Stereoselective Synthesis of a Highly Oxygenated δ-Lactone Related to the Core Structure of (-)-Enterocin

Article abstract of DOI:10.1055/s-0035-1562539

The title compound was prepared in a concise route starting from an appropriately protected (S)-glyceraldehyde. A highly diastereoselective (d.r. >95:5) Mukaiyama aldol reaction of an acetoacetate-derived silyl enol ether served as the initial step of the synthetic sequence. It was found that protection of the glyceraldehyde as a butane-2,3-dione acetal is required to achieve the desired diastereoselectivity. Upon lactonization, a Tsuji-Trost allylation and a subsequent one-pot reaction cascade including an ozonolysis and an α-hydroxylation gave diastereoselective access to the desired α-hydroxy-β-oxo-δ-lactone. Alternative synthetic approaches are discussed and proof for the configuration of the product is presented.

Full text of DOI:10.1055/s-0035-1562539

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
M. Wegmann, T. Bach
Paper
Synthesis
Stereoselective Synthesis of a Highly Oxygenated δ-Lactone
Related to the Core Structure of (–)-Enterocin
Marcus Wegmann
hydroxylation
O
OH
Thorsten Bach*
O
O
4 steps
O
28% overall
Ph
Lehrstuhl für Organische Chemie I, Technische Universität
München, Lichtenbergstr. 4, 85747 Garching, Germany
thorsten.bach@ch.tum.de
O
O
O
MeO
MeO
O
O
single
diastereoisomer
Mukaiyama
aldol reaction
OMe
Dedicated to Professor Dieter Enders on the occasion of his 70th
birthday
OMe
Received: 18.07.2016
Accepted: 22.07.2016
Published online: 09.09.2016
DOI: 10.1055/s-0035-1562539; Art ID: ss-2016-z0504-op
O
O
Ph
Ph
O
O
4
1
3
O
O
O
OMe
O
O
OH
OH
OH
9
HO
HO
OH
O
O
O
7
8
O
HO
Ph
Abstract The title compound was prepared in a concise route starting
from an appropriately protected (S)-glyceraldehyde. A highly diastereo-
selective (d.r. >95:5) Mukaiyama aldol reaction of an acetoacetate-de-
rived silyl enol ether served as the initial step of the synthetic sequence.
It was found that protection of the glyceraldehyde as a butane-2,3-di-
one acetal is required to achieve the desired diastereoselectivity. Upon
lactonization, a Tsuji–Trost allylation and a subsequent one-pot reac-
tion cascade including an ozonolysis and an α-hydroxylation gave dia-
stereoselective access to the desired α-hydroxy-β-oxo-δ-lactone. Alter-
native synthetic approaches are discussed and proof for the
configuration of the product is presented.
O
O
8
4
O
O
OH
MeO
O
MeO
O
1
2
O
O
OH
O
O
O
MeO
S
+
Ph
PGO
PGO
O
O
6
OPG
OPG
3
4
5
Scheme 1 Structure of (–)-enterocin (1) and retrosynthetic disconnec-
tion by biomimetic aldol retrons (C3/C4; C8/C9) via intermediate 2 and
oxygenated δ-lactone 3 to a protected S-configured glyceraldehyde 4
and methyl acetoacetate (5)
Key words aldol reaction, diastereoselectivity, natural product syn-
thesis, oxygenation, polyketides
(–)-Enterocin (1) (Scheme 1) was first isolated in 1976
from Streptomyces candidus var. enterostaticus WS-8096
and Streptomyces viridochromogenes.1 After full characteri-
zation, its structure was proven to be identical to the
known structure of the antibiotic vulgamycin.2 The com-
pound exhibited static activities against both Gram-posi-
tive and Gram-negative bacteria.1a
Compared to the biosynthetically related wailupemy-
cins,3 (–)-enterocin (1) features an exceptional bicy-
clo[3.2.1]octane core. Extensive studies concerning the bio-
synthesis were performed by Moore and co-workers, re-
vealing that the oxygenase EncK and the methyltransferase
EncM of the polyketide synthase complex enable the selec-
tive formation of (–)-enterocin (1).4 Furthermore, EncK was
shown to catalyze an unusual Favorskii type rearrangement
of the generated linear octaketide, in the course of which
the bond between carbon atoms C2 and C3 is formed.5 The
remaining bonds of the bicyclic skeleton are formed in aldol
reactions between carbon atoms C3/C4 and C8/C9. Finally,
the Moore group was able to perform the first enzymatic
total synthesis of (–)-enterocin (1).6
Our interest in a potential synthesis of (–)-enterocin (1)
was mainly kindled by its antibiotic activity and by the fact
that no chemical total synthesis7 has yet been reported. In
previous work, we have successfully completed the first to-
tal synthesis of a biogenetically related polyketide natural
product, (+)-wailupemycin B.8 Although it seemed feasible
to access the bicyclo[3.2.1]octane core of enterocin by a
meta-photocycloaddition reaction, it turned out to be diffi-
cult to implement the required high density of oxygen
functionality in a suitable substrate.9 An alternative was
conceived to follow a biogenetically inspired approach1c,5
and aimed at a two-fold aldol reaction to establish the
bonds between carbon atoms C3/C4 and C8/C9 in the natu-
ral product (Scheme 1). Precursor compound 2 features an
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
M. Wegmann, T. Bach
Paper
Synthesis
α-pyrone ring, which we – in analogy to the synthesis of
wailupemycin B8,10 – envisaged to be installed by addition
to a carbonyl carbon atom at C4. This strategy thus led to
the highly oxygenated δ-lactone 3 (PG = protecting group)
as a putative target compound, which was required to be
available in enantio- and diastereomerically pure form. In
this paper, we describe full details of our successful at-
tempts to prepare a compound of structure 3.
both α-chiral diastereomers of glyceraldehyde from the
same starting material, namely D-mannitol.18a,b Although a
chelation control was invoked to account for the observed
diastereoselectivity in the Grignard addition reaction it
seemed equally likely that a Felkin–Anh type transition
state11 was involved. Indeed, we were pleased to note that
silyl ketene acetal 6 produced a diastereomerically pure
product upon BF3-promoted reaction with aldehyde 4b
(Scheme 3). The Lewis acid was used in stoichometric
amounts and the desired δ-hydroxy-β-oxoalkanoate 10 was
obtained as a single product in 85% yield. The absolute con-
figuration at the newly formed stereogenic center was de-
termined by the Mosher method19 and the desired R-con-
figuration could be unambiguously established (see Sup-
porting Information for further details). The conformation
4b′ responsible for the required approach of the nucleophile
is closely related to a chelate-type conformation, in which
one oxygen atom of the 1,4-dioxane ring and the carbonyl
oxygen atom form a six-membered chelate with an appro-
priate Lewis acid. This unusual β-chelation may account for
the fact that also in the presence of a chelating Lewis acid
(TiCl4) the same diastereoselectivity was observed. The
preference for the desired diastereoisomer 10 was high (d.r.
>95:5) but the yield was lower (50%). With trimethylsilyl
trifluoromethanesulfonate (TMSOTf) as Lewis acid, the
yield remained low (8%).
As already outlined in the retrosynthetic scheme
(Scheme 1), an obvious disconnection to set up the stereo-
genic center in δ-position (carbon atom C6) of the lactone
ring would be a diastereoselective aldol reaction of an ace-
toacetate, for example 5, and a suitably protected (S)-gly-
ceraldehyde 4. The reaction needs to occur by Felkin–Anh
control11,12 to establish the desired configuration at C6 and
it was therefore attempted to involve the known protected
glyceraldehyde 4a13,14 in a diastereoselective aldol reaction.
Scheme 2 shows examplarily the outcome of two represen-
tative experiments. Silyl ketene acetal 615 derived from
methyl acetoacetate (5) produced in the presence of a mono-
valent Lewis acid such as boron trifluoride a diastereomeric
mixture of aldol products 7 (d.r. = diastereomeric ratio =
75:25). In a similar fashion, the dianion derived from aceto-
acetate 5 delivered products 7 as a 67:33 mixture of diaste-
reoisomers. Apart from dianion equivalents, ketone 816
(TBS = tert-butyldimethylsilyl) served as monoanion equiv-
alent, which was converted into the respective boron eno-
late. With dibutylboron triflate,17 the aldol reaction pro-
ceeded with low diastereoselectivity and products 9 were
obtained in 68% yield (d.r. = 66:34). Although the diastereo-
selectivity could be improved by the use of chiral boron tri-
flates, it did not reach a satisfactory level.
O
OH
O
O
6, BF3·OEt2
O
−78 °C (CH2Cl2)
O
OMe
R
MeO
MeO
O
O
85%
OMe
OMe
4b
10 (d.r. > 95:5)
MeO
β
H
H
TMSO
OTMS
O
H
O
O
β
6
MeO
O
OMe
O
MeO
O
OH
O
O
O
BF3·OEt2
H
via
4b'
OMe
−78 °C (CH2Cl2)
OMe
O
O
O
Scheme 3 Highly diastereoselective Mukaiyama aldol reaction with
protected (S)-glyceraldehyde 4b. Lewis acid coordination has been
omitted in the reactive conformation 4b′ (see narrative for further de-
tails)
O
41%
O
7 (d.r. = 75:25)
4a
8
OTBS
Bu2BOTf, iPr2NEt
OH
O
−78 °C (Et2O)
OTBS
O
Treatment of ester 10 with aqueous sodium hydroxide
led to facile formation of lactone 11 (Scheme 4).20 Initial at-
tempts to oxidize the β-ketolactone in α-position met with
failure. With 2-iodoxybenzoic acid (IBX)21 and with m-chlo-
roperbenzoic acid (mCPBA),22 no conversion was observed.
Stronger oxidants, like selenium dioxide23 or 2,5-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ),24 led to decomposi-
tion as did several two-step procedures with an iodonium
ylide25 or an aminomethylene compound26 as putative in-
termediates. Eventually, a two-step sequence could be suc-
cessfully implemented, in the course of which diazo com-
pound 12 was formed upon diazo transfer from 4-(acetami-
do)benzenesulfonyl azide (ABSA).27
4a
O
68%
9 (d.r. = 66:34)
Scheme 2 Representative examples for attempted diastereoselective
aldol reactions with protected (S)-glyceraldehyde 4a and methyl aceto-
acetate equivalents
In search for alternative aldehydes 4, we were intrigued
by the protected glyceraldehyde 4b, which had been first
prepared by Ley and co-workers and had shown extremely
high anti-diastereoselectivities in Grignard addition reac-
tions.18 Butane-2,3-dione acetal protection renders high
stability to the respective aldehyde and allows the access to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
M. Wegmann, T. Bach
Paper
Synthesis
O
O
ABSA
NaOtBu
Ph
O
NaOH (4 M)
NaH2PO4
(DMF)
O
O
O
45 °C (DMSO)
(Et2O)
Br
11
+
O
O
O
O
10
MeO
51%
Ph
MeO
85%
88%
O
O
14
15
OMe
OMe
11
O
H
O
[Pd(PPh3)4]
(THF)
O
O
O
O
O
OH
OH
Ph
AcO
[Rh2(OAc)4]
65 °C (DCE)
N2
O
11
+
O
O
MeO
Ph
65%
O
16
17
O
O
O
71%
MeO
MeO
OMe
O
O
Scheme 5 Alkylation of β-ketolactone 11 to the O-alkylated product
15 and Pd-catalyzed allylation to the C-allylated product 17
OMe
OMe
13
12
Scheme 4 Conversion of β-ketoester 10 into β-ketolactone 11 and
subsequent oxidation to the hydrate 13 of an α,β-diketolactone
Regarding the constitution and configuration of com-
pound 17, a distinct NOE contact between the protons in α-
and δ-position of the lactone ring was observed, which sug-
gests a cis-relationship of the protons in a boat conforma-
tion (Figure 1). The fact, that allylated lactone 17 exists as a
50/50 mixture (as detected by 1H NMR spectroscopy) of the
ketone and the corresponding enol form 18, implies a ther-
modynamic preference for the depicted relative configura-
tion, in which the large substituents at the carbon atoms
are both pseudoequatorial. Given the high amount of enol
form in the product, a hydroxylation at the α-position
seemed reasonable at this stage. Unfortunately, the intro-
duction of the hydroxy group was not possible by conven-
tional methods. Treatment with either mCPBA or the Davis
oxaziridine34 led to a complex product mixture, whereas no
reaction was observed upon stirring compound 17 under
oxygen atmosphere.35 Since we speculated that the styrene
double bond interfered with the desired oxidation, our at-
tention turned towards the formation of the respective
phenyl ketone by oxidative olefin cleavage.
A rhodium-catalyzed oxygen transfer from 1,2-epoxy-
butane28 led to the formation of the desired tricarbonyl
compound, which was isolated as its hydrate 13. Disap-
pointingly and despite the fact that precedence for the suc-
cessful introduction of a 2-phenyl-2-oxoethyl unit in 1,2,3-
tricarbonyl compounds exists,29 it was not possible to in-
volve compound 13 in a related C–C bond formation reac-
tion.
Alternatively, an initial α-alkylation of the β-ketolactone
was envisaged followed by a subsequent hydroxylation.
However, reaction of the lactone 11 with bromoacetophe-
none (14) under basic conditions30 was only possible at ele-
vated temperatures and led to the formation of the corre-
sponding O-alkylation product 15, exclusively (Scheme 5).
Variations of the base and the solvent (CsHCO3, MeOH) did
not alter the reaction outcome. Based on the assumption
that the desired α-alkylation was too slow to compete with
the O-alkylation, the use of allylpalladium complexes was
thought to suppress the unwanted side reaction and to al-
low for the selective formation of the C-allylation product.31
Indeed, no O-allylation product was detected upon treat-
ment of 11 with the known allylic acetate 1632 in the pres-
ence of a palladium catalyst. Initial experiments were con-
ducted both with acetate 16 and with the respective tert-
butyl carbonate,33 providing the desired allylation product
17 in low yields along with considerable amounts of the
double-allylation product. Attempts to increase the steric
bulk of the allylation reagent by installing methyl groups at
the terminal end of the double bond and thus disfavor the
formation of the double-allylation product failed. An opti-
mization regarding reaction time, order of addition, and
purity of the allyl acetate eventually enabled the isolation
of the desired product 17 in 65% yield.
Ph
O
OMe
O
H
H
MeO
α
Ph
O
H
δ
O
O
O
OH
O
MeO
γ
O
O
17
18
OMe
Figure 1 Boat conformation of compound 17 as suggested by NOESY
spectra (↔ NOE contact) and structure of the enol form 18
Gratifyingly, it was found that ozonolysis under stan-
dard conditions employing Sudan III as the indicator and in-
cluding a reductive workup36 with dimethyl sulfide led to
the desired ketone 19 in good yield (Scheme 6). Overoxida-
tion was observed, which hinted at the possibility that the
desired hydroxy group could be readily installed. The target
compound 3 was isolated in 21% yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
M. Wegmann, T. Bach
Paper
Synthesis
O
X
H
OMe
O
OMe
O
O
O
H
O
O
O
H
H
O3, Me2S
O
MeO
MeO
Ph
Ph
O
−78 °C (CH2Cl2)
H
H
δ
δ
Ph
O
O
17
O
O
O
O
O
O
MeO
O
O
3'
3''
19 X = H
(61%)
(21%)
OMe
3 X = OH
Scheme 8 Putative equilibrium between hydrogen-bridged β-hy-
droxyketone 3′ and its unbridged isomer 3′′, which accounts for a weak
NOE contact (↔) between the indicated hydrogen atoms
Scheme 6 Ozonolysis of styrene 17 to the desired ketone 19 with con-
comitant overoxidation to product 3
Further experiments revealed that the hydroxylation
could indeed be combined with the ozonolysis if the reac-
tion was performed in the presence of pyridine (py).37 Pre-
sumably, the base facilitates the formation of the more nu-
cleophilic enol form, which is trapped by ozone as electro-
phile. The oxygenated product 3 was isolated in 60% yield
as a single diastereoisomer. Likewise, hydroxylactone 3
could be obtained if ozonolysis product 19 was treated with
sodium hydride as the base and Davis oxaziridine 2034 as
the oxygen source (Scheme 7).
contact was more visible in ROESY spectra (rotating frame
NOE).
The relatively weak NOE contact can be explained by the
fact that the hydroxy group can engage in a hydrogen bond
with the neighboring aromatic ketone38b (3′ in Scheme 8).
This form presumably exists in equilibrium with the re-
spective open form 3′′, which is likely to be thermodynami-
cally disfavored. As only 3′′ can contribute to the NOE con-
tact, the intensity of the latter is low due to the low equilib-
rium concentration of 3′′. However, with increasing mixing
time, magnetization transfer from the OH to the δ-proton
becomes more and more efficient, accounting for the in-
creasing intensity of the contact. Together with the ob-
served coupling constants (vide supra), the data support a
cis-configuration of the hydroxy group relative to the pro-
ton in δ-position, which makes 3 a suitable precursor for
the remaining steps of the total synthesis of (–)-enterocin
(1).
In summary, we have established a concise route for the
synthesis of the functionalized α-hydroxy-β-keto-δ-lactone
3. Key elements of the strategy are a diastereoselective
Mukaiyama aldol reaction, a Tsuji–Trost allylation of the β-
keto-δ-lactone and a one-pot ozonolysis-hydroxylation cas-
cade towards hydroxylactone 3 in excellent diastereoiso-
meric ratios. The absolute and relative configurations of re-
spective intermediates were proven by Mosher and NOE
analyses.
O
O
Ph
N
OH
O3, py
−78 °C
SO2Ph
O
O
20
γ
Ph
(CH2Cl2)
NaH, −78 °C (THF)
δ
O
O
17
19
MeO
O
60%
66%
3
OMe
Scheme 7 Diastereoselective synthesis of the desired building block 3
by ozonolysis of allylated β-ketolactone 17 or by hydroxylation of dike-
tone 19
The relative configuration of product 3 remained to be
clarified. Comparison of its NMR data with substrate 17
seemed to indicate that neither conformation nor relative
configuration were different. The protons within the δ-lac-
tone ring showed the same coupling pattern in the 1H NMR
spectrum. In compound 17, the diastereotopic γ-protons
and the δ-proton were identified as an ABX system with
2JAB = 19.2 Hz, 3JAX = 11.6 Hz, and 3JBX = 2.7 Hz. The large cou-
3
pling constant JAX confirms that the δ-proton (Figure 1) is
All reactions involving moisture-sensitive chemicals were carried out
in flame-dried glassware under positive pressure of argon with mag-
netic stirring. THF, CH2Cl2, and Et2O were purified using a SPS-800
solvent purification system (M. Braun). iPr2NH was distilled over
CaH2, all other chemicals were obtained commercially. The aldehydes
4a13 and 4b,18b silyl enol ether 6,15 ketone 8,16 4-(1-phenylvinyl)mor-
pholine,39 acetate 16,32 phenylallyl carbonate,33 and the Davis oxaziri-
dine 2034a were prepared according to known procedures. TLC was
performed on silica-coated glass plates (silica gel 60 F254) with de-
tection by UV (λ = 254 nm) or KMnO4 (0.5% in H2O) with subsequent
heating. Flash chromatography was performed on silica gel 60
(Merck, 230–400 mesh) with the indicated eluent. Common solvents
for chromatography [pentane (Pn), EtOAc, Et2O, MeOH] were distilled
prior to use. Solutions refer to saturated aqueous solutions unless
otherwise stated. IR spectra were recorded on a JASCO IR-4100 (ATR)
spectrophotometer. MS/HRMS measurements were performed on a
Finnigan MAT 8200 or Thermo Fisher DFS (EI)/Finnigan LSQ classic or
Thermo Fisher LTY Orbitrap XL (ESI) instruments. 1H and 13C NMR
pseudoaxial. The same protons in compound 3 gave a simi-
lar ABX pattern with 2JAB = 17.8 Hz, 3JAX = 11.3 Hz, and 3JBX
=
2.7 Hz. In the 13C NMR spectra, the chemical shift of all car-
bon signals remote from the secondary alcohol in α-posi-
tion were virtually identical. Final proof for the relative
configuration was obtained again by NOESY spectra
(Scheme 8). A weak NOE contact between the OH group
and the proton in δ-position was observable in DMSO-d6 as
the solvent.38 Furthermore, a dependency of the intensity
of the contact on the applied mixing time during the exper-
iment was observed. Thus, prolonging the mixing time
from 0.3 to 1.5 seconds increased the relative intensity of
the corresponding cross peak compared to a diagonal peak
(for details see the Supporting Information). The very same
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
M. Wegmann, T. Bach
Paper
Synthesis
spectra were recorded in CDCl3 or DMSO-d6 at 303 K on a Bruker AV-
360, Bruker AVHD-400, Bruker AV-500, or a Bruker AVHD-500 instru-
ment. Chemical shifts are reported relative to CHCl3 (δ = 7.26) or
DMSO-d5 (δ = 2.50). Apparent multiplets that occur as a result of the
accidental equality of coupling constants to those of magnetically
nonequivalent protons are marked as virtual (virt.). The multiplicities
of the 13C NMR signal were determined by DEPT-edited phase sensi-
tive HSQC experiments, assignments are based on COSY, HMBC,
HSQC, and NOESY experiments. Signals that could not be assigned un-
ambiguously are marked with an asterisk (*).
(4′S)-5-(tert-Butyldimethylsilyloxy)-1-(2′,2′-dimethyl-1′,3′-dioxol-
an-4′-yl)-1-hydroxypentan-3-one (9)
A solution of the ketone 8 (156 mg, 768 μmol, 1.0 equiv) in Et2O (6
i
mL) was cooled to –78 °C, before Pr2NEt (144 μL, 109 mg, 845 μmol,
1.1 equiv) and Bu2BOTf (922 μL, 922 μmol, 1.0 M in Et2O) were added.
After 45 min, a solution of protected glyceraldehyde 4a (100 mg, 768
μmol, 1.0 equiv) in Et2O (3 mL) was added and stirring was continued
for 1 h. A mixture of pH 7 buffer and MeOH (0.6 mL, v/v = 1:1) was
added and the reaction mixture was warmed to 0 °C. MeOH and H2O2
(1.2 mL, v/v = 1:1) were added, and the resulting mixture was stirred
for another 30 min. After warming to r.t., H2O (3 mL) was added, and
the layers were separated. The aqueous layer was extracted with Et2O
(3 × 10 mL), the organic layers were combined, and dried (Na2SO4).
After filtration and removal of the volatile components in vacuo, the
crude product was purified by flash chromatography (3 × 7 cm, Pn–
EtOAc, 1:1) to give the title compound as a colorless oil in a diastereo-
meric ratio of 66/34 (174 mg, 522 μmol, 68%).
Methyl (4′S)-(2′,2′-Dimethyl-1′,3′-dioxolan-4′-yl)-5-hydroxy-3-
oxopentanoate (7)
A solution of glyceraldehyde 4a (50.0 mg, 384 μmol, 1.00 equiv) and
silyl enol ether 6 (200 mg, 768 μmol, 2.00 equiv) in CH2Cl2 (1 mL) was
cooled to 0 °C. Then, BF3·OEt2 (51.1 μL, 57.2 mg, 403 μmol, 1.05 equiv)
was added dropwise. After 30 min, NaHCO3 solution (0.5 mL) was
added and the mixture was warmed to r.t. The layers were separated,
and the aqueous layer was extracted with EtOAc (3 × 5 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and the volatile
components were removed in vacuo. Purification by flash chromatog-
raphy (3 × 15 cm, Pn–EtOAc, 1:1) yielded the title compound as a col-
orless oil in a diastereomeric ratio of 75/25 (43.8 mg, 157 μmol, 41%).
Major Diastereoisomer
[α]D20 –17.6 (c 0.99, CHCl3); Rf = 0.23 (Pn–EtOAc, 4:1) [UV, KMnO4].
IR (ATR): 3481 (br), 2930 (m), 1709 (m), 835 (s), 777 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.05 [s, 6 H, Si(CH3)2], 0.87 [s, 9 H,
SiC(CH3)3], 1.36 [s, 3 H, C(CH3)2], 1.44 [s, 3 H, C(CH3)2], 2.62 (dd, 2J =
3
2
17.3 Hz, J = 3.5 Hz, 1 H, H-2), 2.64–2.66 (m, 2 H, H-4), 2.72 (dd, J =
17.3 Hz, 3J = 8.4 Hz, 1 H, H-2), 3.85 (dd, 2J = 8.2 Hz, 3J = 6.0 Hz, 1 H, H-
5′), 3.89–3.91 (m, 2 H, H-5), 4.02 (dd, 2J = 8.2 Hz, 3J = 6.3 Hz, 1 H, H-5′),
4.08–4.13 (m, 2 H, H-1, H-4′).
Major Diastereoisomer
[α]D20 +13.1 (c 0.96, CHCl3); Rf = 0.31 (Pn–EtOAc, 1:1) [UV, KMnO4].
IR (ATR): 3464 (br), 2980 (w), 1736 (s), 1716 (s), 1222 (s), 1055 (s),
851 (m) cm–1
.
13C NMR (100 MHz, CDCl3): δ = –5.3 [q, Si(CH3)2], 18.4 [s, SiC(CH3)3],
25.3 [q, C(CH3)2], 26.0 [q, SiC(CH3)3], 26.5 [q, C(CH3)2], 46.6 (t, C-2*),
46.8 (t, C-4*), 58.9 (t, C-5), 65.7 (t, C-5′), 67.9 (d, C-4′*), 77.8 (d, C-1*),
109.7 (s, C-2′), 209.7 (s, C-3).
MS (EI, 70 eV): m/z (%) = 317 (2, [M – CH3]+), 275 (3, [M – C3H6O]+),
187 (7, [C9H19O2Si]+), 145 (46, [C7H13O3]+), 101 (28, [C5H9O2]+), 75
(100, [(CH3)2Si=OH]+).
1H NMR (400 MHz, CDCl3): δ = 1.34 [s, 3 H, C(CH3)2], 1.40 [s, 3 H,
C(CH3)2], 2.71 (dd, 2J = 17.8 Hz, 3J = 8.6 Hz, 1 H, H-4), 2.94 (dd, 2J = 17.8
Hz, 3J = 2.7 Hz, 1 H, H-4), 3.52 (s, 2 H, H-2), 3.75 (s, 3 H, CO2CH3), 3.92–
3.99 (m, 2 H, H-4′, H-5′), 4.00–4.05 (m, 1 H, H-5), 4.06–4.11 (m, 1 H,
H-5′).
13C NMR (100 MHz, CDCl3): δ = 25.3 [q, C(CH3)2], 26.8 [q, C(CH3)2],
46.2 (t, C-4), 49.8 (t, C-2), 52.7 (q, CO2CH3), 66.8 (t, C-5′), 69.0 (d, C-5*),
77.5 (d, C-4′*), 109.7 (s, C-2′), 167.3 (s, C-1), 203.4 (s, C-3).
HRMS (EI): m/z [M – CH3]+ calcd for C15H29O5Si: 317.1779; found:
317.1783.
MS (EI, 70 eV): m/z (%) = 231 (12, [M – CH3]+), 101 (100, [C5H9O2]+).
HRMS (EI): m/z [M – CH3]+ calcd for C10H15O6: 231.0863; found:
Minor Diasteroisomer
[α]D20 +17.9 (c 0.94, CHCl3); Rf = 0.29 (Pn–EtOAc, 4:1) [UV, KMnO4].
231.0864.
IR (ATR): 3481 (br), 2930 (m), 1709 (m), 835 (s), 777 (s) cm–1
.
Minor Diastereoisomer
[α]D20 –22.3 (c 1.00, CHCl3); Rf = 0.25 (Pn–EtOAc, 1:1) [UV, KMnO4].
1H NMR (400 MHz, CDCl3): δ = 0.06 [s, 6 H, Si(CH3)2], 0.87 [s, 9 H,
SiC(CH3)3], 1.34 [s, 3 H, C(CH3)2], 1.39 [s, 3 H, C(CH3)2], 2.63 (dd, 2J =
3
2
IR (ATR): 3464 (br), 2988 (w), 1741 (s), 1715 (s), 1214 (s), 1062 (s),
17.4 Hz, J = 8.5 Hz, 1 H, H-2), 2.64–2.66 (m, 2 H, H-4), 2.89 (dd, J =
17.4 Hz, 3J = 3.0 Hz, 1 H, H-2), 3.91 (t, 3J = 6.2 Hz, 2 H, H-5), 3.93–3.98
(m, 3 H, H-1, H-4′, H-5′), 4.07–4.11 (m, 1 H, H-5′).
850 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.35 [s, 3 H, C(CH3)2], 1.44 [s, 3 H,
C(CH3)2], 2.70 (dd, 2J = 17.0 Hz, 3J = 3.7 Hz, 1 H, H-4), 2.81 (dd, 2J = 17.0
Hz, 3J = 8.0 Hz, 1 H, H-4), 3.53 (s, 2 H, H-2), 3.74 (s, 3 H, CO2CH3), 3.85
(dd, 2J = 8.2 Hz, 3J = 5.6 Hz, 1 H, H-5′), 4.02 (dd, 2J = 8.2 Hz, 3J = 6.7 Hz,
1 H, H-5′), 4.07–4.11 (m, 2 H, H-4′, H-5).
13C NMR (100 MHz, CDCl3): δ = –5.3 [q, Si(CH3)2], 18.4 [s, SiC(CH3)3],
25.3 [q, C(CH3)2], 26.0 [q, SiC(CH3)3], 26.9 [q, C(CH3)2], 46.5 (t, C-4),
46.8 (t, C-2), 59.0 (t, C-5), 67.1 (t, C-5′), 69.3 (d, C-4′*), 77.7 (d, C-1*),
105.6 (s, C-2′), 211.3 (s, C-3).
13C NMR (100 MHz, CDCl3): δ = 25.2 [q, C(CH3)2], 26.5 [q, C(CH3)2],
46.3 (t, C-4), 49.9 (t, C-2), 52.6 (q, CO2CH3), 65.7 (t, C-5′), 67.9 (d, C-5*),
77.7 (d, C-4′*), 109.8 (s, C-2′), 167.5 (s, C-1), 202.1 (s, C-3).
MS (EI, 70 eV): m/z (%) = 317 (2, [M – CH3]+), 275 (3, [M – C3H6O]+),
187 (7, [C9H19O2Si]+), 145 (46, [C7H13O3]+), 101 (28, [C5H9O2]+), 75
(100, [(CH3)2Si=OH]+).
MS (EI, 70 eV): m/z (%) = 231 (12, [M – CH3]+), 101 (100, [C5H9O2]+).
HRMS (EI): m/z [M – CH3]+ calcd for C15H29O5Si: 317.1779; found:
HRMS (EI): m/z [M – CH3]+ calcd for C10H15O6: 231.0863; found:
317.1781.
231.0861.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
M. Wegmann, T. Bach
Paper
Synthesis
Methyl (5R,2′S,5′S,6′S)-5-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-di-
oxan-2′-yl)-5-hydroxy-3-oxopentanoate (10)
(6R,2′S,5′R,6′R)-3-Diazo-6-(5′,6′-dimethoxy-5′,6′-dimethyl-1′,4′-di-
oxan-2′-yl)dihydro-2H-pyran-2,4(3H)-dione (12)
A solution of aldehyde 4b (1.00 g, 4.90 mmol, 1.00 equiv) and silyl
enol ether 6 (2.55 g, 9.79 mmol, 2.00 equiv) in CH2Cl2 (100 mL) was
cooled to –78 °C, before BF3·OEt2 (652 μL, 730 mg, 5.14 mmol, 1.05
equiv) was added dropwise. After stirring for 15 min, H2O (15 mL)
was added and the mixture was warmed to r.t. The layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3 × 30 mL).
The organic layers were combined, dried (Na2SO4), and filtered. After
removal of the solvents in vacuo, the crude product was purified by
flash chromatography (4 × 10 cm, Pn–Et2O, 1:2) to give the title com-
To a solution of the ketolactone 11 (600 mg, 2.08 mmol, 1.0 equiv) in
DMF (16 mL) were added NaH2PO4·2H2O (357 mg, 2.29 mmol, 1.1
equiv) and 4-(acetamido)benzenesulfonyl azide (ABSA) (550 mg, 2.29
mmol, 1.1 equiv) sequentially. After stirring at r.t. for 45 min,
Na2HPO4 (357 mg) and H2O (10 mL) were added, and the mixture was
extracted with Et2O (6 × 10 mL). The organic layers were combined,
dried (Na2SO4), and filtered. After removal of the volatile components
in vacuo, the crude product was purified by flash chromatography (3
× 20 cm, Pn–EtOAc, 4:1) to give the title compound as a bright yellow
solid (576 mg, 1.83 mmol, 88%); mp 105–107 °C; [α]D20 –72.5 (c 1.05,
CHCl3); Rf = 0.66 (Pn–EtOAc, 1:1) [UV, KMnO4].
20
pound as a highly viscous colorless oil (1.34 g, 4.17 mmol, 85%); [α]D
–85.4 (c 1.00, CHCl3); Rf = 0.27 (Pn–EtOAc, 1:1) [UV, KMnO4].
IR (ATR): 3477 (br), 2994 (m), 2836 (m), 1747 (s), 1715 (s), 1145 (s),
IR (ATR): 2988 (m), 2152 (s), 1721 (s), 1673 (s), 1143 (s), 1111 (s) cm–1
.
1037 (m), 872 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.31 (s, 3 H, CH3), 1.34 (s, 3 H, CH3),
2.64 (dd, 2J = 17.3 Hz, 3J = 11.4 Hz, 1 H, H-5), 2.98 (dd, 2J = 17.3 Hz, 3J =
2.9 Hz, 1 H, H-5), 3.30 (s, 3 H, OCH3), 3.31 (s, 3 H, OCH3), 3.90–4.02 (m,
3 H, H-2′, H-3′), 4.76 (ddd, 3J = 11.4 Hz, 3J = 8.9 Hz, 3J = 2.9 Hz, 1 H, H-
6).
13C NMR (100 MHz, CDCl3): δ = 18.0 (q, CH3), 18.3 (q, CH3), 38.7 (t, C-
5), 48.5 (q, OCH3), 50.0 (q, OCH3), 59.4 (t, C-3′), 71.1 (d, C-2′), 74.7 (d,
C-6), 99.6 (s, C-5′*), 100.5 (s, C-6′*), 161.2 (s, C-2), 185.5 (s, C-4). Car-
bon atom C-3 could not be detected.
1H NMR (400 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.34 (s, 3 H, CH3),
2.71 (dd, 2J = 16.9 Hz, 3J = 8.9 Hz, 1 H, H-4), 2.88 (dd, 2J = 16.9 Hz, 3J =
3.4 Hz, 1 H, H-4), 3.30 (s, 3 H, OCH3), 3.32 (s, 3 H, OCH3), 3.41 (d, 3J =
3.3 Hz, 1 H, OH), 3.53–3.55 (m, 2 H, H-2), 3.69 (virt. td, 3J ≈ 3J = 5.9 Hz,
3J = 4.7 Hz, 1 H, H-2′), 3.74 (s, 3 H, CO2CH3), 3.84 (dd, 2J = 11.5 Hz, 3J =
5.7 Hz, 1 H, H-3′), 3.94 (dd, 2J = 11.5 Hz, 3J = 4.7 Hz, 1 H, H-3′), 4.22
(virt. ddt, 3J = 8.9 Hz, 3J = 5.9 Hz, 3J ≈ 3J = 3.3 Hz, 1 H, H-5).
13C NMR (100 MHz, CDCl3): δ = 17.9 (q, CH3), 18.3 (q, CH3), 46.8 (t, C-
4), 48.5 (q, OCH3), 49.2 (q, OCH3), 49.9 (t, C-2), 52.6 (q, CO2CH3), 59.9
(t, C-3′), 69.4 (d, C-5), 72.4 (d, C-2′), 99.2 (s, C-5′), 99.8 (s, C-6′), 167.5
(s, C-1), 202.8 (s, C-3).
MS (EI, 70 eV): m/z (%) = 283 (6, [M – OCH3]+), 166 (21, [C7H6N2O3]+),
43 (100, [C2H3O]+).
HRMS (EI): m/z [M – OCH3]+ calcd for C12H15O6: 283.0925; found:
283.0930.
MS (EI, 70 eV): m/z (%) = 204 (6, [C8H12O6]+), 174 (8, [C6H15O4]+), 105
(70, [C4H5O3]+), 42 (100, [C2H2O]+).
HRMS (EI): m/z [M]+ calcd for C14H24O8: 320.1466; found: 320.1483.
(6R,2′S,5′R,6′R)-6-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-dioxan-2′-
yl)-3,3-dihydroxydihydro-2H-pyran-2,4(3H)-dione (13)
(6R,2′S,5′R,6′R)-6-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-dioxan-2′-
yl)dihydro-2H-pyran-2,4(3H)-dione (11)
A solution of 1,2-epoxybutane (6.21 μL, 5.14 mg, 71.4 μL, 1.1 equiv)
and Rh2(OAc)4 (2.87 mg, 6.49 μmol, 0.1 equiv) in DCE (0.5 mL) was
heated to 65 °C before the addition of a solution of the diazo com-
pound 12 (20.4 mg, 64.9 μmol, 1.0 equiv) in DCE (0.5 mL). After 15
min, the solution was cooled to r.t. and the volatile components were
removed in vacuo. Flash chromatography (1 × 5 cm, EtOAc–MeOH,
99:1) yielded the title compound as a bright turquoise solid (14.8 mg,
46.2 μmol, 71%); mp >100 °C (dec.); Rf = 0.15 (EtOAc–MeOH, 99:1)
[UV, KMnO4].
To a solution of aldol 10 (1.34 g, 4.17 mmol, 1.0 equiv) in Et2O (40 mL)
was added aq 4 M NaOH (5 mL) and the mixture was stirred at r.t. for
10 min. The solution was acidified to pH 2 with aq 3 M HCl and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(3 × 20 mL) and the organic layers were combined. After drying
(Na2SO4) and filtration, the volatile components were removed in vac-
uo, and the crude product was purified by flash chromatography (4 ×
10 cm, Pn–EtOAc, 1:1 + 0.5% AcOH). The title compound was obtained
as a slowly crystallizing colorless oil (1.02 g, 3.55 mmol, 85%); mp 96–
IR (ATR): 3456 (br), 3175 (br), 2948 (m), 1697 (m), 1620 (m), 1375 (s),
1036 (s), 870 (s) cm–1
.
20
98 °C; [α]D –42.6 (c 0.99, CHCl3); Rf = 0.10 (Pn–EtOAc, 1:2) [UV,
1H NMR (500 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.35 (s, 3 H, CH3),
2.83 (dd, 2J = 17.7 Hz, 3J = 11.1 Hz, 1 H, H-5), 2.94 (dd, 2J = 17.7 Hz, 3J =
4.4 Hz, 1 H, H-5), 3.30 (s, 3 H, OCH3), 3.32 (s, 3 H, OCH3), 3.89–4.01 (m,
3 H, H-2′, H-3′), 4.66 (ddd, 3J = 11.1 Hz, 3J = 8.7 Hz, 3J = 4.4 Hz, 1 H, H-
6).
13C NMR (125 MHz, CDCl3): δ = 17.9 (q, CH3), 18.3 (q, CH3), 30.3 (t, C-
5), 48.5 (q, OCH3), 49.7 (q, OCH3), 60.0 (t, C-3′), 70.8 (d, C-2′), 74.2 (d,
C-6), 98.3 (s, C-3), 99.6 (s, C-5′*), 100.4 (s, C-6′*), 161.7 (s, C-2), 164.0
(s, C-4).
KMnO4].
IR (ATR): 2949 (m), 1674 (s), 1619 (s), 1147 (s), 944 (m), 867 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.34 (s, 3 H, CH3),
2.51 (dd, 2J = 18.5 Hz, 3J = 11.2 Hz, 1 H, H-5), 3.05 (dd, 2J = 18.5 Hz, 3J =
2.7 Hz, 1 H, H-5), 3.22 (s, 3 H, OCH3), 3.30 (s, 3 H, OCH3), 3.47 (d, 2J =
19.0 Hz, 1 H, H-3), 3.60 (d, 2J = 19.0 Hz, 1 H, H-3), 3.90 (virt. dt, 3J = 8.7
Hz, 3J ≈ 3J = 4.4 Hz, 1 H, H-2′), 3.95 (dd, 2J = 11.7 Hz, 3J = 4.8 Hz, 1 H, H-
3′), 4.01 (dd, 2J = 11.7 Hz, 3J = 4.2 Hz, 1 H, H-3′), 4.96 (ddd, 3J = 11.2 Hz,
3J = 8.7 Hz, 3J = 2.7 Hz, 1 H, H-6).
13C NMR (100 MHz, CDCl3): δ = 17.9 (q, CH3), 18.3 (q, CH3), 41.4 (t, C-
5), 47.4 (t, C-3), 48.6 (q, OCH3), 50.2 (q, OCH3), 59.0 (t, C-3′), 71.5 (d, C-
2′), 74.1 (d, C-6), 99.6 (s, C-5′), 100.4 (s, C-6′), 166.6 (s, C-2), 199.6 (s,
C-4).
MS (ESI): m/z (%) = 321 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C13H21O9: 321.1180; found:
321.1189.
(6R,2′S,5′R,6′R)-6-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-dioxan-2′-
yl)-4-(2′′-oxo-2′′-phenylethoxy)-5,6-dihydro-2H-pyran-2-one (15)
To a solution of NaOtBu (10.5 mg, 109 μmol, 1.1 equiv) in DMSO (0.5
mL) was added a solution of the ketolactone 11 (28.6 mg, 99.2 μmol,
1.0 equiv) in DMSO (0.5 mL). Then, a solution of bromoacetophenone
MS (EI, 70 eV): m/z (%) = 257 (33, [M – OCH3]+), 199 (29, [C10H15O4]+),
140 (42, [C7H8O2]+), 101 (100, [C5H9O2]+).
HRMS (EI): m/z [M – OCH3]+ calcd for C12H17O6: 257.1020; found:
257.1018.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
M. Wegmann, T. Bach
Paper
Synthesis
(14; 21.7 mg, 109 μmol, 1.1 equiv) in DMSO (0.5 mL) was added, and
the mixture was warmed to 45 °C for 30 min. After cooling to r.t., aq 1
M HCl (1 mL) was added and the mixture was extracted with Et2O (5 ×
2 mL). The combined organic layers were dried (Na2SO4), filtered, and
the solvents were removed in vacuo. After flash chromatography (1 ×
15 cm, Pn–EtOAc, 1:1 + 1% HOAc), the title compound was obtained as
a colorless amorphous solid (20.6 mg, 50.6 μmol, 51%); [α]D20 –8.65 (c
0.77, CHCl3); Rf = 0. 63 (Pn–EtOAc, 1:1 + 1% AcOH) [UV, KMnO4].
5.32 (br s, 1 H, H-3′′a,K), 5.41 (s, 1 H, H-3′′b,K), 5.54 (s, 1 H, H-3′′b,E),
7.28–7.37 (m, 6 H, H-Armeta, H-Arpara), 7.40–7.43 (m, 2 H, H-Arortho,K*),
7.46–7.49 (m, 2 H, H-Arortho,E*).
13C NMR (125 MHz, CDCl3): δ = 17.8 (q, CH3), 17.9 (q, CH3), 18.2 (q,
CH3), 18.2 (q, CH3), 28.1 (t, C-1′′K), 29.9 (t, C-1′′E), 30.3 (t, C-5E), 41.4 (t,
C-5K), 48.6 (q, OCH3), 49.4 (2 q, 2 × OCH3), 50.2 (q, OCH3), 56.3 (d, C-
3K), 58.9 (t, C-3′K), 60.8 (t, C-3′E), 71.1 (d, C-2′K), 71.3 (d, C-2′E), 72.4 (d,
C-6K), 74.0 (d, C-6E), 99.4 (s, C-5′K), 99.6 (s, C-5′E), 100.2 (s, C-6′K),
100.3 (s, C-6′E), 101.3 (s, C-3E), 113.5 (t, C-3′′E), 115.4 (t, C-3′′K), 126.2
(d, C-Arortho,E), 126.4 (d, C-Arortho,K), 128.5 (d, C-Armeta*,E), 128.5 (d, C-
Armeta,K), 128.7 (d, C-Arpara*,E), 128.8 (d, C-Arpara,K), 139.6 (s, C-Aripso,E),
139.6 (s, C-Aripso,K), 144.7 (s, C-2′′K), 146.4 (s, C-2′′E), 166.7 (s, C-2E**),
167.1 (s, C-4E**), 168.1 (s, C-2K), 200.0 (s, C-4K).
IR (ATR): 3086 (w), 2921 (w), 1704 (s), 1225 (s), 971 (s), 687 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.34 (s, 3 H, CH3), 1.36 (s, 3 H, CH3),
2.74 (dd, 2J = 17.4 Hz, 3J = 10.7 Hz, 1 H, H-5), 2.86 (dd, 2J = 17.4 Hz, 3J =
4.1 Hz, 1 H, H-5), 3.32 (s, 3 H, OCH3), 3.33 (s, 3 H, OCH3), 3.94 (dd, 2J =
11.6 Hz, 3J = 7.2 Hz, 1 H, H-3′), 3.98–4.06 (m, 2 H, H-2′, H-3′), 4.59
(ddd, 3J = 10.7 Hz, 3J = 9.2 Hz, 3J = 4.1 Hz, 1 H, H-6), 5.07 (br s, 1 H, H-
3), 5.24 (br s, 2 H, H-1′′), 7.53 (virt. t, 3J ≈ 3J = 7.7 Hz, 2 H, H-Armeta),
7.66 (t, 3J = 7.7 Hz, 1 H, H-Arpara), 7.91 (d, 3J = 8.0 Hz, 2 H, H-Arortho).
MS (EI, 70 eV): m/z (%) = 404 (3, [M]+), 372 (7, [M – CH3OH]+), 315 (9,
[M – C4H9O2]+), 184 (100, [C8H8O5]+), 158 (67, [C11H10O]+), 129 (71,
[C10H10]+), 101 (89, [C5H9O2]+).
13C NMR (100 MHz, CDCl3): δ = 17.9 (q, CH3), 18.3 (q, CH3), 30.2 (t, C-
5), 48.5 (q, OCH3), 49.6 (q, OCH3), 60.7 (t, C-3′), 70.3 (t, C-1′′), 71.1 (d,
C-2′), 75.2 (d, C-6), 92.0 (d, C-3), 99.7 (s, C-5′), 100.4 (s, C-6′), 127.0 (d,
C-Arortho), 129.3 (d, C-Armeta), 133.9 (s, C-Aripso), 134.6 (d, C-Arpara),
166.9 (s, C-2*), 171.3 (s, C-4*), 191.1 (s, C-2′′).
HRMS (EI): m/z [M]+ calcd for C22H28O7: 404.1830; found: 404.1839.
Double-Allylation Product
[α]D20 –38.5 (c 0.96, CHCl3); Rf = 0.40 (Pn–Et2O, 3:1) [UV, KMnO4].
IR (ATR): 3082 (w), 2940 (m), 1755 (m), 1718 (s), 1237 (s), 1036 (s),
MS (EI, 70 eV): m/z (%) = 228 (13, [C10H12O6]+), 105 (100, [C6H5O]+), 77
704 (s) cm–1
.
(17, [C6H5]+).
1H NMR (400 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.29 (s, 3 H, CH3),
1.80 (dd, 2J = 16.2 Hz, 3J = 12.7 Hz, 1 H, H-5), 2.49 (dd, 2J = 16.2 Hz, 3J =
2.1 Hz, 1 H, H-5), 3.02 (s, 3 H, C-6′ OCH3), 3.07 (d, 2J = 13.3 Hz, 1 H, H-
HRMS (EI): m/z [M]+ calcd for C21H26O8: 406.1628; found: 406.1640.
2
(3R,6R,2′S,5′R,6′R)-6-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-dioxan-
2′-yl)-3-(2′′-phenylallyl)dihydro-2H-pyran-2,4(3H)-dione (17) and
(6R,2′S,5′R,6′R)-6-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-dioxan-2′-
yl)-3,3-bis(2′′-phenylallyl)dihydro-2H-pyran-2,4(3H)-dione
1′′), 3.12 (d, J = 13.1 Hz, 1 H, H-1′′), 3.26 (s, 3 H, C-5′ OCH3), 3.35 (d,
2J = 13.1 Hz, 1 H, H-1′′), 3.40–3.46 (m, 1 H, H-2′), 3.44 (d, 2J = 13.3 Hz, 1
H, H-1′′), 3.53 (dd, 2J = 11.6 Hz, 3J = 5.3 Hz, 1 H, H-3′), 3.71 (dd, 2J = 11.6
Hz, 3J = 4.0 Hz, 1 H, H-3′), 4.09 (ddd, 3J = 12.7 Hz, 3J = 8.9 Hz, 3J = 2.1 Hz,
1 H, H-6), 5.13 (br s, 1 H, H-3′′), 5.14 (br s, 1 H, H-3′′), 5.27 (d, 2J = 1.4
Hz, 1 H, H-3′′), 5.32 (d, 2J = 1.4 Hz, 1 H, H-3′′), 7.23–7.30 (m, 8 H, H-Ar),
7.33–7.36 (m, 2 H, H-Ar).
To a solution of the ketolactone 11 (961 mg, 3.36 mmol, 1.00 equiv)
and the freshly purified acetate 16 (592 mg, 3.36 mmol, 1.00 equiv) in
THF (20 mL) was added Pd(PPh3)4 (193 mg, 168 μmol, 0.05 equiv) and
the mixture was stirred at r.t. for 4 h. NH4Cl solution (50 mL) was add-
ed, the layers were separated, and the aqueous layer was extracted
with Et2O (3 × 100 mL). The combined organic layers were dried
(Na2SO4), filtered, and the volatile components were removed in vac-
uo. Flash chromatographic purification (1 × 25 cm, Pn–EtOAc, 1:1)
yielded the title compound as a bright yellow solid (885 mg, 2.19
mmol, 65%) along with the double-allylation product (192 mg, 370
μmol, 11%).
13C NMR (100 MHz, CDCl3): δ = 18.0 (q, CH3), 18.3 (q, CH3), 43.0 (t, C-
5), 43.6 (t, C-1′′), 45.5 (t, C-1′′), 48.4 (q, C-6′ OCH3), 49.8 (q, C-5′ OCH3),
58.9 (t, C-3′), 62.4 (s, C-3), 71.6 (d, C-2′), 71.7 (d, C-6), 99.4 (s, C-5′),
99.9 (s, C-6′), 119.7 (2 t, 2 × C-3′′), 127.1 (2 d, 2 × C-Arortho), 128.3 (d, C-
Arpara), 128.4 (d, C-Arpara), 128.4 (d, C-Armeta), 128.6 (d, C-Armeta), 139.1
(s, C-2′′), 140.1 (s, C-2′′), 143.7 (2 s, 2 × C-Aripso), 171.8 (s, C-2), 205.5
(s, C-4).
MS (EI, 70 eV): m/z (%) = 520 (2, [M]+), 488 (7, [M – CH3OH]+), 277
(100), 91 (83, [C7H7]+).
Monoallylation Product 17
Mp 117–119 °C; [α]D20 –11.8 (c 0.97, CHCl3); Rf = 0.35 (Pn–EtOAc, 1:1)
HRMS (EI): m/z [M]+ calcd for C31H36O7: 520.2456; found: 520.2457.
[UV, KMnO4].
(3R,6R,2′S,5′R,6′R)-6-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-dioxan-
2′-yl)-3-(2′′-oxo-2′′-phenylethyl)dihydro-2H-pyran-2,4(3H)-dione
(19)
IR (ATR): 3196 (v br), 2941 (m), 1720 (s), 1683 (s), 873 (m) cm–1
.
The index K refers to the keto form, the index E refers to the enol form
of the product.
A solution of the styrene 17 (250 mg, 618 μmol, 1.0 equiv) in CH2Cl2
(30 mL) was cooled to –78 °C. After the addition of a small amount of
Sudan III, a stream of O3 was passed through the solution until decol-
orization. The setup was purged with O2 and then with argon, before
Me2S (137 μL, 115 mg, 1.85 μmol, 3.0 equiv) was added. After stirring
for 10 min, the solution was warmed to r.t. and the volatile compo-
nents were removed in vacuo. Purification by flash chromatography
(3 × 5 cm, Pn–EtOAc, 1:1 + 0.5% AcOH) yielded the title compound 19
as a highly viscous, colorless oil (154 mg, 378 μmol, 61%, keto–enol =
77:23) along with the hydroxyketone 3 (55.1 mg, 130 μmol, 21%);
[α]D20 –34.1 (c 1.00, CHCl3); Rf = 0.40 (Pn–EtOAc, 1:1 + 0.5% AcOH) [UV,
KMnO4].
1H NMR (500 MHz, CDCl3): δ = 1.29 (s, 3 H, CH3), 1.31 (s, 6 H, CH3),
1.32 (s, 3 H, CH3), 2.47 (dd, 2J = 19.2 Hz, 3J = 11.6 Hz, 1 H, H-5K), 2.58–
2.61 (m, 2 H, H-5E), 3.03 (dd, 2J = 19.2 Hz, 3J = 2.7 Hz, 1 H, H-5K), 3.11
(dd, 2J = 15.5 Hz, 3J = 6.0 Hz, 1 H, H-1′′K), 3.25 (s, 3 H, OCH3), 3.26 (s, 3
H, OCH3), 3.29 (s, 3 H, OCH3), 3.30 (s, 3 H, OCH3), 3.32 (dd, 2J = 15.5 Hz,
3J = 4.8 Hz, 1 H, H-1′′K), 3.51 (dd, 3J = 6.0 Hz, 3J = 4.8 Hz, 1 H, H-3K), 3.61
(d, 2J = 16.9 Hz, 1 H, H-1′′E), 3.70 (d, 2J = 16.9 Hz, 1 H, H-1′′E), 3.83 (virt.
dt, 3J = 9.0 Hz, 3J ≈ 3J = 4.3 Hz, 1 H, H-2′E), 3.87–3.96 (m, 4 H, H-2′K, H-
3′K, H-3′E), 3.99 (dd, 2J = 11.7 Hz, 3J = 4.2 Hz, 1 H, H-3′K), 4.40 (virt. td,
3
3
3
3
3J ≈ J = 8.6 Hz, J = 6.1 Hz, 1 H, H-6E), 4.89 (ddd, J = 11.6 Hz, J = 9.0
Hz, 3J = 2.7 Hz, 1 H, H-6K), 5.28 (virt. q, 2J ≈ 4J = 1.2 Hz, 1 H, H-3′′a,E),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
M. Wegmann, T. Bach
Paper
Synthesis
IR (ATR): 2944 (m), 1718 (m), 1684 (m), 1374 (m), 1144 (s), 1112 (s),
873 (m) cm–1
(dd, 2J = 11.4 Hz, 3J = 4.2 Hz, 1 H, H-3′), 3.90 (d, 2J = 17.9 Hz, 1 H, H-1′′),
4.02 (ddd, 3J = 7.5 Hz, 3J = 6.0 Hz, 3J = 4.2 Hz, 1 H, H-2′), 5.24 (ddd, 3J =
11.3 Hz, 3J = 7.5 Hz, 3J = 2.7 Hz, 1 H, H-6), 7.41 (s, 1 H, OH), 7.55 (virt. t,
3J ≈ 3J = 7.9 Hz, 2 H, H-Armeta), 7.69 (tt, 3J = 7.5 H, 4J = 1.3 Hz, 1 H, H-
Arpara), 7.95 (dd, 3J = 8.4 Hz, 4J = 1.3 Hz, 2 H, H-Arortho).
13C NMR (100 MHz, DMSO): δ = 17.7 (q, CH3), 18.1 (q, CH3), 38.9 (t, C-
5), 43.5 (t, C-1′′), 47.8 (q, OCH3), 49.0 (q, OCH3), 58.2 (t, C-3′), 70.3 (d,
C-2′), 71.8 (d, C-6), 74.8 (s, C-3), 99.0 (s, C-5′), 99.5 (s, C-6′), 128.0 (d,
C-Arortho), 128.9 (d, C-Armeta), 134.1 (d, C-Arpara), 135.1 (s, C-Aripso),
169.1 (s, C-2), 198.3 (s, C-2′′), 200.8 (s, C-4).
.
1H NMR (500 MHz, CDCl3): δ = 1.34 (s, 3 H, CH3), 1.36 (s, 3 H, CH3),
2.78 (dd, 2J = 18.5 Hz, 3J = 11.9 Hz, 1 H, H-5), 3.17 (dd, 2J = 18.5 Hz, 3J =
2.3 Hz, 1 H, H-5), 3.33 (s, 3 H, OCH3), 3.34 (s, 3 H, OCH3), 3.73 (dd, 2J =
18.1 Hz, 3J = 4.5 Hz, 1 H, H-1′′), 3.80 (dd, 2J = 18.1 Hz, 3J = 4.4 Hz, 1 H,
3
3
H-1′′), 3.93 (virt. dt, 3J = 9.2 Hz, J ≈ J = 4.3 Hz, 1 H, H-2′), 3.94–4.02
2
3
(m, 2 H, H-3′, H-3), 4.06 (dd, J = 12.0 Hz, J = 4.2 Hz, 1 H, H-3′), 5.13
(ddd, 3J = 11.9 Hz, 3J = 9.2 Hz, 3J = 2.3 Hz, 1 H, H-6), 7.48 (virt. t, 3J ≈ 3J =
7.7 Hz, 2 H, H-Armeta), 7.60 (tt, 3J = 7.4 Hz, 4J = 1.2 Hz, 1 H, H-Arpara),
7.99 (d, 3J = 8.4 Hz, 2 H, H-Arortho).
MS (ESI): m/z (%) = 423 (100, [M + H]+).
1H NMR (500 MHz, CDCl3): δ (characteristic signals of the enol form) =
1.32 (s, 3 H, CH3), 1.34 (s, 3 H, CH3), 2.70 (dd, 2J = 17.8 Hz, 3J = 11.0 Hz,
1 H, H-5), 2.76 (dd, 2J = 17.8 Hz, 3J = 4.3 Hz, 1 H, H-5), 3.30 (s, 3 H,
OCH3), 3.32 (s, 3 H, OCH3), 4.11 (d, 2J = 14.5 Hz, 1 H, H-1′′), 4.14 (d, 2J =
14.5 Hz, 1 H, H-1′′), 4.51 (ddd, 3J = 11.0 Hz, 3J = 8.2 Hz, 3J = 4.3 Hz, 1 H,
H-6), 7.51 (virt. t, 3J ≈ 3J = 7.9 Hz, 2 H, H-Armeta), 7.65 (tt, 3J = 7.5 Hz, 4J =
HRMS (ESI): m/z [M + H]+ calcd for C21H27O9: 423.1650; found:
423.1653.
Acknowledgment
3
4
1.2 Hz, 1 H, H-Arpara), 8.22 (dd, J = 8.5 Hz, J = 1.2 Hz, 2 H, H-Arortho),
10.51 (br s, 1 H, OH).
We thank Anil Candas and Sabrina Hackl for excellent technical assis-
tance. Financial support by the Fonds der Chemischen Industrie
(scholarship to M.W.) is gratefully acknowledged. Prof. Wolfgang
Eisenreich is thanked for helpful discussions regarding the NMR spec-
tra.
13C NMR (91 MHz, CDCl3): δ = 18.0 (q, CH3), 18.3 (q, CH3), 34.6 (t, C-
1′′), 41.2 (t, C-5), 48.6 (q, OCH3), 50.2 (q, OCH3), 51.9 (d, C-3), 58.7 (t,
C-3′), 71.4 (d, C-2′), 72.9 (d, C-6), 99.4 (s, C-5′), 100.2 (s, C-6′), 128.5
(d, C-Arortho), 128.8 (d, C-Armeta), 130.1 (d, C-Arpara), 133.9 (s, C-Aripso),
168.7 (s, C-2), 196.3 (s, C-2′′), 200.7 (s, C-4).
Supporting Information
MS (EI, 70 eV): m/z (%) = 375 (2, [M – CH3OH]+), 153 (29, [C8H9O3]+),
139 (13, [C7H7O3]+), 105 (100, [C7H5O]+).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562539.
HRMS (EI): m/z [M – CH3OH]+ calcd for C20H23O7: 375.1438; found:
375.1433.
S
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Primary Data
(3S,6R,2′S,5′R,6′R)-6-(5′,6′-Dimethoxy-5′,6′-dimethyl-1′,4′-dioxan-
2′-yl)-3-hydroxy-3-(2′′-oxo-2′′-phenylethyl)dihydro-2H-pyran-
2,4(3H)-dione (3)
Primary data for this article are available online at http://www.thieme-
connect.com/products/ejournals/journal/10.1055/s-00000084 and can
be cited using the following DOI: 10.4125/pd0082th.
a) By Ozonolysis in the Presence of Pyridine: A solution of the styrene
19 (20.0 mg, 49.5 μmol, 1.0 equiv) and pyridine (12.0 μL, 11.8 mg, 148
μmol, 3.0 equiv) in CH2Cl2 (15 mL) was treated with a small amount of
Sudan III and cooled to –78°C. A stream of O3 was passed through the
solution until decolorization. After purging the setup with O2 and ar-
gon, the solution was warmed to r.t. and the solvents were removed
in vacuo. Purification by flash chromatography (1 × 10 cm, Pn–EtOAc,
2:1 + 0.5% AcOH) yielded the title compound as a colorless amor-
phous solid (12.7 mg, 30.1 μmol, 60%).
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I