Synthesis of (+)-9-demethyl-7,8-dideoxycalopin as a model for the determination of the absolute stereochemistry of a new group of fungal metabolites

Article abstract of DOI:10.1002/1099-0690(200209)2002:17<2905::AID-EJOC2905>3.0.CO;2-3

A key step in the synthesis of (+)-9-demethyl-7,8-dideoxycalopin (3) is the highly stereoselective ene reaction between phenylmenthyl glyoxylate 8 and β,β-dimethylstyrene (7). Hydroboration of the resulting homoallyl alcohol 9 afforded only the undesired epimer 10, which was ultimately converted into target 3 by a sequence of oxidation, epimerization, and reduction steps. ¹H NMR comparison of the MTPA esters derived from compound 3 with those from natural calopin supported the assignment of the (2S,3R,4S) configuration to this new group of fungal metabolites. Further evidence of the absolute configuration was obtained by comparison of the CD spectra of calopin and of model compound 3. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200209)2002:17<2905::AID-EJOC2905>3.0.CO;2-3

FULL PAPER
Synthesis of (؉)-9-Demethyl-7,8-dideoxycalopin as a Model for the
Determination of the Absolute Stereochemistry of a New Group of Fungal
Metabolites
Heiner Ebel,[a] Kurt Polborn,[a][‡] and Wolfgang Steglich*[a]
Dedicated to Prof. Lutz F. Tietze on the occasion of his 60th birthday
Keywords: Asymmetric synthesis / Calopins / Configuration determination / Ene reactions / Lactones / Natural products
A key step in the synthesis of (+)-9-demethyl-7,8-dideoxy- derived from compound 3 with those from natural calopin
calopin (3) is the highly stereoselective ene reaction between
supported the assignment of the (2S,3R,4S) configuration to
phenylmenthyl glyoxylate 8 and β,β-dimethylstyrene (7). Hy- this new group of fungal metabolites. Further evidence of the
droboration of the resulting homoallyl alcohol 9 afforded only
the undesired epimer 10, which was ultimately converted
into target 3 by a sequence of oxidation, epimerization, and
reduction steps. 1H NMR comparison of the MTPA esters
absolute configuration was obtained by comparison of the
CD spectra of calopin and of model compound 3.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
The bitter taste of Boletus calopus and some closely re-
lated toadstools attracted our attention and resulted in the
discovery of the calopins and cyclocalopins, a new class of
natural product.[1] These compounds possess some unusual
structural characteristics. Common to all compounds is a
δ-lactone subunit. In the cases of O-acetylcalopin (1a) and
calopin (1b) a 3-methylcatechol residue is attached, whereas
in the more complex cyclocalopins this residue forms part
of a spiro substructure. Crucial for the correlation of both
types of compounds is the oxidative transformation of
cyclocalopin A (2b) into 1a, which proves that the stereo-
chemistries of calopins and cyclocalopins are identical.[1]
However, their absolute configurations could not be deter-
mined unambiguously. To solve this problem we carried out
an asymmetric synthesis of the calopin analogue
(2S,3R,4S)-9-demethyl-7,8-dideoxycalopin (3) and then
compared the 1H NMR properties of the corresponding
Mosher esters.
Results and Discussion
Retrosynthetic Analysis
A notable structural feature of calopin (1b) is the pres-
ence of three contiguous stereogenic centres. In order to
simplify the synthetic problems, the unusual methylcatechol
moiety of 1b was replaced by a phenyl substituent to give
the analogue 3 (Scheme 1). Retrosynthetically speaking,
opening of the lactone ring should yield δ-hydroxy ester 4,
[a]
Department
München,
Chemie,
Ludwig-Maximilians-Universität
Butenandtstrasse 5Ϫ13 (F), 81377 München, Germany
Fax: (internat.) ϩ 49-(0)89/2180-7756
E-mail: wos@cup.uni-muenchen.de
[‡]
Crystal structure determination
Eur. J. Org. Chem. 2002, 2905Ϫ2912  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0917Ϫ2905 $ 20.00ϩ.50/0
2905

H. Ebel, K. Polborn, W. Steglich
FULL PAPER
which should be obtainable by hydroboration of homoallyl
alcohol 5. The latter compound should be available by me-
ans of an enantio- and diastereoselective glyoxylate-ene re-
action between compounds 6 and 7.[2,3]
Scheme 1. Retrosynthetic analysis of model compound 3
Synthesis of Model Compound 3
Crucial for the synthesis of model compound 3 is the Figure 1. ORTEP plot derived from a single-crystal X-ray analysis
of (Ϫ)-8-phenylmenthyl ester 9
simultaneous introduction of two stereocentres at C-2 and
C-3 in an anti configuration. The glyoxylate-ene reaction
developed by Whitesell et al.[2,3] would fulfill these require-
ments, although there has been no reported application to
β,β-disubstituted styrenes. In the event, phenylmenthyl
glyoxylate 8[2,3] reacted with β,β-dimethylstyrene (7) in the
presence of SnCl4 to yield the desired α-hydroxy ester 9 as
the only detectable diastereomer (as judged by GC/MS), in
81% yield (Scheme 2). The observed selectivity is explained
by a transition state in which the aromatic residue adopts
an equatorial orientation, as described before.[3] The abso-
lute configuration of 9 was confirmed as (2S,3R) by a
single-crystal X-ray diffraction analysis (Figure 1).
chemical course of the reaction with (ϩ)-diisopinocam-
pheylborane (Ipc2BH) was the same as described earlier
(72%, matched case). In contrast, use of (Ϫ)-Ipc2BH (mis-
matched) and catecholborane in combination with Wilkin-
son’s catalyst[5,6] failed to produce any reaction whatsoever.
In order to investigate the influence of the free alcohol on
the stereochemical course of the hydroboration reaction,
homoallyl alcohol 9 was converted into silyl ether 12 with
TBSOTf (94% yield). However, this compound proved
inert to hydroboration, epoxidation, transesterification or
saponification reactions.
Scheme 2. Synthesis of all-cis δ-valerolactone 11; reagents and con-
ditions: i) SnCl4, 7, CH2Cl2, Ϫ78 °C Ǟ Ϫ25 °C (81%); ii) 9-BBN
or (ϩ)-Ipc2BH, THF, then NaOH, H2O2, ultra sound (99%); iii)
pTsOH, CH2Cl2, 28 °C (63%); iv) TBSOTf, 2,6-lutidine, DMAP,
CH2Cl2 (94%); R* ϭ (Ϫ)-8-phenylmenthyl, 9-BBN ϭ 9-borabicy-
clo[3.3.1]nonane, Ipc2BH ϭ diisopinocampheylborane, TBS ϭ tert-
butyldimethylsilyl, DMAP ϭ 4-(dimethylamino)pyridine
Unfortunately, hydroboration of the alkene 9 with 9-
borabicyclo[3.3.1]nonane (9-BBN) and lactonization of the
resulting alcohol 10 with pTsOH afforded only the un-
desired all-cis diastereomer 11,[4] the structure of which was
unambiguously determined by a single-crystal X-ray dif-
fraction analysis (Figure 2). All attempts to form the de-
Figure 2. ORTEP plot derived from a single-crystal X-ray analysis
of all-cis-valerolactone 11
The highly selective but undesired stereochemical out-
sired epimer by the use of different hydroboration agents come of the hydroboration step might have been caused by
and either the unprotected or the TBS-protected homoallyl the sterically demanding auxiliary. In an effort to eliminate
alcohols 9 and 12, respectively, failed. For 9, the stereo- this possibility, the phenylmenthyl group was cleaved by sa-
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Eur. J. Org. Chem. 2002, 2905Ϫ2912

Synthesis of (ϩ)-9-Demethyl-7,8-dideoxycalopin
FULL PAPER
ponification (90%, Scheme 3). Esterification of the resulting deprotection of silyl ether 21 to afford target 3 was accomp-
carboxylic acid 13 with MeOH and protection of the carbi- lished by treatment of the former with concentrated HCl.[7]
nol 14 with TBSOTf then afforded the silyl ether 15 (protec- Overall then, the synthesis of model compound 3 proceeded
tion of the α-hydroxy ester 14 was necessary, since attempts in nine steps and 11% yield, starting from styrene 7 and 8-
to use the free hydroxy compound for hydroboration ended phenylmenthyl glyoxylate (8).
in decomposition). The conversion of olefin 15 into the
primary alcohol 16 with 9-BBN again provided the un-
desired diastereomer in 98% yield. The stereochemistry of
the newly generated chiral centre was determined by
NOESY experiments, after acid-catalysed lactonization to
17. Furthermore, deprotection of 17 with concentrated
HCl[7] yielded the previously described all-cis-valerolactone
11. Again, no correction of the stereochemistry during the
hydroboration process was possible.
Scheme 4. Synthesis of δ-valerolactone 3; reagents and conditions:
i) (COCl)2, DMSO, NEt3, CH2Cl2, Ϫ78 °C; ii) NaHCO3, EtOH,
∆; iii) NaBH4, MeOH, 0 °C, separation of 20 [34%, steps i)Ϫiii)]
and 21 [23%, steps i)Ϫiii)]; iv) concd. HCl, THF, MeOH (96%)
NOESY experiments performed on the δ-valerolactones
21 and 3 served to confirm the cis relationship between 2-
H and 3-H and the trans arrangement of 3-H and 4-H. In
MeOH, cat. DMF, ∆ (79%); iii) TBSOTf, 2,6-lutidine, DMAP,
Scheme 3. Alternative synthesis of all-cis-δ-valerolactone 11; re-
agents and conditions: i) NaOH, THF, MeOH, ∆ (90%); ii) SOCl2,
CH2Cl2 (85%); iv) 9-BBN, THF, then NaOH, H2O2, ultra sound
(98%); v) TFA, CHCl3 (96%); vi) concd. HCl, THF, MeOH (42%);
TFA ϭ trifluoroacetic acid (concd. ϭ concentrated)
addition, lactone 3 and, to a lesser extent, precursor 21 ex-
hibited NOESY correlation signals between 2-H and 5α-H,
indicating the same preference of these δ-lactones to adopt
a boat conformation as seen in calopin (1b).[1] This observa-
tion is pivotal to the determination of the absolute config-
uration of 1b as described in the following paragraph.
Other methods such as allylic oxidation of 15 with SeO2
or reductive and regioselective ring-opening of an oxirane
intermediate were examined in an effort to introduce the
desired stereochemistry, but all proved unsuccessful.
Assignment of Absolute Configuration
With model compound 3 of known absolute configura-
tion to hand, the high-field NMR variant of Mosher’s
method[10Ϫ13] should allow the absolute configuration of
calopin (1b) to be assigned. To this end, the MTPA esters
22 and 23 were prepared (Scheme 5) from alcohol 3 by
treatment with (S)- and (R)-MTPA-Cl, respectively.
The failure of standard procedures to establish the (S)
configuration at the γ-position suggested the epimerization
of this centre as an alternative. For this purpose, alcohol 16
was oxidized to aldehyde 18 by Swern’s method (Scheme 4).
Epimerization at C-4 by use of NaHCO3 in refluxing
EtOH[8] yielded a 1:1 mixture of the diastereomeric ethyl
esters 19, indicating a transesterification under these mild
conditions.[9] This can be explained by hemiacetal forma-
tion, subsequent cyclization to a lactone intermediate and
ring-opening with EtOH. This mechanism is supported by
the observation that no transesterification occurred with ol-
efin 15 under the same conditions. Because of their instabil-
ity, the aldehydes 19 were immediately reduced with NaBH4
in MeOH, which yielded two diastereomeric alcohols that
could be separated by kinetic resolution techniques. Specif-
Scheme 5. Preparation of Mosher esters 22 and 23; reagents and
conditions: i) (S)-(ϩ)-MTPA-Cl, NEt3, DMAP, CH2Cl2; ii) (R)-
ically, acidic workup of the reaction mixture afforded the (Ϫ)-MTPA-Cl, NEt3, DMAP, CH2Cl2; MTPA ϭ α-methoxy-α-(tri-
desired δ-valerolactone 21 (23% yield from 16) and the epi-
fluoromethyl)phenylacetic acid
meric alcohol 20 (34% from 16), and these were readily sep-
arated by flash chromatography. The latter product could
The ∆δ values obtained from these compounds agree well
be re-used in the epimerization sequence just described. The with those for calopin[1] (Table 1), confirming the
Eur. J. Org. Chem. 2002, 2905Ϫ2912
2907

H. Ebel, K. Polborn, W. Steglich
FULL PAPER
brine (1 ϫ 200 mL), and then dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Flash chromatography of the residue
on silica gel with EtOAc/petroleum ether (1:15, v/v) yielded 9,
which on recrystallization from hexanes gave colourless crystals,
m.p. 77 °C. Yield: 1.59 g (81%) over 2 steps. [α]2D3 ϭ ϩ44.9 (c ϭ
0.014, CHCl3). UV (CH3CN): λmax (ε) ϭ 210 nm (sh, 16110), 265
(1410). IR (KBr): ν˜ ϭ 3484 cmϪ1 (s), 3060 (w), 3029 (w), 2961 (s),
2949 (s), 2923 (m), 2864 (w), 1715 (s), 1647 (w), 1600 (w), 1495 (w),
1454 (m), 1390 (w), 1375 (w), 1292 (m), 1227 (m), 1208 (m), 1182
(w), 1131 (w), 1095 (s), 984 (w), 898 (w), 764 (m), 745 (m), 699 (s),
542 (w). 1H NMR (300 MHz, CDCl3, TMS): δ ϭ 7.19Ϫ7.33 (m,
6 H), 7.06Ϫ7.14 (m, 4 H), 4.90 (m, 1 H), 4.88 (m, 1 H), 4.74 (td,
J ϭ 4.3, 10.7 Hz, 1 H), 3.54 (d, J ϭ 6.3 Hz, 1 H), 3.19 (d, J ϭ
6.2 Hz, 1 H), 1.91Ϫ2.01 (m, 1 H), 1.82 (dq, J ϭ 3.4, 13.4 Hz, 1 H),
1.60Ϫ1.69 (m, 1 H), 1.56 (s, 3 H), 1.46Ϫ1.54 (m, 1 H), 1.31Ϫ1.45
(m, 1 H), 1.27 (s, 3 H), 1.16 (s, 3 H), 1.04Ϫ1.20 (m, 1 H), 0.75Ϫ0.90
(m, 1 H), 0.80 (d, J ϭ 6.4 Hz, 3 H), 0.44 (q, J ϭ 11.8 Hz, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 173.5, 152.0, 143.9, 139.2,
128.7, 128.0, 127.9, 126.7, 125.3, 125.1, 113.2, 75.6, 72.1, 55.9, 50.2,
40.7, 39.3, 34.4, 31.1, 29.6, 26.1, 22.8, 22.3, 21.7 ppm. EI MS: m/z
(%) ϭ 420 (1) [Mϩ], 402 (1), 301 (1), 215 (26), 214 (23), 206 (15),
199 (17), 189 (5), 143 (16), 131 (88), 119 (100), 91 (42), 41 (10).
HRMS: calcd. 420.2664; found 420.2638. C28H36O3 (420.59): calcd.
C 79.96, H 8.63; found C 80.19, H 8.67.
(2S,3R,4S) configuration for this class of natural products.
We considered the use of a model compound for the pur-
pose of comparison to be essential, since calopin possesses
protons on only one side of the MTPA plane.[14]
Table 1. 1H NMR (CDCl3, 600 MHz, 300 K) analysis of Mosher
derivatives of 3 and 1b
Compound
∆δ(3-H)[a]
∆δ(OCH3)[a]
MTPA ester of 3
Ϫ72
Ϫ42
ϩ222
ϩ180
MTPA ester of 1b[1]
[a]
∆δ values are given in Hz [∆δ ϭ δ(S-MTPA ester) Ϫ δ(R-
MTPA ester)].[12,13]
Independent evidence for the same absolute configura-
tion of synthetic (ϩ)-9-demethyl-7,8-dideoxycalopin (3) and
(ϩ)-calopin (1b) was obtained from the similarity of the
CD spectra of both compounds (Figure 3).
(؊)-8-Phenylmenthyl (2S,3R,4R)-2,5-Dihydroxy-4-methyl-3-phenyl-
pentanoate (10). Hydroboration with 9-BBN: A solution of 9
(250 mg, 594 µmol) in dry THF (5 mL) was treated with 9-BBN
(420 mg, 3.442 mmol). After the mixture had been stirred for 12 h
at room temperature, 2  NaOH (2 mL) and 30% H2O2 (2 mL)
were added. The mixture was sonicated in an ultrasound bath for
20 min, and then acidified with 2  HCl, diluted with water
(100 mL) and extracted with EtOAc (3 ϫ 100 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. Flash chromatography on silica gel with
EtOAc/petroleum ether (1:2, v/v) gave 10 (258 mg, 99%) as a col-
ourless solid. Hydroboration with (؉)-Ipc2BH: A solution of 9
(50 mg, 119 µmol) in dry THF (1 mL) was treated with (ϩ)-
(Ipc2BH) (204 mg, 713 µmol). After the mixture had been stirred
for 3 h at room temperature 2 , NaOH (0.5 mL) and 30% H2O2
(0.5 mL) were added. The mixture was sonicated for 20 min in an
ultrasound bath, and then diluted with EtOAc (100 mL) and
washed with satd. aqueous NaHCO3 (3 ϫ 50 mL) and brine
(1 ϫ 50 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. Flash chromatography on sil-
ica gel with EtOAc/petroleum ether (1:8 Ǟ 1:3, v/v) gave 10 (38 mg,
72%) as a colourless solid; 14 mg (27%) of the starting material 9
was recovered. Compound 10: M.p. 90 °C. [α]2D3 ϭ Ϯ0. UV
(CH3CN): λmax (ε) ϭ 206 nm (15870), 265 (1410). IR (KBr): ν˜ ϭ
3464 cmϪ1 (br, s), 3060 (w), 3030 (w), 2957 (s), 2924 (s), 2879 (s),
1712 (s), 1600 (w), 1495 (m), 1455 (m), 1389 (w), 1372 (w), 1313
(w), 1210 (s), 1100 (m), 1030 (m), 984 (w), 960 (w), 766 (m), 703
Figure 3. CD spectra of (ϩ)-calopin (1b, solid line) and (ϩ)-9-de-
methyl-7,8-dideoxycalopin (3, dotted line) (CH3CN)
Experimental Section
General: Melting points (uncorrected): Büchi SMP 535. Optical ro-
tations: PerkinϪElmer 241. UV/Vis: PerkinϪElmer Lambda 16.
CD: S. A. Jobin Yvon CD-6-Dichrograph. FT IR: PerkinϪElmer
Spectrum 1000. NMR: Varian Mercury 200, Bruker ARX 300, and
AMX 600, solvent peak or TMS as internal standard. MS: Finni-
gan MAT 90 and MAT 95 Q. EI mass spectra were obtained at
70 eV with direct inlet. Column chromatography: silica gel 60
(40Ϫ63 µm, Merck). All solvents were distilled before use. Petro-
leum ether (40Ϫ60°C) was used for chromatography. (Ϫ)-8-
Phenylmenthol was purchased from Aldrich, (S)-(ϩ)- and (R)-(Ϫ)-
MTPA-Cl from Fluka. The elemental analyses were carried out by
the Microanalytical Laboratory of the Chemistry Department at
the University of Munich.
1
(s), 646 (w), 560 (w), 518 (w). H NMR (300 MHz, CDCl3, TMS):
δ ϭ 6.96Ϫ7.28 (m, 10 H), 4.83 (td, J ϭ 4.2, 10.7 Hz, 1 H), 3.55 (d,
J ϭ 4.9 Hz, 1 H), 3.35 (dd, J ϭ 6.0, 10.6 Hz, 1 H), 3.23 (dd, J ϭ
5.0, 10.7 Hz, 1 H), 2.68 (dd, J ϭ 5.9, 5.9 Hz, 1 H), 2.09Ϫ2.17 (m,
1 H), 1.93Ϫ2.04 (m, 1 H), 1.74Ϫ1.86 (m, 2 H), 1.61Ϫ1.70 (m, 2 H),
1.36Ϫ1.48 (m, 1 H), 1.25 (s, 3 H), 1.16 (s, 3 H), 1.03Ϫ1.15 (m, 1 H),
0.87 (d, J ϭ 6.9 Hz, 3 H), 0.85 (d, J ϭ 6.5 Hz, 3 H), 0.67 (q, J ϭ
11.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3, TMS): δ ϭ 174.0,
(؊)-8-Phenylmenthyl (2S,3R)-2-Hydroxy-4-methyl-3-phenylpent-4-
enoate (9): SnCl4 (1.64 mL, 13.93 mmol) was added to a solution
of freshly prepared glyoxylate 8[2,3] (prepared by ozonolysis of
4.65 mmol of the corresponding acrylate) and β,β-dimethylstyrene
(7, 685 µL, 4.66 mmol) in dry CH2Cl2 (45 mL), maintained at Ϫ78
°C. The ensuing mixture was stirred for 2.5 h at Ϫ78 °C and for 151.5, 139.4, 129.4, 128.0, 128.0, 126.8, 125.3, 125.2, 75.8, 72.3,
19 h at Ϫ25 °C, and then quenched with satd. aqueous NaHCO3
(150 mL) and diluted with EtOAc (300 mL). The separated organic
phase was washed with satd. aqueous NaHCO3 (3 ϫ 200 mL) and
65.7, 52.9, 50.3, 41.0, 39.5, 36.5, 34.4, 31.2, 28.9, 26.3, 23.7, 21.7,
15.9 ppm. EI MS: m/z (%) ϭ 438 (0.1) [Mϩ], 420 (0.1), 319 (1), 301
(1), 215 (12), 214 (11), 149 (5), 131 (33), 119 (100), 91 (54), 41 (10).
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Synthesis of (ϩ)-9-Demethyl-7,8-dideoxycalopin
FULL PAPER
HRMS: calcd. 438.2770; found 438.2794. C28H38O4 (438.60): calcd.
C 76.68, H 8.73; found C 76.19, H 8.93.
125.3, 125.1, 114.0, 74.8, 74.7, 55.1, 50.1, 40.8, 39.4, 34.6, 31.2,
29.5, 26.4, 25.6, 23.9, 23.1, 21.7, 18.0, Ϫ5.1, Ϫ6.2 ppm. EI MS: m/
z (%) ϭ 534 (ϽϽ 0.1) [Mϩ], 477 (1), 263 (84), 219 (96), 215 (40),
214 (1), 131 (22), 119 (58), 105 (100), 91 (19). FAB MS: m/z (%) ϭ
535 [Mϩ ϩ H], 477 [Mϩ Ϫ C(CH3)3]. HR FAB MS: calcd. 535.3607
[Mϩ ϩ H]; found 535.3601. C34H50O3Si (534.85): calcd. C 76.35,
H 9.42; found C 76.28, H 9.52.
(2S,3R,4R)-2-Hydroxy-4-methyl-3-phenyl-δ-valerolactone (11). Cy-
clization of 10: A solution of 10 (208 mg, 474 µmol) and p-tolu-
enesulfonic acid (180 mg, 946 µmol) in CH2Cl2 (3 mL) was stirred
for 40 h at 28 °C. The mixture was diluted with EtOAc (200 mL)
and washed with satd. aqueous NaHCO3 (2 ϫ 100 mL) and brine
(1 ϫ 100 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. Flash chromatography on sil-
ica gel with EtOAc/petroleum ether (2:5, v/v) furnished 11 (62 mg,
63%) as a colourless solid. Deprotection of 17: Concd. HCl (5
drops) was added to a solution of 17 (2.1 mg, 6.5 µmol) in THF
(0.4 mL) and MeOH (0.5 mL). After the mixture had been stirred
for 4 h at room temperature, EtOAc (20 mL) was added. The or-
ganic phase was washed with 2  NaOH (2 ϫ 10 mL), water
(1 ϫ 10 mL), and brine (1 ϫ 10 mL), dried (Na2SO4), and filtered.
The solvents were evaporated, and the residue was purified by pre-
parative TLC on silica gel (0.25 mm, 5 ϫ 20 cm) with EtOAc/petro-
leum ether (2:1, v/v) to afford 11 (0.6 mg, 45%) as a colourless
solid. M.p. 142 °C. [α]2D3 ϭ ϩ50.8 (c ϭ 0.007, CHCl3). UV
(CH3CN): λmax (ε) ϭ 203 nm (sh, 9600), 205 (9660), 208 (sh, 9450),
217 (sh, 5130), 258 (430). CD (CH3CN): λmax (∆ε) ϭ 219 nm
(ϩ0.3), 222 (ϩ0.3), 224 (ϩ0.3). IR (KBr): ν˜ ϭ 3537 cmϪ1 (s), 3476
(s), 3065 (w), 3032 (w), 2992 (w), 2969 (w), 2938 (w), 2906 (w),
1720 (s), 1604 (w), 1498 (m), 1469 (m), 1452 (m), 1411 (w), 1394
(w), 1376 (w), 1329 (w), 1244 (w), 1181 (s), 1125 (s), 1060 (m), 1031
(s), 1014 (m), 952 (w), 882 (m), 774 (w), 734 (s), 698 (s), 590 (w),
530 (w), 464 (w). 1H NMR (300 MHz, CDCl3): δ ϭ 7.27Ϫ7.39 (m,
3 H), 7.05Ϫ7.10 (m, 2 H), 4.53 (d, J ϭ 6.4 Hz, 1 H), 4.26 (ddd, J ϭ
1.2, 5.6, 11.6 Hz, 1 H), 4.00 (dd, J ϭ 11.8, 11.8 Hz, 1 H), 3.58 (dd,
J ϭ 4.9, 4.9 Hz, 1 H), 3.15 (br., s, OH), 2.57Ϫ2.72 (m, 1 H), 0.79
(d, J ϭ 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 174.8,
133.8, 129.4, 128.6, 127.6, 72.0, 69.5, 48.8, 31.9, 14.1 ppm. EI MS:
m/z (%) ϭ 206 (20) [Mϩ], 188 (1), 177 (12), 131 (100), 129 (7), 120
(10), 118 (16), 117 (29), 115 (16), 91 (58). HRMS: calcd. 206.0943;
found 206.0933. C12H14O3 (206.24): calcd. C 69.89, H 6.84; found
C 69.86, H 7.19.
(2S,3R)-2-Hydroxy-4-methyl-3-phenylpent-4-enoic Acid (13): NaOH
(1 , 3.4 mL) was added to a solution of 9 (475 mg, 1.13 mmol) in
THF (3.5 mL) and MeOH (7 mL). The mixture was heated under
reflux for 15 h and then cooled to room temperature. After addition
of water (200 mL) and 2  NaOH, the mixture was extracted with
Et2O (3 ϫ 200 mL). The combined organic layers were dried
(Na2SO4) and filtered, and the solvent was removed in vacuo to
recover (Ϫ)-8-phenylmenthol (262 mg, quantitative). The aqueous
layer was acidified with concd. HCl to pH ϭ 1 and extracted with
EtOAc (3 ϫ 200 mL). The combined organic layers were washed
with brine (1 ϫ 200 mL), dried (Na2SO4), and filtered to yield
(after evaporation of the solvent) 210 mg (90%) of 13 as a colour-
less solid, m.p. 94Ϫ95 °C. [α]2D9 ϭ ϩ44.7 (c ϭ 0.002, CHCl3). UV
(CH3CN): λmax (ε) ϭ 210 nm (sh, 10070), 261 (660). IR (KBr): ν˜ ϭ
3516 cmϪ1 (s), 3420 (m), 3089 (s), 1716 (s), 1676 (s), 1493 (m), 1451
(m), 1373 (w), 1325 (m), 1282 (m), 1231 (s), 1207 (s), 1109 (s), 1032
(w), 955 (m), 900 (s), 861 (m), 828 (m), 779 (w), 748 (m), 700 (s),
675 (w), 623 (m), 511 (w). 1H NMR (300 MHz, CDCl3, TMS): δ ϭ
7.23Ϫ7.37 (m, 5 H), 5.08 (s, 1 H), 5.05 (s, 1 H), 4.68 (d, J ϭ 5.2 Hz,
1 H), 3.82 (d, J ϭ 5.1 Hz, 1 H), 1.70 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 177.7, 143.3, 138.8, 128.5, 128.5, 127.2,
114.3, 73.1, 55.5, 22.7 ppm. EI MS: m/z (%) ϭ 206 (2) [Mϩ], 204
(4), 160 (5), 159 (9), 132 (34), 131 (100), 117 (32), 116 (18), 115
(28), 91 (41). HRMS: calcd. 206.0943; found 206.0958. C12H14O3
(206.24): calcd. C 69.89, H 6.84; found C 69.42, H 6.83.
Methyl (2S,3R)-2-Hydroxy-4-methyl-3-phenylpent-4-enoate (14):
DMF (3 drops) and SOCl2 (96 µL, 1311 µmol) were added to a
solution of 13 (180 mg, 872 µmol) in MeOH (9 mL). The mixture
was heated under reflux for 4 h and then allowed to cool to room
temperature and concentrated in vacuo. The residue was dissolved
in toluene and the solvents were evaporated again. The crude prod-
uct was purified by flash chromatography on silica gel with EtOAc/
petroleum ether (1:10, v/v) to yield 14 (152 mg, 79%) as a colourless
solid, m.p. 60Ϫ61 °C. [α]2D9 ϭ ϩ69.4 (c ϭ 0.002, CHCl3). UV
(CH3CN): λmax (ε) ϭ 210 nm (sh, 9620), 258 (210). IR (KBr): ν˜ ϭ
3403 cmϪ1 (s), 3083 (w), 3028 (w), 2958 (w), 2931 (m), 1727 (s),
1711 (s), 1646 (w), 1493 (w), 1450 (m), 1435 (s), 1374 (w), 1353
(m), 1236 (s), 1205 (s), 1178 (m), 1089 (m), 969 (w), 893 (m), 755
(w), 734 (m), 702 (s), 609 (w), 541 (w). 1H NMR (300 MHz, CDCl3,
TMS): δ ϭ 7.21Ϫ7.35 (m, 5 H), 5.04 (s, 1 H), 5.03 (s, 1 H), 4.64
(dd, J ϭ 5.4, 5.4 Hz, 1 H), 3.72 (d, J ϭ 5.9 Hz, 1 H), 3.64 (s, 3 H),
2.76 (d, J ϭ 5.3 Hz, 1 OH), 1.68 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 174.3, 143.7, 139.1, 128.5, 128.4, 127.0, 113.7, 73.3,
56.2, 52.3, 22.5 ppm. EI MS: m/z (%) ϭ 220 (ϽϽ 0.1) [Mϩ], 202
(2), 161 (1), 143 (6), 131 (100), 117 (4), 116 (10), 115 (11), 103
(2), 91 (23). HRMS: calcd. 220.1099; found 220.1112. C13H16O3
(220.26): calcd. C 70.89, H 7.32; found C 70.58, H 7.48.
(؊)-8-Phenylmenthyl (2S,3R)-2-(tert-Butyldimethylsilyloxy)-4-
methyl-3-phenylpent-4-enoate (12): TBSOTf (480 µL, 2.09 mmol),
2,6-lutidine (370 µL, 3.18 mmol), and a catalytic amount of DMAP
were added at room temperature to a solution of 9 (440 mg,
1.05 mmol) in dry CH2Cl2 (10 mL), and the reaction mixture was
stirred for 2.5 h. The mixture was diluted with EtOAc (200 mL)
and washed with satd. aqueous NaHCO3 (3 ϫ 100 mL) and brine
(1 ϫ 100 mL). The organic layer was dried (Na2SO4) and filtered,
and the solvent was removed under reduced pressure. Flash chro-
matography on silica gel with EtOAc/petroleum ether (1:100, v/v)
yielded 12 (527 mg, 94%) as a colourless oil. [α]2D9 ϭ ϩ34.8 (c ϭ
0.003, CHCl3). UV (CH3CN): λmax (ε) ϭ 209 nm (sh, 21860), 259
(830). IR (KBr): ν˜ ϭ 3087 cmϪ1 (w), 3060 (w), 3028 (w), 2956 (s),
2928 (s), 2855 (s), 1743 (s), 1649 (w), 1600 (w), 1495 (m), 1471 (m),
1453 (m), 1389 (m), 1372 (m), 1280 (w), 1249 (s), 1204 (s), 1145 (s),
1077 (w), 1029 (m), 988 (w), 939 (w), 909 (m), 892 (m), 837 (s), 810
(m), 777 (s), 764 (m), 742 (m), 700 (s), 582 (w). 1H NMR
(300 MHz, CDCl3, TMS): δ ϭ 7.01Ϫ7.31 (m, 10 H), 5.26 (s, 1 H),
Methyl (2S,3R)-2-(tert-Butyldimethylsilyloxy)-4-methyl-3-phenyl-
4.85 (s, 1 H), 4.73 (td, J ϭ 4.1, 10.7 Hz, 1 H), 3.47 (d, J ϭ 4.1 Hz, pent-4-enoate (15): TBSOTf (210 µL, 914 µmol), 2,6-lutidine
1 H), 3.09 (d, J ϭ 4.1 Hz, 1 H), 2.04 (td, J ϭ 3.3, 11.3 Hz, 1 H), (160 µL, 1374 µmol) and a catalytic amount of DMAP were added
1.71Ϫ1.81 (m, 2 H), 1.57Ϫ1.67 (m, 1 H), 1.45 (s, 3 H), 1.31Ϫ1.42 at room temperature to 14 (100 mg, 454 µmol) in dry CH2Cl2
(m, 1 H), 1.24 (s, 3 H), 1.11 (s, 3 H), 1.01Ϫ1.16 (m, 1 H), 0.82Ϫ0.93 (5 mL), and the solution was stirred for 2.5 h. The mixture was
(m, 1 H), 0.78 (d, J ϭ 6.5 Hz, 3 H), 0.71 (s, 9 H), 0.56Ϫ0.69 (m,
diluted with EtOAc (50 mL) and washed with satd. aqueous
1 H), Ϫ0.14 (s, 3 H), Ϫ0.60 (s, 3 H) ppm. 13C NMR (75 MHz, NaHCO3 (3 ϫ 30 mL) and brine (1 ϫ 30 mL). The organic layer
CDCl3): δ ϭ 171.7, 152.5, 142.5, 139.3, 129.5, 127.9, 127.7, 126.5,
Eur. J. Org. Chem. 2002, 2905Ϫ2912
was dried (Na2SO4) and filtered, and the solvent was removed un-
2909

H. Ebel, K. Polborn, W. Steglich
FULL PAPER
der reduced pressure. Flash chromatography on silica gel with
(2S,3R,4R)-2-(tert-Butyldimethylsilyloxy)-4-methyl-3-phenyl-δ-
valerolactone (17): TFA (4.8 µL, 62.3 µmol) was added to 16
EtOAc/petroleum ether (1:70, v/v) yielded 15 (129 mg, 85%) as a
colourless liquid. [α]2D9 ϭ ϩ48.0 (c ϭ 0.002, CHCl3). UV (CH3CN): (4.4 mg, 12.5 µmol) in CHCl3 (1.0 mL), and the mixture was stirred
λmax (ε) ϭ 210 nm (sh, 9980), 259 (290). IR (KBr): ν˜ ϭ 3063 cmϪ1
for 4 h at room temperature. Evaporation of the solvent afforded
(w), 3028 (w), 2951 (s), 2930 (s), 2895 (m), 2857 (s), 1758 (s), 1649 the pure product (3.9 mg, 96%) as a colourless solid, m.p. 73Ϫ75
(w), 1600 (w), 1492 (w), 1472 (m), 1452 (m), 1435 (m), 1389 (w), °C. [α]3D0 ϭ ϩ40.5 (c ϭ 0.001, CHCl3). UV (CH3CN): λmax (ε) ϭ
1362 (w), 1253 (s), 1202 (m), 1147 (s), 1028 (m), 1006 (w), 954 (w), 204 nm (sh, 11990), 208 (sh, 10510), 217 (sh, 6230), 257 (290). CD
896 (m), 886 (m), 838 (s), 810 (m), 778 (s), 742 (w), 701 (m), 618
(CH3CN): λmax (∆ε) ϭ 216 nm (ϩ3.7), 227 (ϩ2.2), 256 (0), 260
(w). H NMR (300 MHz, CDCl3, TMS): δ ϭ 7.17Ϫ7.31 (m, 5 H), (Ϫ0.2), 268 (Ϫ0.2). IR (KBr): ν˜ ϭ 3454 cmϪ1 (m), 3031 (w), 2954
5.26 (s, 1 H), 4.98 (s, 1 H), 4.51 (d, J ϭ 6.3 Hz, 1 H), 3.75 (d, J ϭ (s), 2931 (s), 2900 (m), 2856 (s), 1743 (s), 1495 (w), 1474 (m), 1460
1
6.2 Hz, 1 H), 3.58 (s, 3 H), 1.65 (s, 3 H), 0.83 (s, 9 H), Ϫ0.05 (s, (w), 1452 (w), 1407 (w), 1388 (w), 1361 (w), 1334 (m), 1259 (m),
3 H), Ϫ0.27 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 173.1,
1233 (s), 1173 (s), 1157 (s), 1118 (m), 1069 (m), 1050 (m), 1033 (m),
143.2, 139.2, 129.0, 128.2, 126.9, 113.4, 75.4, 56.3, 51.6, 25.6, 23.0,
962 (w), 905 (m), 842 (s), 778 (s), 731 (m), 700 (m), 673 (w), 583
1
18.1, Ϫ5.3, Ϫ5.9 ppm. EI MS: m/z (%) ϭ 319 (1), 277 (96), 245 (6), (w). H NMR (600 MHz, CDCl3, TMS): δ ϭ 7.23Ϫ7.33 (m, 3 H),
235 (9), 217 (9), 203 (4), 171 (6), 159 (12), 143 (44), 131 (100), 115 7.07Ϫ7.10 (m, 2 H), 4.48 (d, J ϭ 6.2 Hz, 1 H), 4.12 (dd, J ϭ 5.2,
(11), 91 (19), 89 (35). HRMS: calcd. 319.1729 [Mϩ Ϫ CH3]; found
319.1740. C19H30O3Si (334.53): calcd. C 68.22, H 9.04; found C
68.35, H 9.11.
11.4 Hz, 1 H), 3.95 (dd, J ϭ 11.7, 11.7 Hz, 1 H), 3.39 (dd, J ϭ 4.8,
4.8 Hz, 1 H), 2.52Ϫ2.59 (m, 1 H), 0.79 (d, J ϭ 7.0 Hz, 3 H), 0.70
(s, 9 H), 0.12 (s, 3 H), 0.02 (s, 3 H) ppm. 13C NMR (150 MHz,
CDCl3): δ ϭ 172.5, 134.6, 129.7, 128.0, 127.0, 70.9, 70.4, 51.2, 32.1,
25.4, 18.1, 14.2, Ϫ4.6, Ϫ5.7 ppm. EI MS: m/z (%) ϭ 305 (1), 263
(70), 219 (100), 205 (1), 177 (24), 163 (9), 161 (12), 131 (21), 117
(6), 103 (4), 91 (7), 75 (26). HRMS: calcd. 305.1573 [Mϩ Ϫ CH3];
found 305.1592.
Epoxidation of 15: Compound 15 (30 mg, 90 µmol) was dissolved
in dimethyldioxirane[15] (0.1  solution in acetone, 5.0 mL) and
stirred at room temperature for 6.5 h. The solvent was then evapor-
ated, and after addition of further dimethyldioxirane solution
(5.0 mL) the stirring was continued for 2 h. The reaction product
was concentrated under reduced pressure to afford a spectroscop-
ically pure epimeric mixture of methyl (2S,2ЈRS,3R)-2-(tert-butyldi-
methylsilyloxy)-3-(2Ј-methyloxiranyl)-3-phenylpropionate in a ratio
(2S,3R,4S)-2-(tert-Butyldimethylsilyloxy)-4-methyl-3-phenyl-δ-
valerolactone (21). i. Swern Oxidation of 16: DMSO (49.6 µL,
697.6 µmol) was added at Ϫ78 °C to a solution of oxalyl chloride
(30.4 µL, 348.2 µmol) in dry CH2Cl2 (0.7 mL), and the mixture was
stirred for 15 min. A solution of methyl ester 16 (41.0 mg,
116.3 µmol) in dry CH2Cl2 (3 ϫ 0.2 mL) was then added by syr-
inge, and after an additional 20 min, the mixture was treated with
NEt3 (97.0 µL, 695.7 µmol). It was stirred for 5 min, allowed to
warm to room temperature and stirred for a further 40 min. After
addition of water (2 mL), the mixture was diluted with CH2Cl2
(50 mL) and washed with water (1 ϫ 30 mL) and brine
(1 ϫ 30 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure to yield aldehyde 18, which
was used without purification for the epimerization experiments.
ii. Epimerization: NaHCO3 (73.0 mg, 868.9 µmol) was added to a
solution of aldehyde 18 in dry EtOH (20 mL), and the mixture was
heated under reflux for 3 h. After cooling to room temperature,
1
of 2:1. Yield: 28 mg (89%), colourless liquid. H NMR (200 MHz,
CDCl3, TMS): δ ϭ 7.27Ϫ7.31 (m, 5 H), 4.35 (d, J ϭ 5.8 Hz, 1 H),
3.65 (s, 3 H), 3.40 (d, J ϭ 5.8 Hz, 1 H), 3.36 (d, J ϭ 5.8 Hz, 1 H),
2.66 (d, J ϭ 5.4 Hz, 1 H), 1.25 (s, 3 H), 0.84 (s, 9 H), Ϫ0.07 (s,
3 H), Ϫ0.31 (s, 3 H); δ ϭ 7.27Ϫ7.31 (m, 5 H), 4.54 (d, J ϭ 6.6 Hz,
1 H), 3.55 (s, 3 H), 2.97 (d, J ϭ 6.6 Hz, 1 H), 2.72 (d, J ϭ 4.6 Hz,
1 H), 2.49 (d, J ϭ 4.8 Hz, 1 H), 1.48 (s, 3 H), 0.92 (s, 9 H), 0.01 (s,
3 H), Ϫ0.02 (s, 3 H) ppm. EI MS: m/z (%) ϭ 293 (7), 275 (11), 265
(11), 263 (16), 261 (13), 233 (100), 205 (18), 169 (9), 159 (16), 131
(39), 115 (19), 91 (20), 89 (26). HRMS: calcd. 293.1209 [Mϩ
C(CH3)3]; found 293.1235.
Ϫ
Methyl
(2S,3R,4R)-2-(tert-Butyldimethylsilyloxy)-5-hydroxy-4-
methyl-3-phenylpentanoate (16): A solution of 15 (56 mg, 167 µmol)
in dry THF (3 mL) was treated with 9-BBN (179 mg, 1467 µmol). filtration, and evaporation of the solvent, the epimeric mixture was
After the mixture had been stirred for 3.5 h at room temperature,
2  NaOH (85 µL) and 30% H2O2 (1 mL) were added. The mixture
was sonicated for 30 min, and then diluted with EtOAc (50 mL)
reduced without further purification. iii. Reduction: NaBH4
(6.6 mg, 174.5 µmol) was added at 0 °C to a solution of epimers
19 in dry MeOH (1.1 mL). After 25 min, the mixture was quenched
and washed with satd. aqueous NaHCO3 (3 ϫ 30 mL) and brine with 5 drops of 2  HCl, diluted with EtOAc (50 mL) and washed
(1 ϫ 30 mL). The organic phase was dried (Na2SO4), filtered, and
with water (3 ϫ 30 mL) and brine (1 ϫ 30 mL). The organic phase
concentrated under reduced pressure. Flash chromatography on sil-
was dried (Na2SO4), filtered, and concentrated under reduced pres-
ica gel with CHCl3/MeOH (100:1, v/v) gave 16 (58 mg, 98%) as a sure. The products were separated by flash chromatography on sil-
colourless liquid. [α]2D9 ϭ ϩ9.8 (c ϭ 0.001, CHCl3). UV (CH3CN):
λmax (ε) ϭ 207 nm (8630), 208 (8600), 258 (290). IR (KBr): ν˜ ϭ
ica gel with EtOAc/petroleum ether (1:15, v/v) to yield 21 (7.3 mg,
20%; 30% relative to recovered 20) as a colourless liquid, together
3452 cmϪ1 (w), 3030 (w), 2953 (s), 2929 (s), 2885 (m), 2857 (s), with unchanged 20 (15.2 mg, 36%). Starting from ethyl ester 20
1754 (s), 1494 (w), 1472 (m), 1462 (m), 1454 (m), 1435 (w), 1361
(70 mg, 191 µmol), the sequence of Swern oxidation, epimerization,
(w), 1253 (s), 1206 (m), 1151 (s), 1129 (s), 1032 (m), 939 (w), 878 and reduction afforded 21 (14 mg, 23%; 35% related to recovered
1
(m), 838 (s), 779 (s), 702 (m). H NMR (600 MHz, CDCl3, TMS): 20) as a liquid, together with recovered alcohol 20 (24 mg, 34%).
δ ϭ 7.21Ϫ7.29 (m, 5 H), 4.53 (d, J ϭ 5.2 Hz, 1 H), 3.59 (s, 3 H),
3.53 (dd, J ϭ 5.6, 10.8 Hz, 1 H), 3.30 (dd, J ϭ 5.9, 10.8 Hz, 1 H),
21: [α]3D1 ϭ Ϫ29.0 (c ϭ 0.01, CHCl3). UV (CH3CN): λmax (ε) ϭ
206 nm (7450), 208 (7370), 228 (250), 258 (200). CD (CH3CN):
3.10 (dd, J ϭ 6.0, 6.0 Hz, 1 H), 2.32Ϫ2.39 (m, 1 H), 1.00 (d, J ϭ λmax (∆ε) ϭ 216 nm (ϩ4.4), 226 (sh, ϩ0.7), 233 (0), 245 (Ϫ0.8). IR
6.9 Hz, 3 H), 0.94 (s, 9 H), 0.01 (s, 3 H), Ϫ0.06 (s, 3 H) ppm. 13C (KBr): ν˜ ϭ 3064 cmϪ1 (w), 3031 (w), 2957 (s), 2929 (s), 2886 (m),
NMR (150 MHz, CDCl3): δ ϭ 173.4, 139.6, 129.4, 128.1, 127.0,
75.1, 65.9, 53.3, 51.6, 35.9, 25.8, 18.2, 15.9, Ϫ5.1, Ϫ5.2 ppm.
2857 (s), 1755 (s), 1495 (w), 1472 (m), 1462 (m), 1455 (m), 1406
(w), 1390 (w), 1361 (w), 1316 (w), 1253 (s), 1199 (w), 1151 (s), 1111
EI MS: m/z (%) ϭ 305 (Ͻ 0.1), 263 (38), 219 (100), 177 (26), 163 (s), 1085 (m), 1044 (m), 1001 (m), 909 (w), 890 (w), 867 (m), 839
(10), 135 (11), 117 (7), 103 (8), 75 (60). HRMS: calcd. 305.1573
(s), 807 (m), 780 (s), 739 (w), 700 (m), 673 (w). 1H NMR (600 MHz,
CDCl3): δ ϭ 7.29Ϫ7.34 (m, 2 H), 7.23Ϫ7.26 (m, 1 H), 7.18 (d, J ϭ
[Mϩ Ϫ CH4O Ϫ CH3]; found 305.1562.
2910
Eur. J. Org. Chem. 2002, 2905Ϫ2912

Synthesis of (ϩ)-9-Demethyl-7,8-dideoxycalopin
7.4 Hz, 2 H), 4.57 (dd, J ϭ 5.4, 11.3 Hz, 1 H), 4.36 (d, J ϭ 5.3 Hz, CDCl3, TMS): δ ϭ 7.07Ϫ7.42 (m, 10 H), 5.87 (d, J ϭ 9.1 Hz, 1 H),
FULL PAPER
1 H), 4.05 (dd, J ϭ 9.2, 10.8 Hz, 1 H), 2.86 (dd, J ϭ 5.4, 8.7 Hz,
1 H), 2.53Ϫ2.62 (m, 1 H), 1.00 (d, J ϭ 6.9 Hz, 3 H), 0.77 (s, 9 H),
4.39 (dd, J ϭ 5.1, 11.5 Hz, 1 H), 4.23 (dd, J ϭ 11.5, 11.5 Hz, 1 H),
3.37 (dd, J ϭ 7.6, 8.7 Hz, 1 H), 3.00 (s, 3 H), 2.41Ϫ2.51 (m, 1 H),
Ϫ0.02 (s, 3 H), Ϫ0.26 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): 1.14 (d, J ϭ 6.7 Hz, 3 H) ppm.
δ ϭ 171.6, 139.0, 129.2, 128.3, 127.1, 72.6, 70.8, 52.3, 31.7, 25.6,
(S)-MTPA Ester of (2S,3R,4S)-2-Hydroxy-4-methyl-3-phenyl-δ-va-
18.1, 16.7, Ϫ5.1, Ϫ5.7 ppm. EI MS: m/z (%) ϭ 320 (0.03) [Mϩ],
305 (1), 263 (92), 219 (47), 205 (2), 177 (20), 163 (4), 161 (12), 131
(44), 117 (20), 103 (10), 91 (28), 75 (100). HRMS: calcd. 263.1103
[Mϩ Ϫ C(CH3)3]; found 263.1113.
lerolactone (23): The esterification was carried out with (R)-(Ϫ)-
MTPA-Cl for 5 d as described in the above example. The 1H NMR
spectrum of the crude product indicated partial epimerization at
C-2. The signals were unambiguously assigned to (S)-MTPA ester
23 by comparison of the coupling constants for 2-H and COSY
experiments. 1H NMR (600 MHz, CDCl3, TMS): δ ϭ 6.96Ϫ7.44
(m, 10 H), 5.84 (d, J ϭ 8.9 Hz, 1 H), 4.40 (dd, J ϭ 5.3, 11.7 Hz,
1 H), 4.21 (dd, J ϭ 11.6, 11.6 Hz, 1 H), 3.37 (s, 3 H), 3.25 (dd,
J ϭ 6.9, 8.9 Hz, 1 H), 2.43Ϫ2.50 (m, 1 H), 1.12 (d, J ϭ 6.9 Hz,
3 H) ppm.
Ethyl (2S,3R,4R)-2-(tert-Butyldimethylsilyloxy)-5-hydroxy-4-methyl-
3-phenylpentanoate (20): [α]3D0
ϭ Ϫ4.3 (c ϭ 0.01, CHCl3).
UV (CH3CN): λmax (ε) ϭ 206 nm (8600), 209 (sh, 8390), 258 (270).
IR (KBr): ν˜ ϭ 3436 cmϪ1 (w), 3030 (w), 2956 (s), 2929 (s), 2857
(s), 1749 (s), 1731 (m), 1494 (w), 1472 (m), 1463 (m), 1454 (m),
1389 (w), 1372 (w), 1253 (s), 1204 (m), 1182 (m), 1127 (s), 1031
(m), 939 (w), 886 (m), 838 (s), 778 (s), 702 (m). 1H NMR
(600 MHz, CDCl3, TMS): δ ϭ 7.20Ϫ7.29 (m, 5 H), 4.51 (d, J ϭ
5.5 Hz, 1 H), 4.04 (q, J ϭ 6.9 Hz, 2 H), 3.55 (dd, J ϭ 5.3, 10.8 Hz,
1 H), 3.31 (dd, J ϭ 5.4, 10.7 Hz, 1 H), 3.10 (dd, J ϭ 6.0, 6.0 Hz,
1 H), 2.32Ϫ2.40 (m, 1 H), 1.12 (t, J ϭ 7.1 Hz, 3 H), 1.00 (d, J ϭ
6.9 Hz, 3 H), 0.94 (s, 9 H), 0.02 (s, 3 H), Ϫ0.05 (s, 3 H) ppm. 13C
NMR (150 MHz, CDCl3, TMS): δ ϭ 173.0, 139.5, 129.5, 128.1,
127.0, 75.2, 65.9, 60.7, 53.4, 36.0, 25.8, 18.2, 16.0, 14.0, Ϫ5.0, Ϫ5.2
ppm. EI MS: m/z (%) ϭ 366 (ϽϽ 0.1) [Mϩ], 309 (7), 279 (17), 263
(82), 235 (100), 219 (57), 205 (13), 177 (27), 161 (29), 143 (33), 131
(57), 117 (51). HRMS: calcd. 309.1522 [Mϩ Ϫ C(CH3)3]; found
309.1492.
X-ray Crystallographic Study: Single-crystal X-ray diffraction ex-
periments were carried out with a STOE IPDS, area detection, and
a Nonius MACH 3, four-circle, computer-controlled, single-crystal
diffractometer. The structures were solved by direct methods and
refined by full-matrix, least squares against F2 of all data, using
SHELXS-86 and SHELXL-93 software.[16,17] Crystal data and de-
tails of structure determinations and refinements are summarized
in Table 2. CCDC-185723 and -185724 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk].
(2S,3R,4S)-2-Hydroxy-4-methyl-3-phenyl-δ-valerolactone
(3):
Concd. HCl (20 drops) was added to a solution of 21 (13.0 mg,
40.6 µmol) in THF (1.5 mL) and MeOH (2.0 mL). After the mix-
ture had been stirred for 4 h at room temperature, the solvent was
evaporated in vacuo. The residue was purified by preparative TLC
on silica gel (0.25 mm, 10 ϫ 20 cm) with EtOAc/petroleum ether
Table 2. Crystal data and measurement conditions for compounds
9 and 11
(2:1, v/v) to afford 3 (8.1 mg, 96%) as a colourless liquid. [α]3D0
ϭ
9
11
ϩ87.6 (c ϭ 0.001, CHCl3). [α]2D3 ϭ ϩ16.2 (c ϭ 0.002, MeOH). UV
(CH3CN): λmax (ε) ϭ 206 nm (7030), 208 (sh, 6940), 257 (210). CD
(CH3CN): λmax (∆ε) ϭ 216 nm (ϩ2.6), 225 (sh, ϩ1.2), 241 (0), 249
(Ϫ0.1). IR (KBr): ν˜ ϭ 3443 cmϪ1 (m), 3062 (w), 3030 (w), 2964
(m), 2928 (m), 2876 (w), 1747 (s), 1495 (m), 1479 (w), 1455 (s),
1387 (w), 1314 (w), 1268 (w), 1239 (m), 1188 (m), 1163 (m), 1131
Empirical formula
Formula mass
Crystal size [mm]
Crystal system
Space group
C28H36O3
420.59
0.27ϫ0.43ϫ0.53 0.13ϫ0.53ϫ0.57
tetrahedral
P41212
C12H14O3
206.24
monoclinic
P21
(s), 1109 (s), 1072 (m), 1040 (s), 998 (w), 955 (w), 889 (w), 790 (w), Lattice parameters
˚
1
a [A]
9.2152(5)
9.2152(5)
58.479(5)
90
4966.0(6)
8
1.125
1824
0.071
6.7228(12)
6.7025(15)
12.184(3)
102.87(2)
535.2(2)
2
1.280
220
0.091
743 (s), 701 (s), 544 (w). H NMR (300 MHz, CDCl3, TMS): δ ϭ
7.25Ϫ7.37 (m, 3 H), 7.13 (d, J ϭ 6.7 Hz, 2 H), 4.67 (d, J ϭ 8.6 Hz,
1 H), 4.37 (dd, J ϭ 5.6, 11.5 Hz, 1 H), 4.13 (dd, J ϭ 11.6, 11.6 Hz,
1 H), 3.25 (dd, J ϭ 6.6, 8.5 Hz, 1 H), 2.63 (s, 1 OH), 2.38Ϫ2.53 (m,
1 H), 1.12 (d, J ϭ 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3,
TMS): δ ϭ 175.0, 139.2, 128.8, 128.8, 127.5, 70.6, 67.2, 51.1, 37.0,
16.7 ppm. EI MS: m/z (%) ϭ 207 (1) [Mϩ ϩ H], 206 (6) [Mϩ], 204
(3), 188 (Ͻ 1), 177 (17), 149 (2), 131 (100), 120 (3), 118 (16), 117
(32), 115 (10), 105 (5), 91 (46). HRMS: calcd. 206.0943; found
206.0929.
˚
b [A]
˚
c [A]
β [°]
3
˚
V [A ]
Z
Dcalcd. [g·cmϪ3
F (000)
]
µ [mmϪ1
]
Radiation type
Mo-Kα
0.71073
41.7
Mo-Kα
0.71073
47.9
˚
λ [A]
2Θmax [°]
(R)-MTPA Ester of (2S,3R,4S)-2-Hydroxy-4-methyl-3-phenyl-δ-va-
hmin/hmax
Ϫ8/9
Ϫ7/7
lerolactone (22): A solution of 3 (1.0 mg, 4.8 µmol), (S)-(ϩ)-MTPA- kmin/kmax
Ϫ8/9
Ϫ57/56
Ϫ7/7
Ϫ13/13
2068
1674
1382
lmin/lmax
Cl (1.4 µL, 7.5 µmol), NEt3 (0.1 mL) and a catalytic amount of
DMAP in CH2Cl2 (0.1 mL) was stirred for 3 d. After addition of
water (1 mL), the stirring was continued for 3 h. The mixture was
diluted with EtOAc (20 mL) and washed with aqueous KHSO4
(1.1 , 3 ϫ 10 mL), 2  NaOH (1 ϫ 10 mL), satd. aqueous
NaHCO3 (2 ϫ 10 mL), and brine (1 ϫ 10 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated in vacuo. The 1H
NMR spectrum of the crude product indicated that the starting
material had been consumed completely. 1H NMR (600 MHz,
No. of measured reflections 11160
No. of unique reflections
No. of observed reflections
[I Ͼ 2σ(I)]
No. of parameters
R factor [I Ͼ 2σ(I)]
wR(F2) (all data)
2551
2229
288
141
0.0357
0.0833
0.961
0.0450
0.1374
0.929
Goodness of fit
Eur. J. Org. Chem. 2002, 2905Ϫ2912
2911

H. Ebel, K. Polborn, W. Steglich
FULL PAPER
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Received March 13, 2002
Acknowledgments
[7]
[8]
This work was supported by the Fonds der Chemischen Industrie
through a PhD fellowship to H. E. We thank Professor Martin
Banwell, ANU, Canberra, for valuable discussions and linguistic
help. Dr. Holger Piotrowski is gratefully acknowledged for his as-
sistance in measuring the X-ray crystal structure and Thomas Rot-
ter for experimental contributions.
[9]
[10]
[11]
[12]
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[O02138]
2912
Eur. J. Org. Chem. 2002, 2905Ϫ2912