Si [M2C(CH3)3]þ 625.0538; found 625.0549.
Anal. calcd for C33H38Cl4O5Si C 57.90, H 5.60; found C
57.20, H 5.60.
3.1.12. Ethyl (2S,3R,4R)-3-[2,3-bis(3,4-dichlorobenzyl-
oxy)-4-methylphenyl]-2-(tert-butyldimethylsilyloxy)-5-
hydroxy-4-methylpentanoate (14). Rf¼0.27 (EtOAc/
petroleum ether, 1:4). [a]2D3¼224.8 (c 0.006, CHCl3). UV
(CH3CN) lmax 1 223 (sh, 128590), 273 nm (8770). IR (KBr)
n 3467 (w), 2929 (s), 2857 (s), 1747 (m), 1565 (w), 1472 (s),
˜
1398 (m), 1361 (m), 1275 (s), 1252 (s), 1211 (m), 1130 (s),
1064 (m), 1032 (s), 877 (m), 837 (s), 778 (s), 687 cm21 (w).
1H NMR (600 MHz, CDCl3) d 20.10 (s, 3H), 0.02 (s, 3H),
0.94 (s, 9H), 1.03 (d, J¼7.0 Hz, 3H), 1.18 (t, J¼7.1 Hz, 3H),
1.87 (s, 1OH), 2.23 (s, 3H), 2.22–2.28 (m, 1H), 3.26 (dd,
J¼10.8, 4.8 Hz, 1H), 3.46 (dd, J¼10.8, 4.7 Hz, 1H), 3.73–
3.80 (m, 1H), 4.06–4.17 (m, 2H), 4.37 (d, J¼3.9 Hz, 1H),
4.85 (d, J¼11.5 Hz, 1H), 4.89 (d, J¼11.5 Hz, 1H), 4.93 (d,
J¼11.1 Hz, 1H), 4.97 (d, J¼11.1 Hz, 1H), 6.90 (d,
J¼8.0 Hz, 1H), 7.06 (d, J¼8.0 Hz, 1H), 7.14 (dd, J¼8.1,
1.8 Hz, 1H), 7.27 (dd, J¼8.1, 1.8 Hz, 1H), 7.39 (d,
J¼8.3 Hz, 1H), 7.42 (d, J¼8.3 Hz, 1H), 7.44 (d,
J¼1.7 Hz, 1H), 7.53 (d, J¼1.7 Hz, 1H). 13C NMR
(150 MHz, CDCl3) d 25.1, 24.8, 14.1, 15.7, 16.0, 18.3,
25.8, 36.7, 43.6, 60.9, 66.3, 73.1, 73.7, 75.1, 124.9, 126.2,
127.2, 127.4, 129.9, 130.0, 130.4, 130.5, 131.1, 132.1,
132.6, 132.6, 133.2, 137.5, 137.6, 149.5, 149.8, 173.2 one
signal obscured. EI MS m/z (%) 671 (0.1) [M(37Cl35Cl3)2
C(CH3)3]þ, 669 (0.2) [M(35Cl4)2C(CH3)3]þ, 657 (0.3), 655
(0.6), 653 (0.4), 631 (1), 629 (6), 627 (11), 625 (7), 601
(0.5), 599 (1), 597 (0.8), 163 (10), 161 (64), 159 (100).
159 (100). HRMS calcd for C31H Cl4O6Si [M2C(CH3)3]þ
35
33
669.0801; found 669.0798. Anal. calcd for C35H42Cl4O6Si
C 57.70, H 5.81, Cl 19.46; found C 57.69, H 5.64, Cl 19.56.
3.1.11. (2S,3R,4S)-3-[2,3-Bis(3,4-dichlorobenzyloxy)-4-
methylphenyl]-2-(tert-butyldimethylsilyloxy)-4-methyl-
d-valerolactone (13). To a solution of 12 (120.0 mg,
164.7 mmol) in dry benzene (5 mL) was added (Ph3P)3RhCl
(15.3 mg, 16.5 mmol) under an argon atmosphere. Hydro-
genation then was carried out at 15 bar hydrogen pressure
for 4 h. After evaporation of the solvent, the residue was
dissolved in CHCl3 (5 mL), TFA (63.0 mL, 817.8 mmol)
was added and the mixture was stirred for 10 min. Then, the
products were concentrated under reduced pressure and
separated by flash chromatography on silica gel (EtOAc/
petroleum ether, 1:12) to yield 13 (57.5 mg, 52%) and 14
(17.0 mg, 14%) as colourless oils. 13: Rf¼0.36 (EtOAc/
petroleum ether, 1:4). [a]2D3¼234.5 (c 0.001, CHCl3). UV
(CH3CN) lmax 1 217 (27800), 231 (sh, 18740), 272 nm
(1490). CD (CH3CN) lmax D1 224 (23.6), 232 (20.7), 237
(0), 243 (þ0.7), 274 (þ0.4) 288 (0), 294 nm (20.1). IR
HRMS calcd for C31H Cl35Cl3O6Si [M2C(CH3)3]þ
37
35
671.0957; found 671.0948. Anal. calcd for C35H44Cl4O6Si
C 57.54, H 6.07; found C 57.67, H 5.95.
3.1.13. (2S,3R,4R)-3-[2,3-Bis(3,4-dichlorobenzyloxy)-4-
methylphenyl]-2-(tert-butyldimethylsilyloxy)-4-methyl-
d-valerolactone (15). To 14 (33.0 mg, 45.2 mmol) in
CH2Cl2 (4 mL) was added TFA (16.0 mL, 207.7 mmol),
and the mixture was stirred for 6 h at room temperature.
Then, the solvent was removed under reduced pressure and
the residue flash chromatographed on silica gel (EtOAc/
petroleum ether, 1:10) to yield 15 (24.4 mg, 79%) as a
colourless oil. Rf¼0.36 (EtOAc/petroleum ether, 1:4).
[a]2D3¼217.9 (c 0.003, CHCl3). UV (CH3CN) lmax 1 216
(24870), 229 (sh, 16460), 271 nm (1200). CD (CH3CN)
lmax D1 223 (þ3.0), 226 (0), 228 (22.7), 233 (0), 240
(KBr) n 3470 (w), 3021 (w), 2954 (s), 2982 (s), 2884 (m),
˜
2856 (m), 2737 (w), 1750 (s), 1596 (w), 1564 (w), 1493 (w),
1472 (s), 1429 (m), 1398 (m), 1379 (m), 1360 (m), 1317 (w),
1277 (m), 1254 (s), 1235 (m), 1214 (s), 1195 (m), 1151 (s),
1129 (s), 1067 (s), 1044 (m), 1032 (s), 1004 (m), 940 (w),
875 (m), 839 (s), 817 (s), 781 (s), 758 (s), 687 (w), 668 (w),
639 (w), 584 (w), 558 (w), 536 cm21 (w). 1H NMR
(600 MHz, CDCl3) d 20.23 (s, 3H), 0.00 (s, 3H), 0.77 (s,
9H), 0.88 (d, J¼6.7 Hz, 3H), 2.25 (s, 3H), 2.45–2.54 (m,
1H), 3.26 (dd, J¼9.2, 5.8 Hz, 1H), 3.99 (dd, J¼11.3, 9.4 Hz,
1H), 4.31 (d, J¼5.8 Hz, 1H), 4.49 (dd, J¼11.3, 5.3 Hz, 1H),
4.74 (d, J¼11.3 Hz, 1H), 4.86 (d, J¼11.4 Hz, 1H), 4.94 (d,
J¼11.9 Hz, 1H), 4.98 (d, J¼11.9 Hz, 1H), 6.88 (d,
J¼7.8 Hz, 1H), 6.93 (d, J¼7.8 Hz, 1H), 7.10–7.15 (m,
2H), 7.37–7.42 (m, 4H). NOESY (600 MHz, CDCl3,
selected correlations) 2-H/5a-H, 2-H/3-H, 3-H/14-H,
3-H/5a-H, 4-H/5b-H, 4-H/11-H, 5a-H/14-H. 13C NMR
(75 MHz, CDCl3) d 25.7, 25.0, 16.0, 16.3, 18.1, 25.6, 31.2,
45.1, 69.8, 72.6, 73.0, 73.9 125.6, 126.0, 126.9, 127.0,
129.5, 129.7, 130.4, 130.5, 130.6, 131.5, 132.1, 132.6,
132.6, 137.4, 137.5, 149.5, 150.0, 171.4 one signal
obscured. EI MS m/z (%) 669 (0.2) [M(37Cl35Cl3)2CH3]þ,
631 (2) [M(37Cl335Cl)2C(CH3)3]þ, 629 (10) [M(37Cl2
35Cl2)2C(CH3)3]þ, 627 (18) [M(37Cl35Cl3)2C(CH3)3]þ,
625 (13) [M(35Cl4)2C(CH3)3]þ, 609 (3), 507 (2), 468 (2),
(þ0.6), 273 (þ0.2) 284 (0), 293 nm (20.1). IR (KBr) n
˜
3436 (s), 2927 (m), 1746 (m), 1636 (w), 1473 (m), 1398 (w),
1359 (w), 1320 (w), 1297 (m), 1212 (w), 1129 (m), 1065
(m), 1031 (m), 874 (w), 815 (m), 783 (w), 687 cm21 (w). 1H
NMR (600 MHz, CDCl3) d 0.05 (s, 3H), 0.13 (s, 3H), 0.74
(s, 9H), 0.77 (d, J¼6.7 Hz, 3H), 2.26 (s, 3H), 2.56–2.61 (m,
1H), 3.82–3.94 (m, 1H), 4.00 (dd, J¼11.5, 11.5 Hz, 1H),
4.15 (dd, J¼11.5, 4.8 Hz, 1H), 4.48 (d, J¼6.7 Hz, 1H), 4.77
(d, J¼11.9 Hz, 1H), 4.78–4.99 (m, 3H), 6.77 (d, J¼7.7 Hz,
1H), 6.93 (d, J¼7.7 Hz, 1H), 7.11–7.19 (m, 2H), 7.32–7.46
(m, 4H). NOESY (600 MHz, CDCl3, selected correlations)
2-H/3-H, 3-H/4-H, 4-H/5a-H, 5b-H/14-H, 11-H/14-H. 13C
NMR (150 MHz, CDCl3) d 25.8, 24.6, 13.9, 16.0, 18.2,
25.5, 32.3, 42.6, 70.1, 71.2, 73.0, 73.1, 126.1, 126.9, 128.7,

H. Ebel et al. / Tetrahedron 59 (2003) 123–129
129
128.7, 129.6, 129.8, 130.3, 130.5, 131.6, 132.0, 132.0,
132.5, 132.5, 137.3, 137.5, 149.5, 151.3, 174.95 one signal
obscured. EI MS m/z (%) 684 (,0.1) [M(37Cl35Cl3)]þ, 673
(,0.1), 671 (0.2), 669 (0.4), 667 (0.3), 631 (2), 629 (9), 627
(16), 625 (11), 468 (1), 466 (1), 163 (9), 161 (61), 159 (100).
238 (20.6), 279 nm (20.5). IR (KBr) n 3369 (s), 3019 (m),
˜
2965 (m), 2928 (m), 1738 (s), 1588 (m), 1470 (s), 1435 (m),
1378 (m), 1359 (m), 1315 (s), 1277 (s), 1216 (s), 1123 (s),
1066 (m), 1042 (m), 1015 (w), 982 (w), 949 (w), 919 (w),
891 (w), 853 (w), 806 (w), 756 (s), 667 (w), 597 (w), 565
(w), 543 cm21 (w). 1H NMR (600 MHz, CDCl3) d 1.10 (d,
J¼6.7 Hz, 3H), 2.22 (s, 3H), 2.72–2.80 (m, 1H), 3.52 (dd,
J¼7.6, 5.3 Hz, 1H), 4.02 (dd, J¼11.6, 11.6 Hz, 1H), 4.51
(dd, J¼11.6, 6.7 Hz, 1H), 4.71 (d, J¼7.6 Hz, 1H), 6.53 (d,
J¼7.8 Hz, 1H), 6.71 (d, J¼7.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 15.4, 17.3, 31.9, 45.0, 69.0, 71.3,
119.3, 123.3, 123.9, 123.9, 141.8, 144.0, 173.9. EI MS m/z
(%) 253 (14) [MþH]þ, 252 (83) [M]þ, 234 (6), 207 (17),
206 (100), 191 (25), 177 (56), 164 (12), 163 (16), 161 (16),
159 (28), 149 (14), 147 (10), 145 (13), 137 (76), 136 (17),
131 (15), 124 (5), 121 (11), 91 (20). HRMS calcd for
C13H16O5 [M]þ 252.0998; found 252.1002.
HRMS calcd for C29H Cl4O5Si [M2C(CH3)3]þ 625.0538;
35
29
found 625.0518.
3.1.14. (2S,3R,4S)-3-[2,3-Bis(3,4-dichlorobenzyloxy)-4-
methylphenyl]-2-hydroxy-4-methyl-d-valerolactone
(16). To a solution of 13 (89.7 mg, 131 mmol) in CH3CN
(6.5 mL) was added aqueous HF (40%, 0.35 mL), and the
mixture was stirred for 18 h. Then, the solution was
concentrated under reduced pressure and the residue
partitioned between Et2O (50 mL) and water (40 mL). The
organic layer was washed with water (2£40 mL) and brine
(1£40 mL), dried (Na2SO4), filtered and concentrated under
reduced pressure. Flash chromatography on silica gel
(EtOAc/petroleum ether, 1:1) afforded 16 (68.7 mg, 92%)
as a colourless oil. Rf¼0.10 (EtOAc/petroleum ether, 1:3).
[a]2D3¼þ2.3 (c 0.002, CHCl3). UV (CH3CN) lmax 1 223 nm
(sh, 123570). CD (CH3CN) lmax D1 228 (21.6), 230
(20.5), 232 (0), 233 (þ1.1), 236 (þ0.3), 239 (0), 247
Acknowledgements
This work was supported by the Fonds der Chemischen
Industrie through a PhD fellowship to H. E. We thank the
Fond der Chemischen Industrie for financial support and
Professor Martin Banwell (ANU, Canberra) for valuable
discussions.
(20.34) 272 nm (20.3). IR (KBr) n 3458 (m), 3019 (w),
˜
2962 (m), 2928 (m), 1747 (s), 1596 (w), 1564 (w), 1493 (m),
1472 (s), 1428 (m), 1398 (s), 1360 (m), 1319 (w), 1279 (s),
1214 (s), 1162 (w), 1130 (s), 1065 (s), 1032 (s), 875 (w), 816
(m), 793 (w), 757 (s), 688 (w), 667 (w), 637 (w), 591 (w),
536 cm21 (w). 1H NMR (400 MHz, CDCl3) d 1.06 (d,
J¼6.8 Hz, 3H), 2.24 (s, 3H), 2.29–2.41 (m, 1H), 2.82 (s,
1OH), 3.79 (dd, J¼9.5, 7.0 Hz, 1H), 4.13 (dd, J¼11.6,
11.6 Hz, 1H), 4.33 (dd, J¼11.6, 5.3 Hz, 1H), 4.63 (d,
J¼9.5 Hz, 1H), 4.81 (d, J¼11.5 Hz, 1H), 4.90 (d,
J¼11.5 Hz, 1H), 4.97 (s, 2H), 6.75 (d, J¼8.0 Hz, 1H),
6.94 (dd, J¼8.0, 0.6 Hz, 1H), 7.12 (dd, J¼8.2, 2.0 Hz, 1H),
7.18 (dd, J¼8.2, 2.0 Hz, 1H), 7.38 (d, J¼8.2 Hz, 1H), 7.39
(d, J¼8.2 Hz, 1H), 7.40 (d, J¼1.9 Hz, 1H), 7.47 (d,
J¼1.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 16.0,
16.6, 36.8, 42.9, 66.7, 70.6, 73.0, 73.9, 123.6, 126.7, 126.9,
127.0, 129.5, 129.7, 130.3, 130.4, 130.5, 131.3, 131.9,
132.0, 132.5, 132.5, 137.4, 137.8, 149.6, 150.9, 175.2. EI
MS m/z (%) 572 (3) [M(37Cl235Cl2)]þ, 570 (6)
[M(37Cl35Cl3)]þ, 568 (5) [M(35Cl4)]þ, 542 (2), 540 (2),
411 (3), 410 (4), 409 (5), 408 (5), 366 (3), 365 (2), 364 (5),
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35
24
(100). HRMS calcd for C27H Cl4O5 [M]þ 568.0378; found
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