Large-scale synthesis of new pyranoid building blocks based on aldolase-catalysed carbon-carbon bond formation

Article abstract of DOI:10.1002/adsc.200800224

A new large-scale approach to the synthetically versatile chloromethyl-substituted, α,β-unsaturated δ-lactone 3 is described. The synthesis is based on a biocatalytic process performed on an industrial scale. Conjugate addition of C-, N-, O-, and S-nucleophiles to lactone 3 affords a variety of new pyranoid building blocks in a highly diastereoselective manner. The operational simplicity of the whole sequence allows for preparing these building blocks on an attractive scale.

Full text of DOI:10.1002/adsc.200800224

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DOI: 10.1002/adsc.200800224
Large-Scale Synthesis of New Pyranoid Building Blocks Based on
Aldolase-Catalysed Carbon-Carbon Bond Formation
Michael Wolberg,a,* Ben H. N. Dassen,b Martin Schürmann,b Stefan Jennewein,c
Marcel G. Wubbolts,d Hans E. Schoemaker,b and Daniel Minkb,*
a
DSM Pharma Chemicals Regensburg GmbH – ResComꢀ, Donaustaufer Strasse 378, 93055 Regensburg, Germany
Fax : (+49)-941-4093-297; e-mail: michael.wolberg@dsm.com
DSM Pharmaceutical Products – Innovative Synthesis & Catalysis, PO Box 18, 6160 MD Geleen, The Netherlands
b
Fax : (+31)-46-47-67604; e-mail: daniel.mink@dsm.com
Fraunhofer Institute for Molecular Biology and Applied Ecology, Forckenbeckstr. 6, 52074 Aachen, Germany
DSM White Biotechnology, Alexander Fleminglaan 1, 2613 AX Delft, The Netherlands
c
d
Received: April 12, 2008; Published online: July 23, 2008
Dedicated to Professor Chi-Huey Wong on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A new large-scale approach to the synthet- manner. The operational simplicity of the whole se-
ically versatile chloromethyl-substituted, a,b-unsatu- quence allows for preparing these building blocks on
rated d-lactone 3 is described. The synthesis is based an attractive scale.
on a biocatalytic process performed on an industrial
scale. Conjugate addition of C-, N-, O-, and S-nucle-
ophiles to lactone 3 affords a variety of new pyra- Keywords: aldolase; conjugate addition; enzymatic
noid building blocks in a highly diastereoselective catalysis; d-lactones; large-scale synthesis; a-pyrones
Introduction
Aldolase-catalysed carbon-carbon bond formation is a
powerful tool for the construction of complex struc-
tures in organic synthesis.[1] The sequential one-pot,
two-step aldol addition of two molecules of acetalde-
hyde to an acceptor aldehyde catalysed by deoxyri-
bose phosphate aldolase (DERA, EC 4.1.2.4), a reac-
tion discovered by Wong and co-workers in 1994,[2] is
a particularly intriguing example in this respect. This
elegant reaction permits the highly stereoselective
construction of 2,4,6-trideoxypyranoses in one opera-
tional step, starting from extremely simple small mol-
ecule raw materials (Scheme 1, chloroacetaldehyde in
the role of the acceptor aldehyde). Chloro trideoxy-
pyranose 1 thus obtained can be oxidised to the crys-
talline hydroxy lactone 2, formally a triketide, which
can be further elaborated in a few steps to the chiral
dihydroxy side chain of HMG CoA reductase inhibi-
tors of the mevinic acid type (vastatins).[3] A scale-up
of this route has been realised by some of us recent-
Scheme 1. Chemoenzymatic synthesis of lactone 3. a)
ly,[4] including the improvement of the operational sta-
DERA, H2O, pH 7 (refs.[2,4a]); b) Br2, H2O, pH 5–6 (ref.[4b]);
bility of the enzyme by directed evolution.[5] Manufac- c) cat. TsOH, toluene, D, 84–87%.
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turing of hydroxy lactone 2 is operated on an industri- about a new large-scale synthesis of lactone 3 and the
al scale at DSM now. highly diastereoselective conjugate addition of various
In order to further broaden the applicability of this nucleophiles to lactone 3. The products of this reac-
powerful biocatalytic reaction we investigated the tion are versatile pyranoid building blocks which are
conversion of hydroxy lactone 2 to the a,b-unsaturat- of interest for the synthesis of pharmaceuticals and
ed d-lactone 3 (Scheme 1). In view of the susceptibili- natural products.
ty of b-hydroxy d-lactones to dehydration, we rea-
soned that the enantiomerically pure hydroxylactone
2 would serve as a privileged starting material for the Results and Discussion
preparation of lactone 3. The a,b-unsaturated d-lac-
tone is a characteristic structural motif in naturally oc- The a,b-unsaturated d-lactone 3 is readily prepared
curring a-pyrones (5,6-dihydropyran-2-ones), a large by acid-catalysed dehydration of hydroxy lactone 2 in
family of physiologically active secondary metabolites toluene, aided by azeotropic removal of water
widely distributed in nature.[6] Apart from this promi- (Scheme 1). After a simple aqueous work-up (bicar-
nent role in natureꢂs molecular architecture, a,b-unsa- bonate washing) and evaporation of the solvent in
turated d-lactones are valuable chiral synthetic inter- vacuum, lactone 3 is obtained as a yellow oil in 84–
mediates, and building blocks based on this motif 87% yield. We performed laboratory batches on 50–
have been applied in the total synthesis of natural 100 g scales routinely without problems. Since a few
products and other complex organic molecules fre- percent toluene (<5%) represents the only significant
quently. Lactone 3 is of particular value in this re- impurity of the crude product 3, it can usually be
spect, since the electrophilic activation of the exocy- used as such without further purification. If required,
clic carbon atom leads to a broad synthetic applicabil- lactone 3 can be further purified by vacuum distilla-
ity. This has been demonstrated by Enders and co- tion.[9]
workers recently who employed lactone 3 and its en-
antiomer in total syntheses of several naturally occur-
ring a-pyrones.[7]
Conjugate Addition to Unsaturated Lactone 3
Apart from the terminal chloro substituent, lactone
3 contains a high density of complemetary functional Kinetically controlled conjugate addition to chiral
groups, namely a carbonyl/ester group (C-1), an acti- a,b-unsaturated d-lactones like 3 is well-known to
vated double bond (C-2, C-3), an allylic methylene proceed with very high diastereoselectivity in favour
(C-4), and a (masked) secondary alcohol (C-5) which of the trans configuration. The preference of a chair-
constitutes a (masked) terminal epoxide together with like transition state over its less favoured twist-like
the chloro substituent (C-5, C-6; carbon chain of all pendant and stereoelectronic control (axial attack
compounds indexed according to the underlying open phenomenon) has been invoked to account for this
chain hexanoates throughout this work). Both enan- observation (Scheme 2).[10]
tiomers of lactone 3 have been prepared via alterna-
We investigated the base-catalysed conjugate addi-
tive chemoenzymatic routes before.[8] Here, we report tion of various C-, N-, O-, and S-nucleophiles to lac-
Scheme 2. Stereochemical course of the base-catalysed conjugate addition of nucleophiles Nu-H to a,b-unsaturated d-lac-
tones.[10]
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tone 3 at ambient temperature (Table 1). Treatment the S-benzoyl-protected derivative 5. The addition of
of lactone 3 with thioacetic acid in the presence of a thiobenzoic acid to lactone 3 turned out to be slightly
catalytic amount of triethylamine resulted in the less diastereoselective (trans:cis 92:8, entry 2), but the
highly diastereoselective formation of S-acetyl-pro- minor cis-isomer was easily removed by a single re-
tected mercapto lactone 4 in 92% yield (trans:cis crystallisation after which lactone 5 was obtained in
94:6, entry 1). Since lactone 4 has a relatively low 75% yield on a 0.5 mol scale. Conjugate addition of
melting point (38.2–39.58C) and is thus difficult to NH-acidic phthalimide to lactone 3 in DMF was slug-
purify by crystallisation, we turned our attention to gish even when a stoichiometric amount of NEt3 and
Table 1. Conjugate addition of C-, N-, O-, and S-nucleophiles (Nu-H) to unsaturated lactone 3.
Entry Nu-H[a]
Product
Base [mol equiv]
NEt3 (0.03)
Solvent Ratio trans:cis[b] Yield [%][c]
1
2
3
4
5
6
AcSH
MTBE94:6 ( >95:5)[d]
MTBE92:8 ( >95:5)[d]
92
75
79
61
60
52
BzSH
NEt3 (0.02)
DBU (0.03)
DBU (0.10)
DBU (0.25)
DBU (0.10)
PhtNH
HCN
DMF
>95:5
CH2Cl2 >95:5
toluene >95:5
t-BuOOH
MeNO2
A
>95:5
7
CH
A
K2CO3 (2.0), 18-crown-6 (0.10) CH2Cl2 95:5 (>95:5)[d]
75
[a]
[b]
[c]
[d]
Ac=acetyl, Bz=benzoyl, Pht=phthaloyl.
Determined for crude products by NMR spectroscopy.
Yields after recrystallisation or flash chromatography, respectively (except entries 1 and 3: crude product).
Ratio trans:cis after recrystallisation or column chromatography, respectively.
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elevated temperatures were applied. In contrast, ap- ethyl malonate to lactone 3 was initially attempted
plication of only 3 mol% DBU as catalyst enabled using the corresponding lithium enolate preformed
this reaction to proceed smoothly at ambient temper- with LiH in THF. At low temperature (À108C) the
ature and full conversion was reached after stirring reaction was prohibitively slow whereas full conver-
overnight. Phthaloyl-protected b-amino lactone 6 pre- sion could be obtained at ambient temperature after
cipitates from the reaction mixture and can be isolat- stirring overnight. Lactone 10 was thus obtained in
ed in pure form by simple filtration which makes this 89% isolated yield. NMR analysis of the crude prod-
reaction particularly convenient to be carried out on uct indicated the presence of significant amounts of
a large scale (79% yield, 0.5 mol scale, entry 3). We the cis diastereomer, however (trans:cis=80:20). A
could not detect any traces of the cis diastereomer in similar result was obtained when NaH was used as
the crude product. The DBU-catalyzed hydrocyana- base whilst application of KO-t-Bu gave even worse
tion of the double bond of lactone 3, carried out with diastereoselectivity (trans:cis=60:40). Better results
acetone cyanohydrin as a convenient source of hydro- in terms of diastereoselectivity (trans:cis=95:5) were
gen cyanide,[11] resulted in smooth and highly diaste- observed with DBU in dichloromethane, but stoichio-
reoselective formation of secondary nitrile
7
metric amounts of DBU had to be applied to get full
ACHTREUNG
in 82% yield after a usual aqueous work-up (61% composition products. We were pleased to see that
after recrystallisation). Our initial attempts to use substitution of solid potassium carbonate under
NEt3 as catalyst for this reaction did not lead to phase-transfer conditions (10 mol% 18-crown-6) for
useful conversion which underlines the privileged role DBU afforded product 10 with equally good diaste-
of DBU as catalyst for the conjugate additions de- reoselectivity (trans:cis=95:5, entry 7) and as virtual-
scribed here. Epoxidation of lactone 3 was achieved ly pure crude product. The minor diastereomer was
by means of the DBU-catalysed conjugate addition of further depleted by means of column chromatography
tert-butyl hydroperoxide,[12] again with very high dia- and lactone 10 could be thus obtained analytically
stereoselectivity (trans:cis>95:5, entry 5). Application pure in 75% yield. Various attempts to bring about a
of azeotropically dried tert-butyl hydroperoxide in tol- base-catalysed conjugate addition of the cyclic malon-
uene gave the best results with regard to yield of ep- ic ester derivative Meldrumꢂs acid to lactone 3 failed.
oxide 8 and catalyst consumption (25 mol% DBU) in
our hands.[13] We found epoxide 8 to be a highly crys-
talline solid that can be readily purified by recrystalli- Stereochemical Assignments
sation (60%, 0.5 mol scale). In contrast, the usual ep-
oxidation with aqueous H2O2 in alkaline medium was Our assignment of the trans configuration for all con-
plagued by significant side-product formation, even jugate addition products described here is based on
when advanced conditions like phase-transfer cataly- the well-established trans-selective stereochemical
sis in a biphasic system were applied. Attempts to course of this type of reaction.[10] For the products 4–7
apply the H2O2/urea complex in the presence of meth- this assignment is clearly supported by analysis of the
yltrioxorhenium for epoxidation of lactone 3 under vicinal H,H coupling constants of the hydrogen nuclei
anhydrous conditions remained fruitless;[14] no conver- attached to the lactone ring (Table 2). The relatively
3
sion could be achieved.
small and almost equal constants JH,H of vicinal cou-
After having evaluated the conjugate addition of pling between H3 and both H2 nuclei (4–7 Hz) as
heteroatom nucleophiles to lactone 3 we turned our well as between H3 and both H4 nuclei (4–5 Hz) rule
attention to p-stabilised anionic C-nucleophiles. Ni- out the cis configuration for lactones 4–7. In the case
tromethane was found to add rapidly to lactone 3 in of a cis configuration H3 would be in pseudo-axial po-
the presence of 10 mol% DBU to afford lactone 9, sition which would lead to significantly larger trans di-
virtually as a single diastereomer (trans:cis>95:5, axial coupling (9–12 Hz) between H3 and H2’ as well
entry 6). Application of neat nitromethane in a large as between H3 and H4’ (Figure 1). The observed
excess (20 equiv.) proved to be the most effective con- values for lactones 4–7 correlate with the trans config-
ditions. Not unexpectedly,[15] this conjugate addition is uration in a half-chair conformation where the heter-
hampered by formation of a secondary double addi- oatom substituent connected to C3 is positioned
tion product which had to be separated from the pseudo-axially and H3 is in a pseudo-equatorial posi-
À
À
À
À
main product 9 by means of column chromatogra- tion, thus bisecting the H2 C2 H2’ and the H4 C4
phy.[16] Yield of purified lactone 9 was limited to a H4’ angles.[17]
moderate 52% under these conditions. Triethylamine
The vicinal coupling constants of H3 as observed
and diisopropylethylamine were ineffective in catalys- for the lactones 9 and 10 draw a less clear picture in
ing the addition of nitromethane under identical con- this respect. Particularly the coupling between H3
ditions and only traces of product 9 could be detected and H2’, but also between H3 and H4’, is significantly
after one day reaction time. Conjugate addition of di- increased here (10 and 7 Hz, respectively). On the
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1
Table 2. Selected H NMR data of the lactones 4–10 (300 MHz, 218C, CDCl3).[a]
Cpd.
no.
d (ppm)
3JH,H (Hz)
H2’ H2
H3 H4’ H4
H5
H2,H2’ H2’,H3 H2,H3 H3,H4’ H3,H4 H4,H4’ H4’,H5 H4,H5
4
5
6
7
8
9
10
2.96 2.70[b] 4.07 2.29 2.14[b] 4.74
18
18
17.5
18
–
6.5
6.5
7.5
7
4
9.5
10.5
5.5
5
4
5
–
5
5
4.5
4
n.r.
4
3
6
14.5
15
n.r.
14.5
15
10
10
n.r.
10.5
12
9
4
3.06 2.83[b] 4.28 2.39 2.26[b] 4.85
4.5
n.r.
4
3
4.5
4.5
2.89 3.00
4.70
2.02–2.16
4.77
n.r.[c]
5.5
~0.5
7
2.82 2.90[b] 3.36 2.16 2.30[b] 4.88
3.60
2.42 2.70
2.54 2.66
–
3.75 2.22 2.50
2.95 2.15 1.90
~2.8 2.12 1.96
4.75
4.64
4.64
16.5
16.5
6
5.5
14.5
14.5
7.5
6.5
9
[a]
Lactone 6 recorded in DMSO-d6.
W-coupling observed additionally: JH2,H4 =1.5 Hz.
n.r.=not resolved.
[b]
[c]
4
lactone in a detailed conformational study before
(benzenesulfonyl substituent at C3).[20]
Conformational flexibility is reduced in epoxide 8
because of the constraints imposed by the rigid three-
3
membered ring. The large coupling constant JH4’,H5 of
12 Hz in combination with the clear absence of diaxial
coupling between H3 and H4’ strongly supports as-
signment of the trans configuration.
Follow-Up Transformations
À
The O C1 ester bond of trans-3,5-disubstituted d-lac-
tones is readily cleaved by solvolysis to give the corre-
sponding open-chain carboxylic acid derivatives. In
the case of the lactones 4–10 this operation unmasks
the chlorohydrin moiety which can be dehydrochlori-
nated to yield a terminal epoxide. Thus, refluxing a
suspension of phthaloyl-protected amino lactone 6 in
Figure 1. Conformers of 3,5-disubstituted d-lactones.
3
other hand, the increase of JH3,H4’ to 7 Hz is not pro- methanol in the presence a catalytical amount of an-
nounced enough to support an assignment of a cis hydrous HCl for 1.5 h affords methyl hexanoate 11
configuration for which JH3,H4’ =9–12 Hz would be ex- which we obtained as a highly viscous, clear colourless
3
pected due to trans diaxial coupling (see above). Fur- syrup in quantitative yield (Scheme 3). The reaction
3
thermore, an equal or increased value for JH4’,H5 com-
pared to the trans cases 4–7 would be expected for
the same reason, if lactones 9 and 10 were obtained
as cis isomers.[18,19] Conversely, a slight decrease of the
3
coupling constant JH4’,H5 from 10 Hz for lactones 4–7
to 9 Hz for lactones 9 and 10 is observed. These ob-
servations are indicative for a trans configuration with
a distortion from the half-chair to a skew-boat confor-
mation which allows for pseude-equatorial positioning
of both substituents at C3 and C5 (Figure 1). Such a
conformational change can be explained by the fact
that the exocyclic tetrasubstituted sp3 carbon atom of
the nitromethyl (lactone 9) and 2-malonyl (lactone
10) substituents exerts a higher sterical influence in
close proximity to the lactone ring as compared to the
heteroatom C3 substituents of the lactones 4–7.
Adoption of a skew-boat conformation has been ob-
Scheme 3. Synthesis of epoxide 12. a) cat. HCl, MeOH, D,
quant.; b) DBU, CH2Cl2, 82%; alternatively: a,b) K2CO3,
served for a similar sterically encumbered 3,5-trans d- MeOH, 69%.
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can be visually followed by the dissolution of the spar- Wongꢂs elegant aldolase-based approach to trideoxy-
ingly soluble lactone 6 as the reaction proceeds. Upon pyranose 1. It has been demonstrated that C-, N-, O-,
treatment of hexanoate 11 with DBU in dichlorome- and S-nucleophiles add to the conjugated double
thane the highly crystalline epoxide 12 is obtained bond of lactone 3 with high diastereoselectivity to
(82% yield). Alternatively, epoxide 12 can be ob- afford the new trans-3,5-disubstituted d-lactones 4–10
tained in a one-pot tandem reaction when lactone 6 is in fair to good yields (52–92%). The whole route to
treated with potassium carbonate in methanol (69% lactones 4–10 (and further to epoxide 12 and tetrahy-
yield). Because of the outstanding synthetic versatility drothiophene 15), starting from the bulk raw materi-
of the terminal epoxide function,[21] we think that ep- als chloroacetaldehyde and acetaldehyde, is void of
oxide 12 can serve as a useful building block for b- low-temperature chemistry, heavy metal catalysts and
amino acids.
metalorganic species. The conjugate additions de-
The acetyl-protected mercapto lactone 4 undergoes scribed here have been performed on a scale up to
a more extended tandem reaction when treated with the 100-g range without any difficulties. Due to their
potassium carbonate in MeOH. Ring cleavage is fol- favourable set of functional groups, lactone 3 and its
lowed by deprotection of the thiol group which subse- derivatives 4–15 are attractive building blocks for the
quently undergoes intramolecular S-alkylation, lead- synthesis of natural products and pharmaceutically
ing to tetrahydrothiophene 13 in a single synthetic relevant compounds like, e.g., b-amino acids.
step (Scheme 4). NMR and TLC analyses of the
Experimental Section
General information and characterisation data of the prod-
ucts 3–13 and 15 can be found in the Supporting Informa-
tion.
Unsaturated Lactone 3
To hydroxy lactone 2 (100 g, 0.61 mol) in toluene (600 mL)
was added toluenesulfonic acid monohydrate (3.5 g, 0.02
mol) and the mixture was heated to reflux for 4 h. Reaction
water was continously removed by means of a Dean–Stark
trap. The batch was cooled to ambient temperature and ex-
tracted with saturated aqueous NaHCO3 solution (2”
200 mL) and water (200 mL). The organic phase was con-
Scheme 4. Synthesis of tosylate 15. a) cat. HCl, MeOH,
centrated under vacuum and azeotropically dried with tolu-
quant.; b) DBU, CH2Cl2, 65%; c) TsCl, NEt3, cat. DMAP,
ene once (200 mL). Residual toluene was removed at 508C
CH2Cl2, 76%; d) K2CO3, MeOH, 53%.
under vacuum (5 mbar) until the weight remained constant.
Lactone 3 was thus obtained in form of a yellow oil, virtual-
1
ly pure by H NMR; yield: 78.0 g (87.6%).
crude product 13 indicated partial epimerisation
under these conditions, however. Conversely, a two-
Lactone 4
step procedure via thiol 14, comprising acid-catalysed
To a solution of unsaturated lactone 3 (73.3 g, 0.50 mol) and
methanolysis and deprotection of lactone 4 followed
NEt3 (1.7 g, 17 mmol) in MTBE(600 mL) was slowly added
thioacetic acid (43.0 g, 0.56 mol), maintaining the tempera-
ture at around 208C by means of a water bath. The mixture
was stirred overnight and washed then, in sequence, with
by base induced 5-exo-tet ring closure, takes place
without affecting the stereochemical integrity of the
product 13 (65% yield). Subsequent tosylation of tet-
rahydrothiophene 13 afforded tosylate 15 in 76%
0.5M aqueous HCl, 5% aqueous NaHCO3, and brine. The
yield after flash chromatography (Scheme 4). Tetrahy-
drothiophenes similar to 15 have been used as chiral
building blocks in the synthesis of modified dideoxy
isonucleosides which are under investigation for po-
tential antiviral activity.[22]
organic phase was dried over Na2SO4 and evaporated to dry-
ness under vacuum, leaving lactone 4 as a yellow solid;
yield: 103.0 g (92%). A sample was redissolved in MTBE
and recrystallised by letting n-pentane diffuse into the solu-
tion at À188C.
Lactone 5
Conclusions
To a solution of unsaturated lactone 3 (73.3 g, 0.50 mol) and
NEt3 (1.3 g, 12 mmol) in MTBE(500 mL) was slowly added
thiobenzoic acid (75.1 g, 0.54 mol), maintaining the tempera-
ture at around 2–58C by means of an ice-water bath. The
In the present work we described a new large-scale
synthesis of the synthetically versatile a,b-unsaturated
d-lactone 3. Key-step of this route is Professor mixture was stirred at ambient temperature for 5 h, diluted
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with ethyl acetate (450 mL) and washed, in sequenece, with
0.5M aqueous HCl (400 mL), 5% aqueous NaHCO3 (3”
100 mL), and brine. The organic phase was dried over
Na2SO4 and evaporated to dryness under vacuum, leaving
lactone 5 as a weakly orange oil that solidified upon seeding.
20% aqueous Na2SO3 (100 mL) thereafter. The mixture was
stirred for 10 min and 2M aqueous HCl (40 mL) was added.
After separating the phases and extraction of the aqueous
phase with toluene (50 mL) the combined organic phases
were washed, in sequence, with 2M HCl (100 mL), half-sa-
turated brine (50 mL), saturated aqueous NaHCO3
(100 mL), and brine (100 mL). The organic phase was dried
over Na2SO4 and evaporated to dryness under vacuum, leav-
ing crude lactone 8 as an orange oil that solidified spontane-
ously; yield: 44.6 g (69%). The crude product was dissolved
in MTBE(600 mL) at reflux and the solution stored at 4 8C
overnight. The precipitate was filtered off, rinsed with chil-
led TBME(20 mL), and dried under vacuum, yielding lac-
tone 8 in form of off-white crystals; yield: 33.6 g (mp 84.4–
85.28C). A second crop (4.9 g) was obtained after concen-
trating the mother liqour to 1/3 of the volume under re-
duced pressure and storage of the concentrate at 48C. Total
yield: 60%.
Recrystallisation from MTBE(500 mL) afforded lactone
5
as an off-white solid; yield: 100.6 g. A second crop (6.3 g)
was obtained after concentrating the combined filtrate and
washings of the recrystallisation to approx. one half of the
original volume; total yield: 75%.
Lactone 6
Phthalimide (73.6 g, 0.50 mol) was dissolved in DMF
(340 mL) at 35–408C and the solution was cooled to ambi-
ent temperature by means of a water bath. Unsaturated lac-
tone 3 (73.3 g, 0.50 mol) and DBU (1.9 g, 12 mmol) were
added and the solution was stirred at ambient temperature.
After stirring overnight a suspension had formed which was
filtered. The filter cake was rinsed with DMF (30 mL) and
MTBE(2”50 mL), to afford, after drying at 40 8C under
vacuum, spectroscopically pure lactone 6 in the form of
heavy, off-white crystals; yield: 115.3 g (79%). A sample
was recrystallised from MeCN.
Lactone 9
A solution of DBU (75 mL, 0.5 mmol) in nitromethane
(5.6 g, 92 mmol) was cooled in a water bath and unsaturated
lactone 3 (0.73 g, 5.0 mmol) was added. After stirring for 5 h
at ambient temperature the reaction was quenched by addi-
tion of 0.5M aqueous HCl (10 mL). The mixture was ex-
tracted with ethyl acetate (40 mL) and the phases separated.
The organic phase was washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4,
and concentrated under vacuum. The viscous residue was
subjected to flash chromatography (5 cm Ø column, 100 g
silica gel, crude product preadsobed on 6 g silica gel, MTBE
as eluent), to afford analytically pure lactone 9 as a clear
colourless syrup; yield: 0.54 g (52%).
Lactone 7
DBU (1.52 g, 10 mmol) was added to a solution of unsatu-
rated lactone 3 (14.7 g, 0.10 mol) and acetone cyanohydrin
(9.4 g, 0.11 mol) in dichloromethane (200 mL) and the solu-
tion was stirred at ambient temperature overnight. Saturated
aqueous NaHCO3 (100 mL) was added and the mixture was
vigorously stirred for 5 min. The aqueous phase was cut and
extracted with a few mL of dichloromethane. The combined
organic phases were washed, in sequence, with 2M aqueous
HCl (2”50 mL), saturated aqueous NaHCO3 (50 mL), and
brine (50 mL). The solution was dried over Na2SO4 and
evaporated to dryness under vacuum, leaving crude lactone
7 as a brownish syrup that solidified slowly on standing at
ambient temperature; yield: 14.2 g (82%). Crude lactone 7
(13.5 g) was dissolved in dichloromethane (41 mL), MTBE
was added (50 mL), and the solution was stored at ambient
temperature overnight for recrystallisation. The mother
liquor was decanted and the crystals washed with chilled
(À208C) MTBEcontaining 5 vol% dichloromethane which
afforded, after drying under vacuum, lactone 7 in the form
of slightly brownish, transparent crystals; yield: 8.1 g, mp
84.5–85.18C. A second crop of recrystallised lactone 7 could
be obtained from the mother liquor after it was stored at
48C overnight (0.5 g, mp 83.9–84.68C). Slow evaporation of
a part of the new mother liquor by keeping the flask open
to the atmosphere in the ventilation hood produced a third
crop (1.4 g, mp 84.3–85.28C): total yield: 61%.
Lactone 10
To a solution of unsaturated lactone 3 (0.73 g, 5.0 mmol)
and dimethyl malonate (0.80 g, 5.0 mmol) in dichlorome-
thane (25 mL) was added powdered K2CO3 (1.38 g,
10 mmol) and 18-crown-6 (0.13 g, 0.5 mmol) and the mixture
was vigorously stirred for 23 h at ambient temperature.
Aqueous HCl (2M, 20 mL) was added and the phases were
seperated. The organic phase was washed with saturated
aqueous NaHCO3 (20 mL) and brine (25 mL), dried over
Na2SO4, and concentrated under vacuum. The oily residue
was subjected to flash chromatography (5 cm Ø column,
145 g silica gel, ethyl acetate/n-hexane 35:65 v/v as eluent),
to afford analytically pure lactone 10 as a clear colourless
syrup; yield:. 1.15 g (75%).
Hexanoate 11 and Epoxide 12
To a suspension of lactone 6 (10.0 g, 34 mmol) in methanol
(100 mL) was added HCl in 1,4-dioxane (560 mL, 2.7M,
1.5 mmol) and the mixture was heated to reflux for 1.5 h
after which time a clear solution was obtained. Volatiles
were removed under vacuum at 508C to afford hexanoate
11 as a clear colurless glass; yield: 11.2 g (100%). The crude
hexanoate 11 was dissolved in dichloromethane (100 mL)
and DBU (7.8 g, 51 mmol) was added. After heating the so-
lution to reflux for 6 h, aqueous HCl (1M, 100 mL) was
added and the phases were separated. The deep brown or-
Lactone 8
An azeotropically dried solution of tert-butyl hydroperoxide
in toluene (129 mL, 3.4M, 0.44 mol)[13] was added dropwise
to a solution of unsaturated lactone 3 (58.6 g, 0.40 mol) and
DBU (15.2 g, 0.1 mol) in toluene (320 mL) within a period
of 20 min, maintaining the temperature at 27–358C by
means of an ice-water bath. The solution was stirred at am-
bient temperature overnight and quenched by addition of
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Michael Wolberg et al.
ganic phase was washed, in sequence, with 0.5M aqueous
HCl (100 mL), 5% aqueous NaHCO3, and brine (100 mL),
dried over Na2SO4, and filtered through a pad of silica gel.
The silica gel pad was rinsed with 50 mL dichloromethane
and the combined filtrates evaporated under vacuum, leav-
ing spectroscopically pure epoxide 12 as almost colourless
syrup that solidified on standing at ambient temperature;
yield: 8.1 g (82%). A sample was recrystallised from MTBE.
Gijsen, D. H. Steensma, J. Am. Chem. Soc. 1995, 117,
3333–3339; d) H. J. M. Gijsen, C.-H. Wong, J. Am.
Chem. Soc. 1995, 117, 7585–7591.
[3] M. Müller, Angew. Chem. 2005, 117, 366–369; Angew.
Chem. Int. Ed. 2005, 44, 362–365.
[4] a) J. G. T. Kierkels, D. Mink, S. Panke, F. A. M.
Lommen, D. Heemskerk, (DSM N. V.), World Patent
WO 03/006656, 2003; Chem. Abstr. 2003, 138, 112523;
b) J. H. M. H. Kooistra, H. J. M. Zeegers, D. Mink,
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02/06266, 2002; Chem. Abstr. 2002, 136, 118454.
[5] a) S. Jennewein, M. Schürmann, M. Wolberg, I. Hilker,
R. Luiten, M. Wubbolts, D. Mink, Biotechnol. J. 2006,
1, 537–548; b) cf. W. A. Greenberg, A. Varvak, S. R.
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[7] a) D. Enders, A. Lenzen, M. Müller, Synthesis 2004,
1486–1496; b) D. Enders, D. Steinbusch, Eur. J. Org.
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Tetrahydrothiophene 13 and Tosylate 15
To a solution of crude (~95%) lactone 4 (0.43 g, 1.8 mmol)
in methanol (4 mL) was added HCl in 1,4-dioxane (350 mL,
2.7M, 0.9 mmol) and the solution was stirred at ambient
temperature for three days. Volatiles were removed under
vacuum to afford thiol 14 as a yellow oil in near quantitative
yield (0.38 g). The residue was taken up in dichloromethane
(8 mL), cooled in an ice-water bath, and DBU (300 mL,
2.0 mmol) was added dropwise over a period of 2 min. The
ice-bath was removed and the solution was stirred for 2 h at
ambient temperature. The solution was washed, in sequence,
with 2M HCl, saturated aqueous NaHCO3, and brine, dried
over Na2SO4, and concentrated under vacuum. The oily resi-
due (0.27 g) was subjected to flash chromatography (3 cm Ø
column,100 mL silica gel, ethyl acetate/n-hexane 55:45 v/v
as eluent), to afford tetrahydrothiophene 13 as a clear col-
ourless oil; yield: 0.21 g (65%). To a solution of tetrahydro-
thiophene 13 thus obtained (0.21 g, 1.2 mmol) in dichloro-
methane (~5 mL) was added NEt3 (180 mLg, 1.3 mmol) and
tosyl chloride (0.23 g, 1.2 mmol) and the mixture was stirred
at ambient temperature for 20 h. Since TLC analysis indicat-
ed incomplete conversion at this point, DMAP (16 mg,
0.1 mmol) and another portion of tosyl chloride (19 mg,
0.1 mmol) and NEt3 (90 mL, 0.6 mmol) were added and stir-
ring was continued for one week. Ethyl acetate (40 mL) was
added and the solution was washed, in sequence, with 2M
HCl, saturated aqueous NaHCO3, and brine, dried over
Na2SO4, and concentrated under vacuum. The viscouse resi-
due (0.33 g) was subjected to flash chromatography (2 cm Ø
column, 60 mL silica gel, ethyl acetate/n-hexane 35:65 v/v as
eluent), to afford tosylate 15 as a pale yellow syrup; yield:
0.30 g (76%).
[8] a) M. Wolberg, W. Hummel, M. Müller, Chem. Eur. J.
2001, 7, 4562–4571; b) M. Wolberg, W. Hummel, C.
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Sakaki, H. Sakoda, Y. Sugita, M. Sato, C. Kaneko, Tet-
rahedron: Asymmetry 1991, 2, 343–346.
[9] Samples of lactone 3 are available from Fluka, product
no. 16749.
[10] a) I. Panfil, D. Mostowicz, M. Chmielewski, Polish J.
Chem. 1999, 73, 1099–1110, and references cited there-
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Granzer, H. Jendralla, B. von Kerekjarto, G. Wess, Tet-
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Tetrahedron Lett. 1987, 28, 3179–3182; g) J. A. Mar-
shall, R. C. Andrews, L. Lebioda, J. Org. Chem. 1987,
52, 2378–2388; h) T. M. Willson, P. Kocienski, K. Jaro-
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Acknowledgements
This work was supported by the EU in the scope of the 5th
Framework Programme (Marie Curie Industry Host Fellow-
ship; M.Wo., M.S., S.J.). We thank the analytical department
RESOLVE of DSM Research for analytical support. Supply
of hydroxy lactone 2 by DSM Pharma Chemicals, Venlo, is
gratefully acknowledged.
[11] a) I. N. Nazarov, S. I. Zav’yalov, Zh. Obshch. Khim.
1954, 24, 466–469; J. Gen. Chem. USSR (Engl.
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[13] For a method to azeotropically dry tert-butyl hydroper-
oxide see: J. G. Hill, B. E. Rossiter, K. B. Sharpless, J.
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3
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1
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1H), 1.71–1.87
A
[17] d-Lactones usually adopt a half-chair conformation
À À
À
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Adv. Synth. Catal. 2008, 350, 1751 – 1759
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1759