Studies on the α-acetylation of δ-valerolactone and ε-caprolactone

Article abstract of DOI:10.1016/S0040-4020(03)00511-8

The synthetic approach to α-acetylated δ-valero- (7a) and ε-caprolactone (7b) is reported. While 7a was isolated in 21% yield from the respective iodoester 5a by an alkylation sequence involving transesterification and Finkelstein reaction, 7b was not obtained from 5b but the dimer 8. Also transesterification and olefin ring closing metathesis (RCM) failed to prepare 7b. RCM resulted in the dimeric lactone 10, showing that the formation of 14-membered rings is favored over that of seven-membered rings. A Mukaiyama-type Claisen reaction finally gave α-acetyl lactones 7a and 7b in practically useful quantity of about 10 g (62% yield): starting lactones 13a,b were converted to silylenolethers 14a,b, which were acetylated with acetic anhydride in presence of the Lewis acid catalyst TiCl₄. However, acetylation depends on the addition sequence of starting materials: if the mixture of Ac₂O/TiCl₄ is added to 14b, lactone 7b can be further converted to give bis-oxepanonyl ethanols 15a,b. Both compounds 15 were characterized by X-ray crystallography and NMR.

Full text of DOI:10.1016/S0040-4020(03)00511-8

Tetrahedron 59 (2003) 3769–3778
Studies on the a-acetylation
of d-valerolactone and 1-caprolactone
*
Jens Christoffers, Heiko Oertling, Peter Fischer and Wolfgang Frey
¨ ¨
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 18 November 2002; revised 23 January 2003; accepted 21 March 2003
Abstract—The synthetic approach to a-acetylated d-valero- (7a) and 1-caprolactone (7b) is reported. While 7a was isolated in 21% yield
from the respective iodoester 5a by an alkylation sequence involving transesterification and Finkelstein reaction, 7b was not obtained from
5b but the dimer 8. Also transesterification and olefin ring closing metathesis (RCM) failed to prepare 7b. RCM resulted in the dimeric
lactone 10, showing that the formation of 14-membered rings is favored over that of seven-membered rings. A Mukaiyama-type Claisen
reaction finally gave a-acetyl lactones 7a and 7b in practically useful quantity of about 10 g (62% yield): starting lactones 13a,b were
converted to silylenolethers 14a,b, which were acetylated with acetic anhydride in presence of the Lewis acid catalyst TiCl4. However,
acetylation depends on the addition sequence of starting materials: if the mixture of Ac2O/TiCl4 is added to 14b, lactone 7b can be further
converted to give bis-oxepanonyl ethanols 15a,b. Both compounds 15 were characterized by X-ray crystallography and NMR. q 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
cally favored E,E-stereoisomer represents one of the rare
cases of stereoselective double bond formation in olefin
metathesis.
b-Dicarbonyl compounds such as 1,3-diketones and
b-ketoesters are valuable substrates in organic synthesis.
In the course of our investigations on the copper(II)-
catalyzed asymmetric Michael reaction1 we decided to
extend the substrate range to heterocyclic donors such as
lactams and lactones. The simplest representative of this
kind of substrate, a-acetyl-g-butyrolactone, is commer-
cially available and frequently used as a building block.
Both a-acetylated valerolactone and caprolactone had to be
prepared. However, the reported yield of a-acetyl-d-
valerolactone obtained by direct acetylation of valerolac-
tone2 could not be reproduced by others.3,4
In this paper we wish to disclose in more detail two methods
for the preparation of the b-dicarbonyl compounds
a-acetyl-valerolactone and a-acetyl-caprolactone in practi-
cally useful quantity.
2. Results and discussion
2.1. Attempts of alkylation and transesterification
Alcohols 1a,b were applied as starting materials for both
pathways (Scheme 1). The first step in the alkylation
sequence is the transesterification of alcohols 1a,b with
methyl acetylacetate following a protocol developed in our
laboratory which allows for the azeotropic removal of
methanol from the reaction mixture (Scheme 1).6 The
resulting chloroalkyl esters 3a and 3b7 were converted to the
corresponding iodoesters 5a,b in a Finkelstein reaction.
In a preliminary communication5 we reported our attempts
of a direct six- and seven-membered ring closure to give
a-acetylated d-valero- and 1-caprolactone by alkylation or
olefin ring closing metathesis (RCM). Both methods,
however, resulted in case of a-acetyl-1-caprolactone in
the formation of dimeric 14-membered products, which
were studied intensively by NMR spectroscopy and X-ray
crystallography.5 The result of RCM disagrees with earlier
reports. Of the six possible diastereoisomers, only the meso-
E,E-isomer is obtained as a crystalline material. Other
diastereoisomers have been detected as impurities of the
major product. Formation of the obviously thermodynami-
Cyclization of v-iodopropyl ester 5a with DBU afforded
a-acetyl-d-valerolactone 7a in moderate yield (21%), while
the respective conversion of 5b, in contrast, did not result in
seven-membered ring formation. With stoichiometric
amounts of base (NaH), only one chromatographically
uniform product could be isolated which surprisingly turned
out to be the dimeric trans isomer trans-8a, as stated by
X-ray diffraction analysis.5 A complete second set of 13C
Keywords: acylation; b-dicarbonyl compounds; lactones; macrocycles;
metathesis.
*
Corresponding author. Fax: þ49-711-685-4269;
e-mail: jchr@po.uni-stuttgart.de
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00511-8

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J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
Scheme 1. Attempts of intramolecular alkylation and lactonization. Reagents and conditions: (a) ethyl vinyl ether, cat. TsOH, 08C, 1.5 h. (b) AcCH2CO2Me,
5 mol% DMAP, cyclohexane, Dean–Stark trap, reflux, 16 h. (c) NaI, Na2CO3, acetone, reflux, 16 h. (d) (1) AcCH2CO2Me, NaH, THF, reflux, 16 h; (2)
HCl/NH4Cl/H2O. (e) DBU, C6H6, reflux, 16 h. (f) NaH, THF, reflux, 16 h. EE¼1-ethoxyethyl.
signals could be assigned to the corresponding minor cis
isomer cis-8b.
increasingly applied for the synthesis of normal-, medium-
sized, and large rings.9–16 We consequently considered to
likewise close the seven-membered ring by RCM of the
corresponding diallyl precursor 9,17,18 catalyzed by benzyli-
denedichloro(1,3-dimesitylimidazolidine-2-ylidene)(tricy-
The second route starts with the preparation of iodobutane 4
from chlorobutanol 1b by a sequence of acetalization8 and
Finkelstein reaction. Both acetals 2 and 4 are extraordinarily
acid-sensitive and need to be distilled from and stored over
Na2CO3. Alkylation of methyl acetylacetate with 4 and
hydrolytic cleavage of the protecting group furnished
v-hydroxyalkyl compound 6, which seemed to be a
reasonable starting material for lactonization. However,
neither with catalytic amounts of DMAP and under
conditions allowing for azeotropic removal of MeOH nor
clohexylphosphane)ruthenium(II),19 one of
a new
generation of Ru-catalysts with N-heterocyclic carbene
ligands combining higher activity with improved stability.20
RCM with 3 mol% Ru-catalyst in refluxing CH2Cl2 yielded,
after column chromatography and recrystallization, a
crystalline product with a predominant single set of 1H
and 13C NMR resonances which were in perfect accordance
with the constitution of the expected product 7c (see
Scheme 2).
¨
with Bronstedt acid catalysts (TsOH, H2SO4) the formation
of lactone 7b was observed. Only dehydration to an olefin
and unspecific decomposition products could be observed.
Intramolecular transesterification thus also proved an
unsuitable strategy for closing the seven-membered ring
of lactone 7b.
Two intense peaks at m/z 155 and 154 in the EI mass
spectrum have been interpreted as the [MH]þ and [M]þz
ions, respectively, of lactone 7c. Formation of 7c has been
proposed in the literature.21 Catalytic hydrogenation of the
presumed RCM product 7c, however, did not afford the
lactone 7b but rather the acyclic diketoester 11 as the only
isolable hydrogenation product, apart from starting material.
Its constitution was established unequivocally by 2D NMR
2.2. Olefin metathesis
Olefin RCM is a recent preparative method which is

J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
3771
Scheme 2. 14-Membered-ring formation is favored over seven-membered ring formation. Reagents and conditions: (a) 3 mol% Ru-catalyst, CH2Cl2, 408C, 1
day. (b) Pd–BaSO4, H2 (1 atm), EtOH, 238C, 1 h.
(H,H-COSY, HMBC, HMQC).5 Formation of 11 definitely
refutes structure 7c for the RCM product; GC–MS analysis
of the crude RCM reaction mixture (after filtration) revealed
not even traces of 7c. Closer inspection of the mass
spectrum of the RCM product in fact revealed two peaks of
low intensity at m/z 308 (6%), 307 (2%), indicating a
dimeric constitution. An X-ray diffraction analysis finally
established the dimeric structure 10.5
bonds, the macrolactone 10 comprises four stereogenic
elements; six diastereoisomers therefore are possible for
compound 10, four of them are 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. To
unequivocally correlate X-ray diffraction data, which
established the structure of the single crystal as the meso-E,E-
diastereoisomer 10a,5 with NMR solution stereochemis-
try,22 another crystal was selected from the single crystal
With two asymmetric carbon atoms and two CvC double
Scheme 3. Mukaiyama-type aldol and Claisen reactions. Reagents and conditions: (a) LDA, THF, 2788C, TMSCl, 2788C!238C, 16 h. (b) BF3·OEt2,
MeCHO, CH2Cl2, 2788C, 2 h. (c) DMP, 238C, 1 h, 85% of 7b. (d) Addition of 14 to TiCl4, Ac2O, CH2Cl2, 2708C, 1 h, 62% each of 7a and 7b. (e) As (d), but
inverted order of addition (Ac2O and TiCl4 to 14b).

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J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
Table 1. X-Ray crystal data collection and refinement for 7b, 15a and 15b
7b
15a
15b
Formula
FW
C8H12O3
156.18
Orthorhombic
Pbca
8.7045(3)
8.7402(6)
21.8142(11)
90
90
90
1659(15)
8
1.250
672
0.790
4.05–67.94
1379/1379
1379/0/101
1.128
C14H22O5
270.32
Triclinic
C14H22O5
270.32
Orthorhombic
Pbca
10.5120(12)
13.1811(9)
20.0925(17)
90
90
90
2784.0(4)
8
1.290
1168
0.803
4.40–59.98
2031/2031
2031/0/177
0.992
Crystal system
Space group
¯
P1
˚
a (A)
7.5515(11)
7.9466(15)
12.5579(19)
74.623(12)
79.888(13)
79.441(14)
707.9(2)
2
1.268
292
0.789
3.68–65.92
2991/2381
2381/0/177
1.076
˚
b (A)
˚
c (A)
a (8)
b (8)
g? (8)
3
˚
V (A )
Z
Dcalc (mg m23
F(000)
)
m (mm21
u range (8)
)
Reflections collected/unique
Data/restraints/parameters
Goodness-of-fit on F 2
Final R indices
[I.2s(I)]
R1¼0.0585
wR2¼0.1666
R1¼0.0767
wR2¼0.2053
0.220
R1¼0.0547
wR2¼0.1519
R1¼0.0639
wR2¼0.1619
0.317
R1¼0.0815
wR2¼0.2025
R1¼0.1234
wR2¼0.2706
0.282
R indices (all data)
Largest diff.
Peak and hole (e A
23
)
˚
20.184
20.182
20.267
crystallization crop (0.5£0.3£0.05 mm3). On the basis of 15
unique reflections, detected by rotation photograph, the
P21/c space group was determined for this crystal, definitely
establishing its structural identity with meso-E,E-diastereo-
protons now almost isochronous around ,4.6 ppm while
the resonances of the other five protons appear but slightly
shifted. The corresponding rac-E,E-diastereoisomer 10b is
therefore presumed to be formed by epimerization of the
stereocenters C-4 and C-11 via the respective enol
tautomers. A ,1:1 equilibrium between 10a and 10b is
established after 24 h. The position of this equilibrium,
however, is matrix-dependent: if sufficient crystalline
material is dissolved in CDCl3, the 1H NMR spectrum
after two weeks integrates for 93:7 (10a/10b). An additional
set of eight signals in the 13C spectrum shows chemical
shifts so close to those of the major isomer 10a to absolutely
rule out a change in double bond configuration.5 A highly
concentrated solution, after 30000 scans, displayed two
additional signal sets (16 lines each) which were assigned,
respectively, to the meso-E,Z-diastereoisomer (10c, trans)
(the term ‘meso’ is misleading, since 10c is in fact chiral)
and the rac-E,Z-diastereoisomer (10d, cis). Resonances of a
Z,Z-isomer were not observed.5
1
isomer 10a. A H NMR spectrum recorded immediately
after dissolving the crystal (,10 mg) in CDCl3 (0.3 ml;
1025 mol dm23 solution) displayed, apart from a minor
1
impurity, a clean set of seven H multiplets. Numerical
analysis for the two olefinic resonances (1/8- and 2/9-H)
afforded a coupling constant of 15.35 Hz which is clearly in
the 3Jtrans range and thus unambiguously establishes the E,E
configuration. The two diastereotopic protons 7/14-HA,HB
appear well differentiated at 4.857 and 4.380 ppm.5
Upon standing at ambient temperature, however, a second
signal set evolved in the NMR sample, with the O–CHAHB
Generally macrocyclizations by RCM are not stereoselec-
tive with respect to C–C double bond configuration. Under
certain conditions, however, reversibility of the RCM
reaction results in exclusive formation of E-isomers.23
A
prerequisite 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 10. With a simple
RCM protocol and from readily available starting material,
this 14-membered ring system is obtained in 73% isolated
yield (after chromatographic purification) and with excep-
tional stereochemical purity. More than 95% of the crystal-
line material is E,E-configured, with C-4/C-11-
configuration exclusively R,S (meso). This preparative
approach is now being extended to larger ring systems.
Figure 1. Molecular structure of the racemic lactone 7b.

J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
3773
Figure 2. Molecular structure of the racemic syn–anti diastereoisomer (R p,R p)-15a.
2.3. Mukaiyama aldol and Claisen reactions
under the reaction conditions the products of the
Mukaiyama–Claisen reaction, e.g. 7b, are further converted
with the silylenolether 14b to give bis-oxepanonyl ethanols
15, if acetic anhydride and TiCl4 were added to 14b
[pathway (e), Scheme 3]. Under optimized reaction
conditions [pathway (d)] we succeeded in a scale up giving
both 7a and 7b in quantities of about 10 g (62% yield). Both,
the concentration of the starting materials and the sequence
of their addition, therefore have to be carefully controlled
(for details see Section 3). Via this route, 7a and 7b are
obtained in two steps from the parent lactones 13a and 13b
[pathways (a) and (d), Scheme 3] in 40–50% overall yield.
Because all attempts failed to prepare the seven-membered
ring lactone 7b by a direct seven-membered ring closure, we
decided to start from the parent d-valero- (13a) and
1-caprolactones (13a) as outlined in Scheme 3. The
literature yields of trimethylsilylketene acetals 14a,b,
derived from 13a and 13b,24 could be improved to 83%
(14a) and 64% (14b). In a Mukaiyama aldol reaction, the
silyl ether 14b was converted with stoichiometric amounts
of acetaldehyde and BF3·OEt2 as Lewis acid in 67% yield to
the hydroxy lactone 12 (mixture of two diastereo-
isomers).25–27 Oxidation of 12 with the Dess–Martin
periodinane (DMP)28 gave the desired a-acetyl lactone 7b
in 85% yield.
2.4. Structural elucidation of 7b and 15a,b
From compound 7b, single crystals suitable for X-ray
structure elucidation were obtained (Table 1, Fig. 1). Two of
the three possible diastereoisomers of 15 could be isolated
and their relative configurations established by single
crystal analysis (Table 1) as the racemic syn–anti
diastereoisomer (R p,R p)-15a (Fig. 2) and the achiral
anti–anti diastereoisomer (R p,S p)-15b (Fig. 3).
Actually, the silyl ethers 14a,b are acetylated directly, with
acetic anhydride and TiCl4 as Lewis acid catalyst, in a
Mukaiyama-type Claisen reaction to give the a-acetylated
lactones 7a and 7b. On an analytical scale, 7b was isolated
in this way in 85% yield. It must be noted, however, that a
scale up following a literature procedure29 is problematic:
Figure 3. Molecular structure of the achiral anti–anti diastereoisomer (R p,S p)-15b.

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J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
Table 2. 13C Chemical shifts of ethanols 12, (R p,R p)-15a, and (R p,S p)-15b
(0.5 M, CDCl3, d, ppm)
3.1.1. 1-Chloro-4-(1-ethoxyethoxy)butane (2). To a sol-
ution of chlorobutanol 1b (8.00 g, 73.7 mmol) in ethyl vinyl
ether (80 ml) was added p-TsOH·H2O (8 mg, 0.05 mmol) at
08C. The mixture was stirred for 1.5 h at 08C, diluted with
MTB (30 ml), washed with saturated aqueous NaHCO3
solution (3£100 ml), and dried over MgSO4. The solvent
was evaporated, and the crude product distilled from
Na2CO3 through a 10 cm-Vigreux column (4–5 mbar, bp
45–468C), yielding acetal 2 as a colorless oil (8.89 g,
C atoms
12 12
(major isomer) (minor isomer)
(R p,S p)-15a (R p,S p)-15b
C1
C2
68.73
20.19
48.46
177.74
68.75
28.54
27.86
26.93
66.92
19.34
50.29
178.58
68.96
28.72
28.08
22.92
74.36
18.84
49.72/46.76
75.07
22.02
49.81
C10/100
C20/200
C40/400
C50/500
C60/600
C70/700
179.13/176.07 176.76
68.65/69.17
28.71/28.72
24.51/24.98
26.94/27.88
67.99
28.01
24.69
26.02
1
49.2 mmol, 67%) which must be stored over Na2CO3. H
NMR (CDCl3, 300 MHz): d¼1.21 (t, J¼7.1 Hz, 3H), 1.31
(d, J¼5.3 Hz, 3H), 1.69–1.77 (m, 2H), 1.83–1.91 (m, 2H),
3.41–3.50 (m, 2H), 3.55–3.67 (m, 2H), 3.58 (t, J¼6.8 Hz,
2H), 4.68 (q, J¼5.3 Hz, 1H) ppm. 13C NMR (CDCl3,
75 MHz): d¼15.32 (CH3), 19.83 (CH3), 27.24 (CH2), 29.58
(CH2), 44.94 (CH2), 60.79 (CH2), 64.20 (CH2), 99.58
(CH) ppm. IR (neat): 2977 (vs), 2938 (vs), 2875 (vs), 1133
(vs), 1102 (vs), 1060 (vs) cm21. MS (EI, 70 eV), m/z (%):
179 (1) [Mþ2H], 91 (64), 73 (100). Anal. calcd for
C8H17ClO2: C, 53.18; H, 9.48; Cl, 19.62. Found: C, 53.10;
H, 9.45; Cl, 19.50.
In Table 2, the 13C chemical shifts of 15a,b are collated with
those of the corresponding ‘mono’ oxepanonyl ethanol 12.
As for the two diastereoisomers of 12, a double signal set is
observed for the two diastereotopic lactone moieties of the
syn–anti isomer 15a. The 13C chemical shift differentia0tion
appears sharply 0 graded: 3.06/3.04 ppm for C10,100/C2 ,200,
0.92 ppm for C7 ,700 (for the corresponding lactone00O, there
is of cours0e0 no signal), and 0.48/0.52 ppm for C60,6 /C40,400.
The C50,5 resonances, finally, can be resolved only with
extreme Gaussian apodization. The crystal structure (Fig. 2)
shows that the CvO function of one of the lactone rings
(C1AvO1A) is oriented towards the O–H group, establish-
3.1.2. 3-Chloropropyl acetoacetate (3a). A solution of
methyl acetoacetate (15.0 g, 129 mmol), chloropropanol 1a
(13.4 g, 142 mmol) and DMAP (158 mg, 1.29 mmol) in
cyclohexane (50 ml) was heated to reflux overnight in a
Dean–Stark trap. Saturated aqueous NH4Cl solution
(200 ml) and HCl (50 ml, 18%) were added, and the
mixture was then extracted with MTB (3£100 ml). The
combined organic layers were dried over MgSO4, the
solvent was evaporated, and the crude product was
chromatographed on SiO2 (MTB/cyclohexane, 1:2,
Rf¼0.25) to give ester 3a as a colorless oil (15.2 g,
˚
ing a loose hydrogen bond or dipole contact (1.8 A), while
the CvO function of the other ring (C1BvO1B) is rotated
1808 away from the O–H group. In this conformation, a
pronounced g-cis interaction becomes apparent bet0ween the
protons of the methyl group and those at C7 (C3A),
explaining the 3 ppm high field shift of the CH3 resonance
for 15a relative to that for 15b.
1
85.1 mmol, 66%). H NMR (CDCl3, 200 MHz): d¼2.11
For the anti–anti diastereoisomer 15b, the 13C spectrum
(11.74 T, 198 K, CDCl3) shows clear indications of
beginning decoalescence. Thus, n1/2 for the C10 line is
almost five times that for, e.g., the methyl carbon line.
Apparently, there is a rapid reorientation in solution, by
1808 rotation around the C7–O3 bond, between two
energetically degenerate conformations where the OH
group is aligned with the CvO function of either one or
the other lactone ring. With the molecule frozen in one
conformation, as in the crystalline state (Fig. 3), the two
lactone subunits are diastereotopic. This holds also in
solution, if the lifetime of the two conformers is long with
respect to the NMR relaxation time.
(quint, J¼6.2 Hz, 2H), 2.27 (s, 3H), 3.47 (s, 2H), 3.62 (t,
J¼6.3 Hz, 2H), 4.31 (t, J¼6.1 Hz, 2H) ppm. 13C NMR
(CDCl3, 50 MHz): d¼30.12 (CH3), 31.28 (CH2), 40.95
(CH2), 49.86 (CH2), 61.91 (CH2), 166.88 (C), 200.35
(C) ppm. IR (ATR): 1741 (vs), 1715 (vs) cm21. HRMS (EI,
70 eV): Mol. mass calcd 178.0397 (for C7H11ClO3), found
178.0400 (Mþ). Anal. calcd for C7H11ClO3: C, 47.07; H,
6.21. Found: C, 46.86; H, 6.34.
3.1.3. 4-Chlorobutyl acetoacetate (3b). A solution of
methyl acetoacetate (10.0 g, 86.1 mmol), chlorobutanol 1b
(9.35 g, 86.1 mmol) and DMAP (530 mg, 4.34 mmol) in
cyclohexane (100 ml) was heated to reflux overnight in a
Dean–Stark trap. Saturated aqueous NH4Cl solution
(200 ml) and HCl (50 ml, 20%) were added, and the
mixture was then extracted with MTB (3£50 ml). The
organic layers were combined and dried over MgSO4. The
solvent was stripped off. Purification of the residual crude
product by chromatography on SiO2 (MTB/hexanes, 1:2,
Rf¼0.23) afforded ester 3b as a colorless oil (15.2 g,
3. Experimental
3.1. General
Compounds 6, 7a, 7b, 8, 10, 12, 14a, and 14b were prepared
under anhydrous conditions in abs. solvents. Column
chromatography was accomplished using SiO2 60, grain
size 0.063–0.200 mm (Merck) with hexanes (bp 40–608C),
EtOAc, or tert-butyl methyl ether (MTB) as eluents. All
starting materials are commercially available. LDA
(2.0 mol dm23 in THF/heptane/ethylbenzene) was pur-
chased from Aldrich Chemical Co. 13C NMR multiplicities
were determined with DEPT experiments. 13C NMR spectra
are proton decoupled.
1
78.9 mmol, 92%). H NMR (CDCl3, 200 MHz): d¼1.82–
1.87 (m, 4H), 2.27 (s, 3H), 3.46 (s, 2H), 3.54–3.60 (m, 2H),
4.17–4.21 (m, 2H) ppm. 13C NMR (CDCl3, 50 MHz):
d¼25.91 (CH2), 28.94 (CH2), 30.20 (CH3), 44.36 (CH2),
50.02 (CH2), 64.49 (CH2), 167.04 (C), 200.41 (C) ppm. IR
(ATR): 1739 (vs), 1713 (vs) cm21. HRMS (EI, 70 eV): Mol.
mass calcd 192.0553 (for C8H13ClO3), found 192.0551
(Mþ). Anal. calcd for C8H13ClO3: C, 49.88; H, 6.80. Found:
C, 49.60; H, 6.86.

J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
3775
3.1.4. 1-(1-Ethoxyethoxy)-4-iodobutane (4). Butylchloride
2 (3.10 g, 17.1 mmol) and Na2CO3 (0.50 g) were added to
100 ml of a saturated NaI solution in acetone. The mixture
was heated to reflux overnight. After addition of saturated
aqueous NaHCO3 solution (150 ml), the mixture was
extracted with hexanes (3£50 ml). The organic layers
were combined and dried over MgSO4. Evaporation of the
solvent yielded pure acetal 4 as a colorless oil (2.78 g,
10.2 mmol, 60%) which needed to be stored over Na2CO3 to
prevent rapid decomposition. 1H NMR (CDCl3, 300 MHz):
d¼1.21 (t, J¼7.1 Hz, 3H), 1.30 (d, J¼5.3 Hz, 3H), 1.63–
1.72 (m, 2H), 1.88–1.98 (m, 2H), 3.22 (t, J¼7.0 Hz, 2H),
3.40–3.53 (m, 2H), 3.56–3.67 (m, 2H), 4.68 (q, J¼5.3 Hz,
1H) ppm. 13C NMR (CDCl3, 75 MHz): d¼6.70 (CH2),
15.28 (CH3), 19.77 (CH3), 30.39 (CH2), 30.71 (CH2), 60.73
(CH2), 63.76 (CH2), 99.51 (CH) ppm. IR (neat): 2975 (vs),
2935 (vs), 2872 (vs), 1131 (vs), 1060 (vs) cm21. MS (EI,
70 eV), m/z (%): 271 (1) [Mþ2H], 183 (45), 73 (100). Anal.
calcd for C8H17IO2: C, 35.31; H, 6.30; I, 46.63. Found; C,
35.39; H, 6.33; I, 46.36.
31.1 mmol) in THF (25 ml) added, and the mixture heated
to reflux overnight. A saturated aqueous NH4Cl solution
(100 ml) and HCl (100 ml, 20%) were added successively at
08C; the mixture was extracted with EtOAc (4£50 ml). The
organic layers were combined and dried over MgSO4. The
solvent was stripped off. Purification of the crude product by
chromatography on SiO2 (hexanes/EtOAc, 1:2, Rf¼0.23)
yielded ester 6 as a colorless oil (3.60 g, 19.1 mmol, 61%).
1H NMR (CDCl3, 300 MHz): d¼1.33–1.41 (m, 2H), 1.53–
1.62 (m, 2H), 1.83–1.91 (m, 2H), 2.24 (s, 3H), 2.84 (s, br,
1H), 3.47 (t, J¼7.3 Hz, 1H), 3.62 (t, J¼6.4 Hz, 2H), 3.74 (s,
3H) ppm. 13C NMR (CDCl3, 75 MHz): d¼23.45 (CH2),
27.66 (CH2), 28.71 (CH3), 31.99 (CH2), 52.21 (CH3), 59.31
(CH), 61.85 (CH2), 170.15 (C), 203.19 (C) ppm. IR (neat):
3422 (s), 1741 (vs), 1713 (vs) cm21. HRMS (EI, 70 eV):
Mol. mass calcd 188.1049 (for C9H16O4), found 188.1052
(Mþ).
3.1.8. Preparation of a-acetyl-d-valerolactone (7a). By
intramolecular alkylation. A mixture of acetoacetate 5a
(16.0 g, 59.2 mmol), DBU (10.0 g, 65.7 mmol) and benzene
(500 ml) was heated to reflux overnight. Saturated aqueous
NH4Cl solution (200 ml) was added, and the mixture then
extracted with MTB (3£150 ml). The combined organic
layers were dried over MgSO4, the solvent evaporated, and
the crude product chromatographed on SiO2 (MTB/
cyclohexane, 1:2, Rf¼0.22) to give lactone 7a as a colorless
oil (1.78 g, 12.5 mmol, 21%).
3.1.5. 3-Iodopropyl acetoacetate (5a). A mixture of
chloroester 3a (15.2 g, 85.1 mmol) and 100 ml of a
saturated NaI solution in acetone was heated to reflux
overnight. Saturated aqueous NH4Cl solution (200 ml) was
added, and the mixture was then extracted with MTB
(3£100 ml). The combined organic layers were dried over
MgSO4, the solvent evaporated, and the crude product
chromatographed on SiO2 (MTB/cyclohexane, 1:2,
Rf¼0.23) to give iodoester 5a as a colorless oil (16.0 g,
By Mukaiyama–Claisen30 reaction. To a mixture of Ac2O
˚
(100 ml, 108 g, 1.06 mol) and molecular sieves (4 A, 4 g) in
1
59.2 mmol, 70%). H NMR (CDCl3, 200 MHz): d¼2.16
(quint, J¼6.3 Hz, 2H), 2.27 (s, 3H), 3.22 (t, J¼6.8 Hz, 2H),
3.47 (s, 2H), 4.23 (t, J¼6.0 Hz, 2H) ppm. 13C NMR (CDCl3,
50 MHz): d¼1.19 (CH2), 30.16 (CH3), 32.02 (CH2), 49.88
(CH2), 64.84 (CH2), 166.84 (C), 200.27 (C) ppm. IR (ATR):
1740 (vs), 1712 (vs) cm21. HRMS (EI, 70 eV): Mol. mass
calcd 269.9753 (for C7H11IO3), found 269.9751 (Mþ).
Anal. calcd for C7H11IO3: C, 31.11; H, 4.11; found: C,
31.28; H, 4.06.
CH2Cl2 (500 ml) at 2788C was slowly added dropwise
TiCl4 (20 ml, 34.5 g, 182 mmol), and the reaction mixture
was stirred for 30 min. Silylenolether 14a (18.4 g,
107 mmol) was added dropwise over a period of 5 h at
2788C (syringe pump). The mixture was then warmed to
238C and stirred for another 16 h, subsequently poured onto
ice (300 g) and extracted with EtOAc (3 £ 200 ml). The
combined organic layers were dried (MgSO4), the solvent
was evaporated and the residue distilled through a 10 cm
Vigreux column (7 mbar, bp 888C) to furnish lactone 7a as a
colorless solid (9.44 g, 66.4 mmol, 62%); mp 43–448C.
NMR spectra show only the enol tautomer. 1H NMR
(CDCl3, 200 MHz): d¼1.86–1.96 (m, 2H), 1.98 (s, 3H),
2.39 (t, J¼6.0 Hz, 2H), 4.24–4.29 (m, 2H), 13.68 (s,
1H) ppm. 13C NMR (CDCl3, 50 MHz): d¼18.72 (CH3),
22.53 (CH2), 22.63 (CH2), 68.94 (CH2), 93.15 (C), 172.65
(C), 175.80 (C) ppm. IR (ATR): 1736 (w), 1718 (w), 1636
(vs), 1416 (s), 1279 (s), 1250 (vs) cm21. HRMS (EI, 70 eV):
Mol. mass calcd 142.0630 (for C7H10O3), found 142.0622
(Mþ). Anal. calcd C7H10O3: C, 59.15; H, 7.09. Found: C,
59.43; H, 7.18.
3.1.6. 4-Iodobutyl acetoacetate (5b). A mixture of
chloroester 3b (817 mg, 4.24 mmol) and 100 ml of a
saturated NaI solution in acetone was heated to reflux
overnight. After addition of a saturated aqueous NH4Cl
solution (100 ml), the mixture was extracted with MTB
(3£50 ml). The organic layers were combined and dried
over MgSO4. The solvent was stripped off. Purification of
the crude product by chromatography on SiO2 [MTB/
hexanes, 1:2, Rf (MTB/hexanes, 1:1)¼0.34] gave ester 5b as
a colorless oil (823 mg, 2.90 mmol, 68%). 1H NMR (CDCl3,
200 MHz): d¼1.64–1.92 (m, 4H), 2.23 (s, 3H), 3.17 (t,
J¼6.5 Hz, 2H), 3.43 (s, 2H), 4.13 (t, J¼6.1 Hz, 2H) ppm.
13C NMR (CDCl3, 50 MHz): d¼5.84 (CH2), 29.31 (CH2),
29.68 (CH2), 30.15 (CH3), 49.93 (CH2), 64.03 (CH2),
166.96 (C), 200.36 (C) ppm. IR (ATR): 1740 (vs), 1715
(vs) cm21. HRMS (EI, 70 eV): Mol. mass calcd 283.9909
(for C8H13IO3), found 283.9907 (Mþ).
3.1.9. a-Acetyl-1-caprolactone (7b). To a mixture of Ac2O
˚
(100 ml, 108 g, 1.06 mol) and molecular sieves (4 A, 4 g) in
CH2Cl2 (500 ml) at 2788C was slowly added dropwise
TiCl4 (20 ml, 34.5 g, 182 mmol), and the reaction mixture
was stirred for 30 min. Silylenolether 14b (20.0 g,
107 mmol) was added dropwise over a period of 5 h at
2788C (syringe pump). The mixture was then warmed to
238C and stirred for another 16 h, subsequently poured onto
ice (300 g) and extracted with EtOAc (3£200 ml). The
combined organic layers were dried (MgSO4), the solvent
3.1.7. Methyl 2-acetyl-6-hydroxyhexanoate (6). A sol-
ution of methyl acetoacetate (14.4 g, 124 mmol) in THF
(20 ml) was added dropwise to a suspension of NaH (55%,
5.56 g, 127 mmol) in THF (33 ml) at 08C. The mixture was
stirred for 1 h at 238C, a solution of iodobutane 4 (8.45 g,

3776
J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
was evaporated and the crude product chromatographed on
SiO2 [EtOAc/petroleum ether, 1:2!1:1, Rf (EtOAc/
petroleum ether 1:1)¼0.25] to give compound 7b as a
colorless solid (10.4 g, 66.4 mmol, 62%); mp 578C. 1H
NMR (CDCl3, 300 MHz): d¼1.54–1.83 (m, 3H), 1.94–
2.07 (m, 2H), 2.12–2.20 (m, 1H), 2.27 (s, 3H), 3.69 (dd,
J¼10.9, 1.9 Hz, 1H), 4.28 (ddd, J¼12.8, 9.7, 0.7 Hz, 1H),
4.32–4.39 (m, 1H) ppm. 13C NMR (CDCl3, 125 MHz):
d¼24.89 (CH2), 27.06 (CH2), 28.57 (CH2), 28.66 (CH3),
56.67 (CH), 69.38 (CH2), 173.05 (C), 202.60 (C) ppm. IR
(KBr): 1725 (vs), 1702 (vs), 1690 (vs) cm21. MS (CI, CH4),
m/z (%): 157 (100) [MþþH]. Anal. calcd for C8H12O3: C,
61.52; H, 7.74. Found: C, 61.48; H, 7.71.
(for C10H14O3), found 182.0943 (Mþ). Anal. calcd for
C10H14O3: C, 65.92; H, 7.74. Found: C, 65.79; H, 7.84.
3.1.12. 4,11-Diacetyl-5,12-dioxo-6,13-dioxa-1,8-cyclo-
tetradecadiene (10). To a solution of ester 9 (500 mg,
2.74 mmol) in CH2Cl2 (30 ml) Ru-catalyst (70 mg,
0.082 mmol) and CH2Cl2 (40 ml) were added. The reaction
mixture was heated to reflux for 1 day, the solvent stripped
off, and the residue was chromatographed on SiO2 (MTB/
hexanes, 1:1, Rf¼0.14) to give 10 as a colorless solid
(307 mg, 0.996 mmol, 73%); mp 1198C. Crystallization
from MeOH afforded a crystalline material which consists
1
predominantly of a single diastereoisomer 10a (single H
and 13C NMR signal set). In CDCl3 solution, 10a epimerizes
to a matrix-dependent 10a/10b equilibrium mixture. meso-
3.1.10. 3,10-Diacetyl-2,9-dioxo-1,8-dioxacyclotetra-
solution of iodoester 5b (500 mg,
1
decane (8).
A
E,E-10a: H NMR (CDCl3, 500 MHz): d¼2.242 (s, 3H;
1.76 mmol) in THF (2 ml) was added dropwise at 08C to a
suspension of NaH (55%, 90.1 mg, 2.06 mmol) in THF
(20 ml), and the reaction mixture was heated to reflux
overnight. Aqueous citric acid solution (20 ml, 20%) was
added, and the mixture extracted with hexanes (3£10 ml).
The organic layers were combined and dried over MgSO4.
The solvent was stripped off, and the crude product
chromatographed on SiO2 (hexanes/EtOAc, 2:1, Rf¼0.24),
yielding lactone 6 as a colorless solid (37 mg, 0.12 mmol,
14%); mp 109–1108C. trans-8a: 1H NMR (CDCl3,
500 MHz): d¼1.36–1.50 (m, 4H), 1.57–1.65 (m, 2H),
1.68–1.75 (m, 2H), 1.77–1.84 (m, 2H), 1.91–1.99 (m, 2H),
2.22 (s, 6H), 3.43 (dd, J¼11.6, 3.5 Hz, 2H), 4.19–4.23 (m,
2H), 4.27–4.31 (m, 2H) ppm. 13C NMR (CDCl3,
125 MHz): d¼23.16 (C-2/9), 27.17 (C-3/10), 28.17
(C-1/8), 28.63 (CH3), 60.47 (C-4/11), 63.99 (C-7/14),
169.68 (C-5/12), 202.38 (CvO). cis-8b: 13C NMR
(CDCl3, 125 MHz): d¼23.19 (C-2/9), 27.26 (C-3/10),
28.05 (C-1/8), 28.67 (CH3), 60.459.877 (C-4/11), 64.08
(C-7/14), 169.94 (C-5/12), 202.50 (CvO). IR (KBr): 1728
(vs), 1705 (vs) cm21. MS (EI, 70 eV), m/z (%): 312 (45)
[Mþ], 270 (44), 157 (91), 139 (60), 43 (100). Anal. calcd for
C16H24O6: C, 61.53; H, 7.74. Found: C, 61.33; H, 7.70.
COCH3), 2.460 (m, 1H; 3-HB), 2.651 [dddd, J¼(2)14.8,
11.3, 8.0, 0.9 Hz, 1H; 3-HA], 3.542 (dd, J¼11.3, 3.6 Hz, 1H;
4-H), 4.380 [ddt, J¼(2)11.85, 5.75, 1.2 Hz, 1H; 7-HB],
4.857 [ddd, J¼(2)11.85, 7.5, 0.8 Hz, 1H; 7-HA], 5.633
(ddddd, J¼15.35, 7.5, 5.75, 1.65, J¼0.9 Hz, 1H; 1-H), 5.725
(ddddd, J¼15.35, 8.0, 5.2, 1.1, 0.8 Hz, 1H; 2-H) ppm. 13C
NMR (CDCl3, 125 MHz): d¼28.64 (CH3), 30.74 (C-3/10),
58.72 (C-4/11), 65.34 (C-7/14), 126.72 (C-1/8), 132.26
(C-2/9), 168.74 (C-5/12), 201.60 (CvO). IR (ATR): 1733
(vs), 1709 (vs), 1641 (w) cm21. MS (EI, 70 eV), m/z (%):
308 (6) [Mþ], 307 (2), 155 (63), 154 (50), 137 (24), 112
(24), 111 (30), 95 (40), 94 (28), 67 (32), 43 (100). Mol. mass
calcd 308.1260 (for C16H20O6), found 308.1265 (Mþ).
Anal. calcd for C16H20O6: C, 62.33; H, 6.54. Found: C,
62.02; H, 6.42.
3.1.13. 6-Oxoheptyl 2-acetylhexanoate (11). A degassed
mixture of lactone 10 (20 mg, 0.065 mmol) and Pd (5%)–
BaSO4 (1.4 mg) in EtOH (1 ml) was stirred for 1 h at 238C
under 1 atm H2. The reaction mixture was filtered with
CH2Cl2, the solvent stripped off, and the residue chromato-
graphed on SiO2 (MTB/hexanes, 1:1, Rf¼0.30), yielding
1
ester 11 as a colorless oil (10 mg, 0.037 mmol, 57%). H
NMR (CDCl3, 500 MHz): d¼0.89 (t, J¼7.2 Hz, 3H), 1.24–
1.37 (m, 6H), 1.55–1.67 (m, 4H), 1.76–1.90 (m, 2H), 2.13
(s, 3H), 2.21 (s, 3H), 2.43 (t, J¼7.3 Hz, 2H), 3.39 (t,
J¼7.4 Hz, 1H), 4.10–4.13 (m, 2H) ppm. 13C NMR (CDCl3,
50 MHz): d¼13.76 (CH3), 22.39 (CH2), 23.21 (CH2), 25.39
(CH2), 27.91 (CH2), 28.32 (CH2), 28.74 (CH3), 29.53
(CH2), 29.87 (CH3), 43.38 (CH2), 59.87 (CH), 65.04 (CH2),
169.94 (C), 203.32 (C), 208.58 (C) ppm. IR (ATR): 1739
(vs), 1714 (vs) cm21. MS (EI, 70 eV), m/z (%): 270 (1)
[Mþ], 228 (10), 213 (20), 141 (27), 131 (10), 113 (100), 98
(22), 55 (18). Mol. mass calcd 270.1831 (for C15H26O4),
found: 270.1833 (Mþ).
3.1.11. Allyl 2-allyl-3-oxobutanoate (9). Allyl acetoacetate
(15.0 g, 105 mmol) was added dropwise to a suspension of
NaH (60%, 4.65 g, 116 mmol) in THF (450 ml) at 08C. The
mixture was stirred for 2 h at 238C, allylbromide (9.90 ml,
14.2 g, 117 mmol) was added dropwise at 08C, and the
reaction mixture stirred overnight at 238C. A saturated
aqueous NH4Cl solution (200 ml) and HCl (200 ml, 20%)
were added successively at 08C; the mixture was extracted
with MTB (3£100 ml). The organic layers were combined
and dried over MgSO4. The solvent was stripped off, and the
residual crude product purified by chromatography on SiO2
(MTB/hexanes, 1:5, Rf¼0.30), yielding 9 as a colorless oil
1
(13.3 g, 73.0 mmol, 70%). H NMR (CDCl3, 300 MHz):
3.1.14. 6-Trimethylsilyloxy-3,4-dihydro-2H-pyran (14a).
Freshly distilled (7 mbar, bp 518C) d-valerolactone (13a)
(16.3 ml, 18.0 g, 180 mmol) was added dropwise to a
solution of LDA in THF (200 mmol, 100 ml of a
commercial 2.0 mol dm23 solution diluted with 170 ml
THF) at 2788C. The reaction mixture was stirred for 1 h at
2788C, then TMSCl (30.0 ml, 25.8 g, 237 mmol) was
added and after removal of the cooling bath, the mixture was
further stirred overnight. After filtration and washing of the
residue with CH2Cl2 (400 ml), the solvent was removed and
the residue distilled through a 10 cm Vigreux column
d¼2.24 (s, 3H), 2.61 (t, br, J¼6.9 Hz, 2H), 3.56 (t,
J¼7.4 Hz, 1H), 4.64 (dt, J¼5.8, 1.3 Hz, 2H), 5.06 (dq,
J¼10.2, 1.4 Hz, 1H), 5.11 (dq, J¼17.2, 1.6 Hz, 1H), 5.26
(dq, J¼10.4, 1.2 Hz, 1H), 5.33 (dq, J¼17.2, 1.4 Hz, 1H),
5.75 (ddt, J¼17.1, 10.2, 6.8 Hz, 1H), 5.90 (ddt, J¼17.2,
10.5, 5.8 Hz, 1H) ppm. 13C NMR (CDCl3, 50 MHz):
d¼29.19 (CH3), 32.18 (CH2), 59.18 (CH), 65.98 (CH2),
117.59 (CH2), 119.01 (CH2), 131.46 (CH), 134.1 (CH),
168.90 (C), 202.27 (C). IR (ATR): 1743 (vs), 1716
(vs) cm21. HRMS (EI, 70 eV): Mol. mass calcd 182.0943

J. Christoffers et al. / Tetrahedron 59 (2003) 3769–3778
3777
(8 mbar, bp 27–308C) to furnish the silylenolether 14a
1
(20%) and extracted with EtOAc (4£100 ml). The combined
organic layers were dried over MgSO4, the solvent was
evaporated and the crude material was chromatographed on
SiO2 (EtOAc/hexanes, 1:1) to give 290 mg (1.07 mmol, 14%)
of 15a (Rf¼0.375), 1.09 g (6.98 mmol, 43%) of lactone 7b
(Rf¼0.25), and 98 mg (0.36 mmol, 5%) of 15b (Rf¼0.21) as
colorless solids.
(25.7 g, 149 mmol, 83%) as a colorless liquid. H NMR
(CDCl3, 300 MHz): d¼0.21 [s, d, J(1H,29Si)¼6.6 Hz, 9H],
1.72–1.79 (m, 2H), 2.01–2.07 (m, 2H), 3.81 (t, J¼3.6 Hz,
1H), 4.05 (t, J¼5.1 Hz, 2H) ppm. 13C NMR (CDCl3,
75 MHz): d¼-0.04 (CH3), 19.85 (CH2), 22.37 (CH2),
67.14 (CH2), 73.92 (CH), 154.47 (C) ppm. IR (neat): 2957
(s), 2850 (s), 1688 (vs), 1386 (s), 1336 (s), 1249 (vs), 1210
(vs), 1063 (s), 987 (s), 913 (vs), 849 (vs) cm21. Mol. mass
calcd 171.0841 (C8H15O2Si), found 171.0840 (Mþ2H).
(R p,R p)-Isomer 15a. Mp 1258C. 1H NMR (CDCl3,
500 MHz): d¼1.32 (s, 3H), 1.39–1.46 (m, 1H), 1.52–1.81
(m, 5H), 1.88–1.97 (m, 3H), 2.04–2.08 (m, 1H), 2.18–2.21
(m, 1H), 2.39–2.42 (m, 1H), 3.32 (d, J¼10.6 Hz, 1H), 3.45
(dd, J¼10.3, 2.2 Hz, 1H), 3.62 (s, br, 1H), 4.18–4.31 (m,
3.1.15. 2-Trimethylsilyloxy-4,5,6,7-tetrahydrooxepin
(14b). Freshly distilled (8 mbar, bp 728C) 1-caprolactone
(13b) (19.0 ml, 20.5 g, 180 mmol) was added dropwise to a
solution of LDA in THF (200 mmol, 100 ml of a
commercial 2.0 mol dm23 solution diluted with 140 ml
THF) at 2788C. The reaction mixture was stirred for 1 h at
2788C, then TMSCl (30.0 ml, 25.8 g, 237 mmol) was
added and after removal of the cooling bath, the mixture was
further stirred overnight. After filtration and washing of the
residue with EtOAc (400 ml), the solvent was removed and
the residue distilled through a 10 cm Vigreux column
(8 mbar, bp 39–418C) to furnish the silylenolether 14b
4H) ppm. IR (KBr): 3510 (s), 2940 (s), 1730 (vs, br) cm21
.
MS (CI, CH4), m/z (%): 271 (30) [MþHþ], 157 (100), 114
(74). Mol. mass calcd 271.1545 (for C14H22O5), found
271.1549 (MþHþ).
1
(R p,S p)-Isomer 15b. Mp 124–1258C. H NMR (CDCl3,
500 MHz): d¼1.43 (s, 3H), 1.54–1.76 (m, 7H), 1.93–2.00
(m, 6H), 3.26 (dd, J¼10.4, 3.2 Hz, 1H), 4.24 (dd, J¼9.0,
1.7 Hz, 1H), 4.27 (dd, J¼9.1, 1.9 Hz, 1H), 4.33 (s, 1H), 4.49
(dd, J¼6.2, 2.8 Hz, 1H), 4.51 (dd, J¼6.1, 2.6 Hz, 1H) ppm.
IR (KBr): 3420 (s, br), 2920 (s), 1720 (vs) cm21. MS (CI,
CH4), m/z (%): 271 (78) [MþHþ], 157 (100). Anal. calcd
for C14H22O5: C, 62.21; H, 8.20. Found: C, 62.00; H, 8.06.
1
(21.6 g, 116 mmol, 64%) as a colorless liquid. H NMR
(CDCl3, 300 MHz): d¼0.20 [s, d, J(1H,29Si)¼6.8 Hz, 9H],
1.59–1.64 (m, 2H), 1.77–1.85 (m, 2H), 1.97–2.03 (m, 2H),
3.96–3.99 (m, 2H), 4.10 (t, J¼5.9 Hz, 1H) ppm. 13C NMR
(CDCl3, 125 MHz): d¼0.06 (CH3), 23.25 (CH2), 26.13
(CH2), 31.25 (CH2), 71.38 (CH), 83.00 (CH2), 160.01
(C) ppm. IR (neat): 1680 (vs), 1251 (vs), 1236 (vs), 1201
(vs) cm21. HRMS (CI, CH4): Mol. mass calcd 187.1154 (for
C9H19O2Si), found 187.1143 (MþHþ).
3.2. X-Ray crystallographic analysis
Crystallization from CH2Cl2/petroleum ether gave single
crystals suitable for X-ray crystallographic analysis. Data
were collected on a Siemens P4 diffractometer with
˚
graphite-monochromated Cu Ka radiation (l¼1.54178 A)
3.1.16. 2-(1-Hydroxyethyl)-6-hexanolide (12). A solution
of F3B·OEt2 (3.29 ml, 3.72 g, 26.2 mmol) in CH2Cl2 (26 ml)
was added to a solution of silylenolether 14b (4.88 g,
26.2 mmol) and MeCHO (1.23 ml, 0.96 g, 21.8 mmol) in
CH2Cl2 (20 ml) at 2788C. The reaction mixture was stirred
at 2788C for 2 h and warmed to 238C. Saturated aqueous
NH4Cl (100 ml) was added, and the mixture extracted with
EtOAc (3£100 ml). The organic layers were combined and
dried over MgSO4. The solvent was stripped off. Purification
of the crude product by chromatography on SiO2 (hexanes/
EtOAc, 1:2, Rf¼0.31) afforded 12 as a colorless oil (2.76 g,
17.4 mmol, 67%) which, on the NMR evidence, represents a
2:1 mixture of two diastereoisomers. 1H NMR (CDCl3,
300 MHz), major isomer: d¼1.30 (d, J¼6.4 Hz, 3H), 1.42–
2.08 (m, 6H), 2.52–2.64 (m, 1H), 3.44 (d, br, J¼5.5 Hz, 1H),
3.93 (sextet, J¼6.2 Hz, 1H), 4.19–4.35 (m, 2H) ppm; minor
isomer: d¼1.24 (d, J¼6.6 Hz, 3H), 1.42–2.08 (m, 6H), 2.52–
2.64 (m, 1H), 3.14 (d, br, J¼3.7 Hz, 1H), 4.19–4.35 (m,
3H) ppm. IR (neat): 3448 (vs, br), 1726 (vs, br) cm21. MS (CI,
CH4), m/z (%): 159 (100) [MþHþ]. Anal. calcd for C8H14O3:
C, 60.74; H, 8.92. Found: C, 60.63; H, 9.03.
at 293 K. The structures were solved by direct methods and
refined against F 2 for all observed reflections. Crystal-
lographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 196492 (7b), CCDC 196490 (15a), and
CCDC 196591 (15b). Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: þ44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
Generous support of this work by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie is
gratefully acknowledged. H. O. thanks the Graduierten-
kolleg ‘Synthetische, mechanistische und reaktionstech-
nische Aspekte von Metallkatalysatoren’ for a fellowship.
Moreover, we are deeply indebted to Dr Simon Gessler,
¨
Technische Universitat Berlin, for providing us with the
Ru-catalyst, and Dr Angelika Baro, Universitat Stuttgart, for
¨
3.1.17. 1,1-Bis-(oxepan-2-on-1-yl)ethanol (15). A mixture
of Ac2O (3.00 ml, 3.24 g, 31.7 mmol), TiCl4 (3.50 ml, 6.04 g,
31.8 mmol) and CH2Cl2 (60 ml) was stirred for 20 min at
2788C and then added to a solution of silylenolether 14b
(3.00 g, 16.1 mmol) in CH2Cl2 (1000 ml). After further
stirring of the resulting mixture for 1 h at 2788C, it was
warmed to 238C overnight and then poured into saturated
aqueous NaHCO3 solution (700 ml), neutralized with HCl
the preparation of this manuscript.
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