Synthesis of α-Acetyl lactones; access to 14-membered bislactones by attempts at direct ring closure

Article abstract of DOI:10.1055/s-2002-31907

α-Acetyl lactones are accessed by Mukaiyama-Claisen reactions. Attempts at direct 7-membered ring closure, by either intramolecular alkylation of 4-iodobutyl acetoacetate or olefin metathesis from allyl 2-allyl-3-oxobutanoate, afford exclusively dimeric 14-membered ring products instead of the expected caprolactones.

Full text of DOI:10.1055/s-2002-31907

LETTER
957
Synthesis of -Acetyl Lactones; Access to 14-Membered Bislactones by
Attempts at Direct Ring Closure
S
J
ynthesis
e
of -Acet yl
n
Lact one
s
s Christoffers,* Heiko Oertling, Peter Fischer, Wolfgang Frey
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax +49(711)6854269; E-mail: jchr@po.uni-stuttgart.de
Received 5 March 2002
Dedicated to Professor Robert G. Bergman on the occasion of his 60 birthday
th
4
sulting chloroalkyl esters were converted to the corre-
sponding iodoesters 4a,b in a Finkelstein reaction.
Cyclization of -iodopropyl ester 4a with DBU afforded
Abstract: -Acetyl lactones are accessed by Mukaiyama–Claisen
reactions. Attempts at direct 7-membered ring closure, by either in-
tramolecular alkylation of 4-iodobutyl acetoacetate or olefin meta-
thesis from allyl 2-allyl-3-oxobutanoate, afford exclusively dimeric valerolactone 2a in moderate yield (21%); respective con-
1
4-membered ring products instead of the expected caprolactones.
version of 4b, in contrast, did not result in seven-mem-
bered ring formation. With stoichiometric amounts of
base (NaH), only one chromatographically uniform prod-
uct could be isolated which surprisingly turned out to be
Key words: acylations -dicarbonyl compounds, lactones, macro-
cycles, metathesis
5
the dimer 5. Crystallization from hexanes/EtOAc yielded
one diastereoisomer, with a single NMR signal set, for
-
-
Ketoesters are valuable substrates in organic synthesis.
Acetyl- -butyrolactone, prepared from acetylacetic es-
which X-ray diffraction analysis established the achiral
6
trans configuration (cf. Figure 1). Closer inspection of
ters and ethylene oxide, is commercially available and fre-
quently used as a building block. The next higher
homologue, -acetyl- -valerolactone (2a), is accessible
via acetylation of the ester enolate, generated by deproto-
nation of the parent 5-pentanolide (1a); the yields,
though, have been reported as not reproducible. In fact,
in all our attempts to prepare 2a, the best result was an iso-
lated yield of 8% obtained with NaH-KH-EtOAc in THF.
Preparation of the seven-membered -acetyl lactone 2b
from -caprolactone (1b) by an analogous deprotonation/
the 13C NMR spectrum, however, revealed a complete
second set of signals (Table). The corresponding racemic
cis configuration was assigned to this minor component
1
3
1
on the basis of the C chemical shifts, and a trans/cis ratio
of 91:9 derived likewise from the NMR spectra. With
these two diastereoisomeric 14-membered ring structures
as the only products characterized, formation of the sev-
en-membered ring obviously is disfavored over that of the
2
1
4-membered ring.
acetylation sequence failed completely; bases applied Transesterification. Iodobutane 6 was prepared from
7
were NaH, KH, LDA, t-BuOK, acetylating agents Ac O, chlorobutanol 3b by a sequence of acetalization and
2
AcCl, EtOAc (see Scheme 1). We hence decided on a di- Finkelstein reaction. Both acetals are extraordinarily acid-
rect ring closure approach for preparing lactones 2a and sensitive and need to be distilled from and stored over
2
b, by either (1) intramolecular alkylation, (2) intramolec-
ular transesterification, or (3) ring-closing olefin metathe-
sis (RCM).
Alkylation. Transesterification of alcohols 3a, b with
methyl acetylacetate followed a protocol developed in our
laboratory which allows for the azeotropic removal of
3
methanol from the reaction mixture (Scheme 2). The re-
Scheme 1 Attempts at -acetylation of lactones. Conditions for 2a:
NaH, cat. KH, EtOAc in THF, 23 °C, 16 h.
Scheme 2 Intramolecular alkylation. a) AcCH CO Me, 5 mol%
2
2
DMAP, cyclohexane, Dean–Stark trap, reflux, 16 h; 66% from 3a,
2% from 3b. b) NaI, acetone, reflux, 16 h; 70% (4a), 68% (4b). c)
DBU, C H , reflux, 16 h, 21%. d) NaH, THF, reflux, 16 h, 14%.
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
9
1
437-2096,E;2002,0,06,0957,0961,ftx,en;G06202ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
©
6
6

9
58
J. Christoffers et al.
LETTER
at all,11 we preferred to utilize benzylidenedichloro(1,3-
dimesitylimidazolidine-2-ylidene)(tricyclohexylphos-
phane)ruthenium(II)12 as metathesis catalyst. This is one
of a new generation of Ru catalysts with N-heterocyclic
carbene ligands which combine higher activity with im-
proved stability.13 RCM with 3 mol% Ru-catalyst in re-
fluxing CH Cl yielded, after column chromatography
2
2
and recrystallization, a crystalline product with once again
1
13
a predominant single set of H and C NMR resonances
which were in perfect accord with the constitution of the
expected product 2c (see Scheme 4). The EI mass spec-
trum displayed two intense peaks at m/z 155 and 154
+
which we have erroneously interpreted as the [MH] and
+
[
M]
·
ions, respectively, of lactone 2c. Formation of 2c
1
4
has been proposed in the literature. Catalytic hydrogena-
tion of the presumed RCM product 2c surprisingly did not
afford the lactone 2b, though, but rather the acyclic dike-
toester 10 as the only isolable hydrogenation product,
apart from starting material. Its constitution was estab-
Figure 1 Molecular structure of the achiral 14-membered ring
trans-5a.
Na CO . Alkylation of methyl acetylacetate with 6 and lished unequivocally by 2D NMR (H,H-COSY, HMBC,
2
3
subsequent hydrolysis of the protecting group furnished HMQC). Formation of 10 definitely refutes structure 2c
-
hydroxyalkyl compound 7, which seemed to be a rea- for the RCM product.
sonable starting material for lactonization. With catalytic
amounts of DMAP and under conditions allowing for
azeotropic removal of MeOH, however, no conversion
was observed. With Brønsted acid catalysts (TosOH,
H SO ), no lactone 2b was formed either. Intramolecular
Closer inspection of the mass spectrum of the RCM prod-
uct in fact revealed two peaks of low intensity at m/z 308
(
6%), 307 (2%), indicating a dimeric constitution. Fortu-
nately, single crystals of the RCM product could be grown
from CH Cl /hexanes, and X-ray diffraction analysis es-
2
4
2
2
transesterification thus appears an unsuitable strategy for
closing the seven-membered ring of lactone 2b
15
tablished the dimeric structure 9 (cf. Figure 2). Once
again, closure of the 14-membered ring has prevailed over
that of the seven-membered lactone. GC-MS analysis,
moreover, of the crude RCM reaction mixture (after filtra-
tion) revealed no traces of the ‘monomeric’ cyclization
product 2c.
(
Scheme 3).
Scheme 3 Attempt at intramolecular lactonization. a) ethylvinyl-
ether, cat. TosOH, 0 °C, 1.5 h; 67%. b) NaI, Na CO , acetone, reflux,
2
3
1
6 h; 60%. c) 1. AcCH CO Me, NaH, THF, reflux, 16 h; 2. HCl–
2 2
NH Cl–H O; 61%. EE = 1-ethoxyethyl.
4
2
Olefin Metathesis. Ring closing olefin metathesis (RCM)
is a recent preparative method which is increasingly ap-
plied for the synthesis of normal-, medium-sized, and
8
,9
large rings. We consequently considered to likewise
close the seven-membered ring by RCM of the corre-
1
0
sponding diallyl precursor 8. Since Ru catalysts of the Scheme 4 14-Membered ring formation is favored over seven-
membered ring formation. a) 3 mol% Ru-catalyst, CH Cl , 40 °C,
first generation showed no conversion with compound 8
2
2
1
d; 73%. b) Pd–BaSO , H (1 atm), EtOH, 23 °C, 1 h; 57%.
4 2
Synlett 2002, No. 6, 957–961 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of -Acetyl Lactones
959
Synthetic Potential. Macrocyclizations by RCM general-
ly are not stereoselective with respect to C-C double bond
configuration. It was recently demonstrated, though, that
the reversibility of the RCM reaction under certain condi-
tions results in exclusive formation of E-isomers.17 Pre-
requisite for such high E-selectivity is strain or steric
hindrance in the Z-isomer; which probably holds also for
the E,Z- and Z,Z-isomers of the bislactone 9. With a sim-
ple RCM protocol and from readily available starting ma-
terial this 14-membered ring system thus is obtained in
73% isolated yield (after chromatographic purification)
and with exceptional stereochemical purity. More than
Figure 2 Molecular structure of meso-E,E-isomer 9a (trans).
9
5% of the crystalline material is E,E-configured, with
Of the six possible diastereoisomers of the macrolactone
C-4/C-11-configuration exclusively R,S (meso).
9
, only the meso-E,E-form 9a is realized in the crystalline
1
state. From the H NMR spectrum of another single crys- Mukaiyama Aldol and Claisen Reactions. Since all at-
tal a complete set of /J data is derived for 9a.15 Upon tempts at direct seven-membered ring closure had been
standing in solution a concentration-dependent equilibri- unsuccessful, we finally decided, as originally planned, to
um is established between 9a and the epimer rac-E,E-9b. start from the parent -valero (1a) and -caprolactone
The C chemical shifts of 9a,b as well as of the corre- (1b). The trimethylsilylketene acetals 11a,b derived from
sponding two E,Z-isomers 9c,d are collected in the Table 1a,b have been described; the literature yields could be
1
3
18
1
6
(Figure 3).
improved in our hands (83% 11a, 66% 11b). The si-
lylether 11b was converted with stoichiometric amounts
of acetaldehyde and BF OEt as Lewis acid in satisfying
3
2
yield into the hydroxy lactone 12 in a Mukaiyama aldol
19
reaction. Oxidation of this material with the Dess–Mar-
2
0
tin periodinane (DMP) at last gave the desired -acetyl
21
lactone 2b. Actually, the silylethers 11a,b can be acety-
lated directly, with acetic anhydride and TiCl as Lewis
4
acid catalyst, in a Mukaiyama-type Claisen reaction. Via
this route, 2a and 2b are obtained in two steps from the
parent lactones 1a,b in 50–60% overall yield (Scheme 5).
Figure 3 Numbering of compounds 5 and 9.
Table 13C NMR Chemical Shiftsa,b of Compounds 5 and 9 (Carbon Numbering of 5a, 5b follows that of 9a)
5
a
5b
9a
9b
9cc
9dc
C-1/8
28.17
23.16
27.17
60.47
202.38
28.63
169.68
63.99
28.05
126.72
126.56
127.03
127.06
124.11
1
25.10
C-2/9
23.19
27.26
59.87
202.50
28.67
169.94
64.08
132.26
30.74
58.72
201.60
28.64
168.74
65.34
132.92
30.68
58.91
201.41
28.54
168.93
65.67
133.03
135.65
131.63
1
30.89
C-3/10
C-4/11
C-4a/11a
C-4b/11b
C-5/12
30.89
31.36
31.15
2
6.22
59.16
59.19
58.24
5
9.06
d
d
d
201.51
2
01.27
28.80
2
8.57
169.05
1
68.98
C-7/14
65.96
66.24
64.01
6
0.74
a
ppm relative to TMS as internal standard; 11.74 T, 298 K, 1.0 mol dm–3 in CDCl3.
/
b
c
d
FID 64 k, zero filled to size 512 k for a digital resolution of 0.03 Hz, (<0.001 ppm).
The double set is not differentiated as to E- or Z-hemisphere.
Not detected.
Synlett 2002, No. 6, 957–961 ISSN 0936-5214 © Thieme Stuttgart · New York

9
60
J. Christoffers et al.
LETTER
(
6) Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-176501 (5a) and no. CCDC-176500
(
9a). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [Fax: +44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
(
(
7) Djakovitch, L.; Eames, J.; Fox, D. J.; Sansbury, F. H.;
Warren, S. J. Chem. Soc., Perkin Trans. 1 1999, 2771.
8) Reviews: (a) Schuster, M.; Blechert, S. Chem. unserer Zeit
2
001, 35, 24. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18. (c) Fürstner, A. Angew. Chem. Int. Ed.
000, 39, 3012; Angew. Chem. 2000, 112, 3140.
2
(
(
(
d) Blechert, S. Pure Appl. Chem. 1999, 71, 1393.
e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
f) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371. (g) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2036; Angew. Chem. 1997, 109, 2124.
9) Recent example for macrolactones: Lee, C. W.; Grubbs, R.
H. J. Org. Chem. 2001, 66, 7155.
(
Scheme 5 Mukaiyama-type aldol and Claisen reactions yield -ace-
tyl- -valero (2a) and -caprolactone (2b).
(
(
10) (a) Nakamura, K.; Miyai, T.; Nagar, A.; Oka, S.; Ohno, A.
Bull. Chem. Soc. Jpn. 1989, 62, 1179. (b) Ralls, J. W.;
Lundin, R. E.; Bailey, G. F. J. Org. Chem. 1963, 28, 3521.
11) Conversion of -dicarbonyl compounds with Ru-catalysts of
the first generation requires the addition of Ti(i-PrO)4:
Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
Acknowledgement
We are grateful to the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie for generous support of this work.
H. O. thanks the Graduiertenkolleg ‘Synthetische, mechanistische
und reaktionstechnische Aspekte von Metallkatalysatoren’ for a fel-
lowship. Moreover, we are deeply indebted to Simon Gessler, Tech-
nische Universität Berlin, for providing us with the Ru catalyst.
9
130.
12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
999, 1, 953.
(
(
1
13) Herrmann, W. A.; Kohl, F. J.; Schwarz, J. In Synthetic
Methods of Organometallic and Inorganic Chemistry,
Transition Metals Part 3, Vol. 9; Herrmann, W. A., Ed.;
Thieme: Stuttgart, 2000, 106.
References
(
1) (a) Korte, F.; Machleidt, H. Chem. Ber. 1957, 90, 2137.
b) Korte, F.; Büchel, K.-H.; Scharf, D.; Zschocke, A. Chem.
(14) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000,
41, 9973.
(
Ber. 1959, 92, 884.
2) (a) Raulins, N. R.; Berdahl, D. R.; Bury, T. G. J. Org. Chem.
(15) 4,11-Diacetyl-5,12-dioxo-6,13-dioxa-1,8-cyclotetra-
decadiene (9). To a solution of 500 mg (2.74 mmol) ester 8
(
1980, 45, 920. (b) Hintzer, K.; Weber, R.; Schurig, V.
in 30 mL CH
mL CH Cl were added. The reaction mixture was heated to
reflux for 1 d, the solvent stripped off, and the residue
purified by chromatography on SiO (MTB/hexanes, 1:1, R
2 2
Cl , 70 mg (0.082 mmol) Ru catalyst and 40
Tetrahedron Lett. 1981, 22, 55.
2
2
(
(
3) Christoffers, J.; Önal, N. Eur. J. Org. Chem. 2000, 1633.
4) Chlorobutyl compound: Lermer, L.; Neeland, E. G.;
Ounsworth, J. P.; Sims, R. J.; Tischler, S. A.; Weiler, L. Can.
J. Chem. 1992, 70, 1427.
5) 3,10-Diacetyl-2,9-dioxo-1,8-dioxacyclotetradecane (5). A
solution of 500 mg (1.76 mmol) iodoester 4b in 2 mL THF
was added dropwise at 0 °C to a suspension of NaH (55%,
2
f
= 0.14) to give 9 as a colorless solid (307 mg, 0.996 mmol,
73%), mp 119 °C. Crystallization from MeOH afforded a
crystalline material which consists predominantly of a single
(
1
13
diastereoisomer 9a (single H and C NMR signal set).
From a CH Cl solution of this material, single crystals of 9a
2
2
9
0.1 mg, 2.06 mmol) in 20 mL THF, and the reaction
mixture heated to reflux overnight. Aq citric acid solution
20 mL, 20%) was added, and the mixture extracted with
could be grown for the X-ray diffraction analysis. In CDCl
3
solution, 9a epimerizes to a matrix-dependent 9a/9b
1
(
equilibrium mixture. H NMR (CDCl , 500 MHz): 9a
3
hexanes (3 10 mL). The organic phases were combined
= 2.242 (COCH , s, 3 H), 2.46 (3-H , m, 1 H), 2.651
3
0
B
and dried over MgSO . The solvent was stripped off, and the
(3-H , dddd, J = (–) 14.8 Hz, J = 11.3 Hz, J = 8.0 Hz,
4
A
crude product purified by chromatography on SiO2
J = 0.9 Hz, 1 H), 3.542 (4-H, dd, J = 11.3 Hz, J = 3.6 Hz,
1 H), 4.380 (7-H , ddt, J = (–)11.8 Hz, J = 5.7 Hz, J = 1.2
(
hexanes/EtOAc, 2:1, R = 0.24), yielding lactone 5 as a
f
B
5
5
colorless solid (37 mg, 0.12 mmol, 14%), mp 109–110 °C.
Crystallization from hexanes/EtOAc afforded a product with
one predominant diastereoisomer (single signal set in the
Hz, 1 H), 4.857 (7-H , ddd, J = (–)11.8 Hz, J = 7.5 Hz,
A
5
J = 0.8 Hz, 1 H), 5.633 (1-H, ddddd, J = 15.3 Hz, J = 7.5
5
Hz, J = 5.7 Hz, J = 1.6 Hz, J = 0.9 Hz, 1 H), 5.725 (2-H,
5
5
NMR spectra) from which single crystals of the meso-
ddddd, J = 15.3 Hz, J = 8.0 Hz, J = 5.2 Hz, J = 1.1 Hz,
5
1
13
1
diastereoisomer 5a could be grown. H NMR (CDCl , 500
J = 0.8 Hz, 1 H) ppm. C{ H}-NMR (CDCl , 125 MHz) of
3
3
MHz): = 1.36–1.50 (m, 4 H), 1.57–1.65 (m, 2 H), 1.68–
the major (9a) and minor (9b) E,E-diastereoisomers as well
1.75 (m, 2 H), 1.77–1.84 (m, 2 H), 1.91–1.99 (m, 2 H), 2.22
as of the two E,Z-diastereoisomers (9c, 9d): cf. Table. IR
(
(
s, 6 H), 3.43 (dd, J = 11.6 Hz, J = 3.5 Hz, 2 H), 4.19–4.23
–1
(
ATR): 1733 (vs), 1709 (vs), 1641 (w)cm . MS (EI, 70 eV):
1
3
1
m, 2 H), 4.27–4.31 (m, 2 H) ppm. C{ H}-NMR (CDCl ,
+
3
m/z (%) = 308 (6) [M ], 307 (2), 155 (63), 154 (50), 137 (24),
12 (24), 111 (30), 95 (40), 94 (28), 67 (32), 43 (100). Mol.
mass calcd. for C1 H O : 308.1260; found: 308.1265 (M ).
1
25 MHz) of the major (5a) and minor (5b) diastereoisomer:
1
–
1
cf. Table. IR (KBr): 1728 (vs), 1705 (vs) cm . MS (EI, 70
eV): m/z (%) = 312 (45) [M ], 270 (44), 157 (91), 139 (60),
+
1
6
20
6
+
Anal. Calcd. for C H O : C, 62.33; H, 6.54. Found: C,
1
6
20
6
4
3 (100). Anal. Calcd. for C H O : C, 61.53; H, 7.74.
16 24 6
62.02; H, 6.42.
Found: C, 61.33; H, 7.70.
Synlett 2002, No. 6, 957–961 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of -Acetyl Lactones
961
(
16) Structural Elucidation. With two asymmetric carbon
atoms and two C=C double bonds, the macrolactone 9
comprises four stereogenic elements; six diastereoisomers
thence are possible for compound 9, four of them chiral. The
two stereocenters can be in either a rac (R,R or S,S) or meso-
R,S relationship, with the acetyl groups cis or trans,
respectively; the two double bonds may have E,E, E,Z, or
Z,Z configuration. As Figure 2 shows, the single crystal
obtained from the purified RCM product represents the
meso-E,E-diastereoisomer 9a, in accord with the
In an even more concentrated solution, and after 30,000
scans, two additional signal sets can be detected, in a 7:3
ratio (overall relative intensity ca. 5%) and with 16 lines
each. Since this per se excludes a Z,Z configuration, these
2
3
resonances were assigned to the meso-E,Z- (9c, trans) and
rac-E,Z-diastereoisomer (9d, cis), respectively (cf. Table).
No resonances of a Z,Z-isomer were observed.
(17) Fürstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett. 2001, 3,
449.
(18) Rubottom, G. M.; Gruber, J. M.; Marrero, R.; Juve, H. D.;
Kim, C. W. J. Org. Chem. 1983, 48, 4940.
(19) (a) Mukai, C.; Suzuki, K.; Nagami, K.; Hanaoka, M. J.
Chem. Soc., Perkin Trans. 1 1992, 141. (b) Mukai, C.;
Mihira, A.; Hanaoka, M. Chem. Pharm. Bull. 1991, 39,
2863. (c) Mukai, C.; Suzuki, M.; Hanaoka, K. Chem. Pharm.
Bull. 1990, 38, 567.
1
3
predominant set of eight C resonances. To unequivocally
correlate X-ray diffraction with NMR solution
2
2
stereochemistry, another crystal was selected from the
single crystal crystallization crop (0.5 0.3 0.05 mm).
On the basis of 15 unique reflexes, detected by rotation
photograph, P2 /c was determined as the space group for this
1
crystal, which definitely established its structural identity
with the single crystal on which the diffraction analysis was
(20) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(21) -Acetyl- -caprolactone (2b). A solution of 0.50 mL (540
mg, 5.29 mmol) Ac O and 0.59 mL TiCl (1.02 g, 5.37
performed. The crystal ( 10 g) was dissolved in CDCl
3
2
4
–3
1
(
0.3 mL; 10–5 mol dm solution), and a H NMR spectrum
mmol) in 10 mL CH Cl was stirred for 20 min at –78 °C and
2 2
recorded immediately. Apart from a minor impurity, the
spectrum displayed a clean set of seven H multiplets. For
then added to a solution of 500 mg (2.68 mmol) of
1
silylenolether 11b in 130 mL CH Cl . The reaction mixture
2
2
the two olefinic resonances at 5.725 and 5.633 ppm (1/8- and
was stirred at –70 °C for 1 h, warmed to 23 °C, stirred for
2
/9-H), numerical analysis afforded a coupling constant of
another 0.5 h, and poured into a sat. aq NaHCO solution
3
3
15.3 Hz which is clearly in the J
range and thus
(400 mL). The mixture was neutralized with HCl (20%) and
extracted successively with CH Cl (2 100 mL) and EtOAc
5
trans
unequivocally establishes the E,E configuration. The two
2
2
diastereotopic protons 7/14-H ,H appear well
(1 100 mL). The organic phases were combined and dried
A
B
differentiated at 4.857 and 4.380 ppm.
over MgSO . The solvent was stripped off, and the crude
4
Upon standing at ambient temperature, though, a second
product purified by filtration through SiO with EtOAc,
2
signal set evolved in the NMR sample, with the O-CH H
affording lactone 2b as a colorless solid (354 mg, 2.27
A
B
1
protons now almost isochronous around 4.6 ppm while the
resonances of the other five protons appear shifted but
slightly. We thence presume that the corresponding rac-E,E-
diastereoisomer 9b is formed by epimerization of the
stereocenters C-4 and C-11 via the respective enol
mmol, 85%), mp 57 °C. H NMR (CDCl , 300 MHz):
3
= 1.54–1.83 (m, 3 H), 1.94–2.07 (m, 2 H), 2.12–2.20 (m, 1
H), 2.27 (s, 3 H), 3.69 (dd, J = 10.9 Hz, J = 1.9 Hz, 1 H),
4.28 (ddd, J = 12.8 Hz, J = 9.7 Hz, J = 0.7 Hz, 1 H), 4.32–
1
3
1
4.39 (m, 1 H) ppm. C{ H}-NMR (CDCl , 125 MHz):
3
tautomers. After 24 h, a 1:1 equilibrium is established
between 9a and 9b. The position of this equilibrium is
matrix-dependent, however: if sufficient crystalline material
= 24.89 (CH ), 27.06 (CH ), 28.57 (CH ), 28.66 (CH ),
2
2
2
3
56.67 (CH), 69.38 (CH ), 173.05 (C), 202.60 (C) ppm. IR
2
–
1
(KBr): 1725 (vs), 1702 (vs), 1690 (vs) cm . MS (CI, CH ):
4
1
3
1
+
is dissolved in CDCl for a C NMR spectrum, the H NMR
m/z (%) = 157 (100) [M + H]. Anal. Calcd. for C H O : C,
3
8
12
3
spectrum after two weeks integrates for 93:7 (9a:9b). The
C spectrum displays an additional set of eight signals (cf.
Table), with chemical shifts so close to those of the major
isomer 9a that a change in double bond configuration is
ruled out absolutely.
61.52; H, 7.74. Found: C, 61.48; H, 7.71.
(22) Fischer, P.; Gräf, R.; Stezowski, J. J.; Weidlein, J. J. Am.
Chem. Soc. 1977, 99, 6131.
(23) The term ‘meso’ for the R,S,E,Z-diastereoisomer is
misleading, since this compound is in fact chiral.
13
Synlett 2002, No. 6, 957–961 ISSN 0936-5214 © Thieme Stuttgart · New York