Lewis Acid-Catalyzed Stereoselective α-Addition of Chiral Aldehydes to Cyclic Dienol Silanes: Aqueous Synthesis of Chiral Butenolides

Article abstract of DOI:10.1002/adsc.201901218

The stereoselective α-addition to cyclic dienol silanes has rarely been exploited, in contrast to the well-studied γ-addition of conjugated butenolides. In this study, an unprecedent catalytic Mukaiyama aldol α-addition of 2-trimetylsiloxy furan to optically pure aldehydes in water-containing solvents is reported. The synthetic utility of this concept was demonstrated in the efficient synthesis of six bioactive natural products: vitexolide D, curcucomosin C, villosin, chinensine C, (+)-coronarin E and (E)-labda-7,11,13-trien-16,15-olid.

Full text of DOI:10.1002/adsc.201901218

Title: Lewis Acid-Catalyzed Stereoselective α-Addition of Chiral
Aldehydes to Cyclic Dienol Silanes: Aqueous Synthesis of Chiral
Butenolides
Authors: Anna Adamkiewicz, Izabela Węglarz, Aleksandra Butkiewicz,
Marta Woyciechowska, and Jacek Mlynarski
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901218
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Lewis Acid-Catalyzed Stereoselective α-Addition of Chiral
Aldehydes to Cyclic Dienol Silanes: Aqueous Synthesis of Chiral
Butenolides
a
b
b
Anna Adamkiewicz, Izabela Węglarz, Aleksandra Butkiewicz, Marta
a
b,
Woyciechowska, Jacek Mlynarski *
a
Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw, Poland, e-mail:
b
jacek.mlynarski@gmail.com, homepage: www.jacekmlynarski.pl
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The stereoselective α‐addition to cyclic dienol
silanes has rarely been exploited, in contrast to the well‐ Keywords: Diastereoselectivity; Labdane diterpenes;
studied γ‐addition of conjugated butenolides. In this study, an Mukaiyama aldol reaction, Natural products, α-
unprecedent catalytic Mukaiyama aldol α-addition of 2- Regioselectivity
trimetylsiloxy furan to optically pure aldehydes in water-
containing solvents is reported. The synthetic utility of this
concept was demonstrated in the efficient synthesis of six
bioactive natural products: vitexolide D, curcucomosin C,
villosin, chinensine C, (+)-coronarin E and (E)-labda-7,11,13-
trien-16,15-olid.
synthesis of compounds 1 and 2 requires 1,3-stereocontrol,
accomplished most probably through an acyclic transition
Introduction
state of β-chiral aldehyde substrate.
Optically active butenolides serve as a prominent class of
chiral building blocks for the synthesis of diverse biological
[
1]
[2]
active compounds and complex molecules. In particular,
various types of butadiene-based silyl dienol ethers and
[
3 ]
cyclic dienoxysilanes
cleverly served to implement
butenoate fragments into diverse, structurally complex
polyketide frameworks and targets[
4 ]
via vinylogous
[
5
]
Mukaiyama aldol reaction (VMAR)
with nicely
[
6 ]
controlled regio- and stereoselectivity.
However, in
contrast to the widely studied γ-attack of silyl dienol ethers,
catalytic diastereoselective Mukaiyama aldol formation of
α-butenolides from silyloxyfuran and chiral aldehydes have
[7,8]
not been reported. Such methodology would be extreme-
ly important tool in the synthesis of naturally occurring
compounds contain the 2(5H)-furanone ring substituted at
α-position. For example, Scheme 1 presents six labdane-
type diterpenoids (1-2 and 4-7) which belong to structurally
[
9]
diverse class of natural terpenoids showing significant
[
10]
analgesic, anti-inflamatory and cytotoxic properties.
Despite the differences in the furan ring structure, all these
compounds (1, 2, 4-7) could be obtained through
regioselective aldol addition of 2-trimethylsiloxy furan (3)
to optically pure aldehyde skeleton, which in fact, is not
known. Apart from regioselectivity issue, such newly
developed efficient methodology should occur with
catalytic amount of promoter controlling reaction
stereoselectivity. This seems to be far from trivial as the
Scheme 1. Biologically active compounds containing α-
substituted 2(5H)-furanone ring.
Development of such general catalytic strategy would
simplify the synthesis of α-substituted α,β-unsaturated-γ-
lactone containing the decalin core considerably in relation
[
11,12]
to known procedures reported previously.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
[a]The reaction was performed with silyloxyfuran 3 (1.2 equiv., 0.85 mmol),
chiral aldehyde 8 (1.0 equiv., 0.71 mmol) and various catalyst loading in 2 mL of
solvent at the specified temperature for 48h. Isolated yield after silica gel
Recently, we showed that water plays significant impact on
the regioselective Mukaiyama aldol reaction between cyclic
dienol silanes and aromatic aldehydes[13] or ketoesters.
This new attempt was demonstrated also by other authors as
a highly regioselective route to α-substituted furan
[b]
[14]
chromatography.
This study exposed zinc triflate as the best candidate for the
initial studies. Reaction of TMSOF (3) with aldehyde 8 in
the presence of zinc salt afforded mixtures of corresponding
α-substituted α,β-unsaturated γ-lactone 9 in low to good
yields, contaminated by the undesired γ-addition product of
vinylogous reaction (Table 1). Reaction yield and
regioselectivity depends on the solvent and catalyst loading.
Good yields and regioselectivity were observed when the
Mukaiyama aldol reaction was carried out in aqueous protic
solvents such as MeOH and EtOH with 10% of water (Table
derivatives,[15] but even more appreciated diastereoselective
variant of this methodology have not yet been
realized. Herein, we report the utility of these concept by
documenting the first diastereoselective catalytic aqueous
Mukaiyama aldol reaction as an alternative method for
efficient construction of α-substituted 2(5H)-furanone
moiety.
Results and discussion
1
, entries 2 and 4). Lowering the temperature from 4 °C
down to –30 °C and using the mixture of ethanol and
tetrahydrofuran (1:1, v/v) with 10% addition of water in the
presence of 10 mol% of zinc triflate resulted in improved
yields of α-substituted α,β-unsaturated-γ-lactone (62%).
Only trace of undesirable product substituted in γ position
(10) was observed under optimized reaction conditions
(Table 1, entry 11). Reaction carried out in the mixture of
aqueous THF-EtOH with 10 mol% catalyst at –30 °C
guaranteed optimal yield and stereoselectivity (Table 1,
entry 11). It is important to notice that reaction carried out
in dry tetrahydrofuran resulted in exclusive formation of the
γ-aldol product in 70 % yield. This additional experiments
unambiguously confirmed crucial impact of water additive
on the reaction regioselectivity.
We initiated this work by evaluating the model reaction
between 2-trimethylsilyloxy furan 3 and optically pure (R)-
glyceraldehyde acetonide 8 promoted by various Lewis
acids to find out which catalyst, if any, promote α-
regioselective reaction of siloxyfurans with aliphatic sugar
aldehyde in water-containing solvents.
Table 1. Mukaiyama aldol reaction under various conditions.[a]
[
b]
Encouraged by the promising results in Table 1,
stereoselective variants of the aldol reaction by using
optically pure glyceraldehyde 8 were investigated. We
assumed that the kind of catalyst could have a general effect
on the formation of syn-and anti-configured aldol products.
To test the viability of our proposed protocol and asses the
reaction stereoselectivity, a variety of water compatible
Lewis acids including zinc, copper, magnesium, calcium
and lanthanide salts have been employed under previously
elaborated reaction conditions (Table 2, entry 1-9). To our
delight, the majority of tested metal triflates promoted the
formation of product 9 in water containing solvent with
strong preferential formation of one stereoisomer.
Interestingly, iron- bismuth- and silver salts turned out to be
entirely ineffective in this reaction (Table 2, entry 10-12).
Yield [%]
Zn(OTf)
2
Temp.
[°C]
Entry
Solvent
[
mol%]
9
10
1
2
MeOH
10
10
4
4
32
36
trace
2
MeOH/H O
8
(9:1)
3
4
THF/H
2
O (9:1)
O (9:1)
10
10
4
4
30
38
10
EtOH/H
2
trace
iPrOH/H
2
O
5
6
7
8
9
10
10
10
10
10
4
4
4
4
4
30
20
25
20
36
12
8
(9:1)
THF/MeOH
1:1)-10% H
(
(
(
(
2
O
From among all tested Lewis acids we selected zinc and
ytterbium triflates as the most promising catalysts in terms
of yields and stereoselectivity. The later reaction parameter
THF/iPrOH
1:1)-10% H
10
2
O
1
was determined by using H NMR of crude reaction mixture
EtOH/MeOH
1:1)-10% H
12
O
and was also measured for individual stereoisomers. For this
reason alcohol 9 was protected in form of acyl esters under
standard reaction conditions (Ac O, Py) resulting in the
2
2
THF/EtOH
1:1)-10% H
trace
2
O
formation of diastereoisomers 11a and 11b with better
separation of signals in NMR spectra.
1
1
1
1
1
0
1
2
3
4
5
-30
-30
-30
-30
-30
58
62
50
45
55
10
trace
12
Table 2. Stereoselectivity studies.[a]
10
15
20
10
THF/EtOH
(
1:1)-10% H
2
O
15
EtOH/H
2
O (9:1)
12
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
carbonyl group in the most reactive conformer delivering anti-
9 (Scheme 2). This explains clearly formation of the (3S)-
configured product. The same rules can be adopted to the
preferential formation of anti-configured 11, 15 and 17. In all
cases, stereogenic center in the chiral aldehyde control the
formation of anti-configured product under non-chelating
Felkin−Anh transition state control.
Yield of
α-product [%]
[
c]
Entry
Lewis acid
dr
[b]
4
3
7
7
:1
:1
:1
:1
1
2
3
4
5
6
7
8
9
Zn(OTf)
Cu(OTf)
Ca(OTf)
Mg(OTf)
Yb(OTf)
2
62
20
30
28
68
53
46
60
57
-
2
2
2
1
0:1
3
5
:1
:1
:1
:1
Sc(OTf)
La(OTf)
Eu(OTf)
3
3
3
5
5
3
Sm(OTf)
3
1
0
AgOTf
-
1
1
1
2
Fe(OTf)
2
-
-
-
-
Bi(OTf)
3
[
a]
Scheme 2. Plausible model of transition state.
The reaction was performed with silyloxyfuran 3 (1.2 equiv., 0.85 mmol),
chiral aldehyde 8 (1.0 equiv., 0.71 mmol) and 10 mol% of Zn(OTf) in 2 mL of solvent
Isolated yield after silica gel chromatography.
2
[b]
at the -30 °C for 48 h.
[c]
1
After establishing optimal reaction conditions, we next
sought to examine the scope and generality of the current
stereoselective α‐addition for other substrates. Scheme 3
illustrates reactivity of chiral aldehyde and a variety of
cyclic dienol silanes based of furan, thiophen and pyrrole
structure under elaborated methodology. Similarly to TMS-
furan (3), thiophene-based 2-siloxy diene reacted with
model chiral aldehyde 8 afforded desired product 15.
Application of this substrate suppressed the competitive
formation of the γ-substituted side products. Both ytterbium
and zinc triflates catalyzed this unique reaction in
exclusively α-selective manner in which comparable, good
results were obtained (60-70% yield and dr 2:1). In contrast
to reactivity of furan- and thiophene-type substrates similar
investigation made for l-methyl-2-(trimethylsiloxy)pyrrole
Diastereomeric ratio determined by H NMR spectroscopy.
Analysis of NMR spectra suggested that all metal triflates
promoted the formation of α-substituted products in a highly
anti-diastereoselective manner. The use of any ligands have
not been required. The absolute configuration of alcohols 9a
and 9b was unambiguously assigned by HPLC-ECD
methodology by comparison of the experimental ECD
spectrum obtained online during the HPLC separation with
the computed ECD spectra of possible diastereoisomers.
Such stereochemical analysis of chiral compounds was
successfully applied for stereochemical analysis of various
compounds.[
16]
1
2 was unsuccessful. We also examined methyl-substituted
siloxyfuran skeleton in the vinylogous Mukaiyama aldol
reaction. Starting from commercially available 3-methyl-
2
(5H)-furanone, which was treated with TMSOTf in the
presence of Et N we obtained silyloxyfuran 13 in 78% yield.
3
The α-product formation of the Mukaiyama aldol reaction
between synthetized 3-methyl-2-(trimethylsilyloxy)furan
1
3 and optically pure aldehyde 8 under optimized reaction
condition was not observed. One of the possible
explanations of this phenomena may be shielding effect of
the additional methyl substituent attached to the terminal
position of the reactive silyl enol ether fragment.
Fig 1. Comparison of on-line ECD (solid lines) and simulated
(dashed lines) ECD spectra of 9a and 9b. In simulations the CAM-
B3LYP/aug-cc-pVDZ/PCM computational level was applied.
As shown in Figure 1, the simulated ECD spectrum of (S)-
product of Mukaiyama aldol reaction (at the CAM-
B3LYP/aug-cc-pVDZ/PCM level) corresponds to the
experimental online ECD data of 9a, in turn the spectrum of
(R)- product fits to online spectra of 9b (for experimental
details see the Supporting Information Materials). Both
simulated ECD spectra show satisfactory compliance with
appropriate experiment and allow to assign absolute
configuration of reaction products.
Observed preferential formation of anti-configured isomer 9a
from (R)-8 could be easily explained by stereoselective
addition of 2-TMS furan to optically pure aldehyde.
Considering Felkin−Anh transition state oxygen at C-2 of
aldehyde, being electronegative, it will lie perpendicular to the
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
Scheme 3. Substrate scope for the Mukaiyama aldol
α-addition.
In addition to β-chiral aldehyde bearing an exo-double bond
its two endo-isomers 22 and 23 were also successfully
converted to the expected alcohols 24 and 25 with similarly
high levels of diastereoselectivity and yields (Scheme 5).
Aldehydes 22 and 23 were synthetized using described
above three-step procedure starting from (+)-sclareolide
This methodology was also successfully applied to the more
demanding protected aldohexose 16. This more sterically
rigid 2,3-O-isopropylidene derivative of D-mannose led to
lower selectivity but better yield when compared to 2,3-O-
isopropylidene-D-glyceraldehyde (Scheme 3). For this
substrate preferential formation of anti-configured aldol
products was also observed with (3:1) or (4:1)
diastereoselectivity depending of Lewis acid.
except the dehydration step that was achieved with SOCl
elevated temperature (0 °C).
2
at
The scope of this reaction was further investigated by using
more challenging group of aldehydes featuring β-
stereogenic centers which represent a class of important
building blocks for the synthesis of various natural products
and pharmaceuticals. It was remarkably important to test the
level of asymmetric induction caused by remoted
stereocenters. This opportunity was investigated in order to
prepare the biologically active compounds containing α-
substituted 2(5H)-furanone ring collected at Scheme 1. For
this family of compounds two types of aldehyde substrates
with exo-21 and endo-placed double bond (22, 23) could be
applied.
Scheme 5. Mukaiyama aldol α-addition of synthetized chiral
aldehydes 22 and 23 to 2-trimethylsilyloxyfuran 3 in new
reaction conditions.
Elimination of water from 1, 2, 24 molecules gave access to
next members of the labdane diterpenoids family named:
villosin, (+)-coronarin E, chinensine C and (E)-labda-
7
,11,13-trien-16,15-olide as presented in Scheme 6. Endo-
natural product 7 was obtained from diastereomeric mixture
of alcohols: 24a and 24b by the refluxing in pyridine with
the presence of Al2O3 with 78% yield. Similar reaction
conditions have been used for the villosin synthesis. The
requisite exo-olefin 4 was prepared from the combination of
two diastereoisomers 2 and 1 with 84% yield. Further
employing different amounts of DIBAL-H in THF at –78 °C
allowed to obtained two additional natural products.
Reduction of villosin with 1.8 equivalent of reducing agent
provides directly to the diastereomeric lactols 5 (chinensine
C) in very good 76% yield. Increasing the amount of
DIBAL-H (4.5 equiv.) was necessary to complete the
Scheme 4. Preparation of aldehyde 21 and its application in
diastereoselective synthesis of curcucomosin
vitexolide D.
C
and
conversion to biologically active compound
+)-coronarin E.
-
The required aldehyde with trisubstituted exo-olefin
structure 21 was efficiently prepared from commercially
(
[
17]
available (+)-sclareolide.
First, the (+)-sclareolide was
converted to Weinreb’s amide in the presence of
dimethylaluminium amide derived from N-methoxy-N-
methylamine (98% yield). Then, the dehydration of tertiary
alcohol 19 with thionyl chloride in pyridine at –78 °C
followed by DIBAL-H reduction afforded the desired
aldehyde with high yield (90%).[11]
Diastereoselective Mukaiyama aldol reaction of 21 with 3
(
2.0 equiv.) under elaborated conditions resulted in the
mixture of two separable natural products: curcucomosin C
2 and vitexolide D - 1 with 70% and 46% overall yields
-
depending on Lewis acid applied. Structure of both natural
products have been confirmed by comparison of NMR
spectra of obtained samples with previously published data.
These data are included in Supporting Information material.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
tetramethylsilane as an internal standard, integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
dd = double-doublet, m = multiplet, br = broad), coupling
constants (in Hz), and assignment. 13C NMR spectra were
measured at 151 MHz and 75 MHz with complete proton
decoupling. Chemical shifts were reported in ppm from the
residual solvent as an internal standard. Optical rotations
were measured at room temperature with a digital
[
18 ]
[19 ]
polarimeter. Trimethylsilyl enol ethers 12,
13,
and
[20]
1
4
were prepared according to the reported procedures.
R)-2,3-O-isopropylidene-glyceraldehyde (8)
benzyl-3,4:5,6-di-O-isopropylidene-D-glucose (16) were
prepared according to the reported procedures. β-
Substituted aldehydes 21, 22, and 23, starting materials for
the synthesis of natural products, were prepared, according
[
21]
(
and 2-O-
[
22]
[
11a]
to the reported procedures.
All of the spectral data of the
synthesized aldehydes were in accordance with the reported
ones.
General procedure for the synthesis of α-butenolides (9,
Scheme 6. Synthesis of biologically active compounds based on
the 2(5H)-furanone structure substituted at α-position.
1
5, 17), curcucomosin (2), vitexolid D (1, 24, 25). The
solution of metal triflate (0.077 mmol, 10 mol%) in
EtOH/THF (1:1)-H O (10%) (2 mL) was stirred at –30 °C
Conclusion
2
for 10 min. Subsequently chiral aldehyde (0.71 mmol, 1.0
equiv.) and trimethylsilyl enol ether (0.85 mmol, 1.2 equiv.)
were added and the resulting mixture was stirred at –30 °C
for 48 h. After complete consumption of starting materials
reaction mixture was purified directly using column
chromatography on silica gel (hexane/ethyl acetate
In conclusion, we have developed unprecedent catalytic
diastereoselective Mukaiyama aldol reaction of chiral
aldehydes with cyclic dienoxy silanes promoted by metal
triflates in water-containing solvents. This efficient protocol
offers a facile access to α-substituted α,β-unsaturated-γ-
lactones with excellent regiocontrol and stereoselectivity.
Furthermore, described methodology has been successfully
applied to the formation of six labdane-type diterpenoids 1-
9
:1→6:1→4:1→2:1 v/v). The volatiles were removed under
reduced pressure to give pure products.
3
-((S)-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)(hydroxy)methyl)furan-2(5H)-one (9a). In the presence
of Yb(OTf) (47.8 mg, 0.077 mmol, 10 mol%) from TMS-
furan 3 (0.143 ml, 0.85 mmol, 1.2 equiv.) and aldehyde 8
92.4 mg, 0.71 mmol, 1.0 equiv.) following the general
2
and 4-7, which are knowns for their pharmacological
properties such as anti-inflammatory, analgesic and
cytotoxic activity. Although there are no rational conclusion
on how the water influences the reaction regioselectivity,
we demonstrate in this paper further synthetic utility of this
phenomena. Considering the unusual regioselectivity of the
reaction carried out in the aqueous solvents and its
3
(
procedure described above, compound 9a (94.0 mg, 0.6
1
mmol) was obtained in 62% yield, as a colorless oil; H
[2,15]
3
NMR (600 MHz, CDCl ) δ 7.49 (dd, J = 3.7, 1.7 Hz, 1H),
usefulness in the synthesis of subsituted α-butenolides
4
.87 (dd, J = 3.1, 1.7 Hz, 2H), 4.58 (ddd, J = 5.4, 3.5, 1.8
further studies on the reaction mechanism are performing in
our laboratory.
Hz, 1H), 4.43 (dt, J = 6.5, 5.7 Hz, 1H), 3.96 (dd, J = 8.5, 6.6
Hz, 1H), 3.93 (dd, J = 8.5, 5.8 Hz, 1H), 3.14 (s, 1H), 1.43
13
(
s, 3H), 1.34 (s, 3H); C NMR (151 MHz, CDCl
3
) δ 172.5,
Experimental section
1
47.1, 132.1, 109.4, 75.1, 70.5, 67.0, 64.5, 26.1, 24.4; max
-
1
(
neat)/cm : 3398, 2987, 2935, 1739, 1649, 1373, 1251,
General information. All starting materials and reagents
were obtained from commercial sources and used as
received unless otherwise noted. Reaction products were
purified by flash chromatography using silica gel 60 (240-
1
207, 1155, 1055, 841, 791; HRMS (ESI-TOF): calculated
+
+
25
for C10
D
H
14
O
5
Na [M+Na] 237.0733 found 237.0732; [α]
= −20.5 (c = 1.0 in CHCl ).
3
4
00 mesh). Reactions were controlled using TLC on silica
3
-((R)-((R)-2,2-dimethyl-1,3-dioxolan-4-
[
alu-plates (0.2 mm)]. Plates were visualized with UV
yl)(hydroxy)methyl)-furan-2(5H)-one (9b). In the presence
of Yb(OTf) (47.8 mg, 0.077 mmol, 10 mol%) from TMS-
furan 3 (0.143 ml, 0.85 mmol, 1.2 equiv.) and aldehyde 8
92.4 mg, 0.71 mmol, 1.0 equiv.) following the general
detection or by use of a basic UV light (254 nm) and by
treatment with aqueous cerium(IV) sulfate solution with
molybdic and sulfuric acid or treatment with acidic p-
anisaldehyde stain followed by heating. High-resolution
mass spectra were in general recorded on ESI-MS-TOF
3
(
procedure described above, compound 9b (9.4 mg, 0.04
mmol) was obtained in 6% yield, as a colorless oil; H NMR
1
(
MicrOTOF II, Bruker, Germany). Infrared (IR) spectra
were recorded on a Fourier transform infrared attenuated
total reflectance (ATR) FTIR spectrometer. H NMR
spectra were recorded on spectrometers operating at 600
(
600 MHz, CDCl
H), 4.51 (d, J = 5.5 Hz, 1H), 4.38 (dd, J = 12.2, 5.9 Hz,
H), 3.95 (dd, J = 8.5, 6.6 Hz, 1H), 3.91 (dd, J = 8.5, 5.7 Hz,
H), 2.27 (s, 1H), 1.39 (s, 3H), 1.31 (s, 3H); 13C NMR (151
3
) δ 7.48 (dd, J = 3.1, 1.6 Hz, 1H), 4.84 (m,
1
2
1
1
MHz and 300 MHz in CDCl
3
. Data were reported as
follows: chemical shifts in parts per million (ppm) from
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
3
MHz, CDCl ) δ 172.9, 147.4, 132.6, 109.9, 76.1, 71.0, 67.5,
-
1
3-((R)-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)(hydroxy)methyl)thiophen-2(5H)-one (15b). In the
presence of Yb(OTf) (47.8 mg, 0.077 mmol, 10 mol%)
from TMS-thiophene 14 (0.146 ml, 0.85 mmol, 1.2 equiv.)
and aldehyde 8 (92.4 mg, 0.71 mmol, 1.0 equiv.) following
the general procedure described above, compound 15b (46.8
6
1
5.0, 26.6, 24.9; max (neat)/cm : 3390, 2985, 2932, 1740,
655, 1375, 1261, 1210, 1158, 1059, 840, 787; HRMS (ESI-
Na+ [M+Na]+ 237.0733
= −4.5 (c = 1.0 in CHCl ).
3
TOF): calculated for C10
found 237.0734; [α]25
14 5
H O
D
3
Acetylation of α-butenolides 9a and 9b. To a stirred
solution of α-butenolide 9a/b (103 mg, 0.5 mmol) in dry
DCM (4 mL) subsequently pyridine (0.06 mL, 0.75 mmol),
acetic anhydride (0.07 mL, 0.75 mmol), and catalytic
amount of DMAP were added. The resulting mixture was
stirred at room temperature for 12 h and then slightly
acidified with 1.0 M HCI. The organic phase was washed
g, 0.2 mmol) was obtained in 24% yield, as a colorless oil;
H NMR (600 MHz, CDCl ) δ 7.52 (td, J = 2.8, 1.4 Hz, 1H),
3
1
4
5
.63 (m, 1H), 4.42 (dd, J = 12.1, 5.9 Hz, 1H), 4.06 (ddd, J =
.1, 2.8, 1.8 Hz, 2H), 3.95 (dd, J = 8.5, 6.7 Hz, 1H), 3.91
(
3
dd, J = 8.5, 6.0 Hz, 1H), 3.01 (d, J = 4.3 Hz, 1H), 1.45 (s,
13
H), 1.36 (s, 3H); C NMR (151 MHz, CDCl
3
) δ 199.9,
1
50.1, 143.7, 109.8, 76.0, 68.3, 64.9, 36.1, 26.5, 24.9; max
-1
(
neat)/cm : 3297, 2966, 2932, 1680, 1590, 1458, 1335,
with saturated solution of NaHCO
3
, dried over anhydrous
1206, 1130, 1069, 824, 790; HRMS (ESI-TOF): calculated
+
+
25
Na SO and the solvent was removed under reduced
2
4
14 4
for C10H O
SNa [M+Na] 253.0505 found 253.0507; [α]
D
= −2.8 (c = 1.0 in CHCl ).
3
pressure. The crude residue was purified by flash
chromatography using hexane/ethyl acetate (3:2, v/v) as
eluent, to afford product 11 (84 mg, 0.33 mmol, 68%) as a
pale yellow oil. This product was isolated as an inseparable
mixture of diastereomers in (10:1) ratio (Table 2, entry 5,
3
-((1S,2R)-2-(benzyloxy)-1-hydroxy-2-((4S,4'S)-2,2,2',2'-
tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)-ethyl)furan-
2
(5H)-one (17a). In the presence of Yb(OTf)
3
(47.8 mg,
0
.077 mmol, 10 mol%) from TMS-furan 3 (0.143 ml, 0.85
for Yb(OTf)
3
as catalyst). The reported dr was determined
mmol, 1.2 equiv.) and aldehyde 16 (249 mg, 0.71 mmol, 1.0
equiv.) following the general procedure described above,
1
1
by H NMR analysis. Major diastereomer 11a: H NMR
compound 17a (182 mg, 0.42 mmol) was obtained in 58%
(
(
(
3
600 MHz, CDCl ) δ 7.49 (dd, J = 2.7, 1.6 Hz, 10H), 5.60
ddd, J = 5.7, 2.2, 1.1 Hz, 10H), 4.84 – 4.83 (m, 20H), 4.55
dt, J = 6.6, 5.5 Hz, 10H), 4.02 (dd, J = 8.8, 6.7 Hz, 10H),
1
yield, as a colorless oil; H NMR (600 MHz, CDCl
3
) δ 7.42
(
dd, J = 3.2, 1.6 Hz, 1H), 7.33 – 7.24 (m, 5H), 4.79 (d, J =
1
1
1.7 Hz, 1H), 4.76-7.30 (m, 2H), 4.55 (dt, J = 18.5, 2.0 Hz,
H), 4.46 (d, J = 11.7 Hz, 1H), 4.32 (dd, J = 7.2, 4.9 Hz,
3
1
1
.88 (dd, J = 8.8, 5.3 Hz, 10H), 2.09 (s, 30H), 1.37 (s, 30H),
.31 (s, 30H); C NMR (151 MHz, CDCl
49.8, 130.3, 110.2, 74.9, 70.4, 68.3, 65.6, 26.4, 25.0, 20.8;
13
3
) δ 171.6, 169.6,
1H), 4.21 (dd, J = 8.7, 6.3 Hz, 1H), 4.10 (dt, J = 8.5, 6.2 Hz,
1H), 4.04 (dd, J = 5.0, 1.8 Hz, 1H), 4.01 (dd, J = 8.5, 7.3 Hz,
1H), 3.94 (dd, J = 8.7, 6.1 Hz, 1H), 1.46 (s, 3H), 1.42 (d, J
1
Minor diastereomer 11b: H NMR (600 MHz, CDCl
3
) δ
13
=
3
1.6 Hz, 6H), 1.38 (s, 3H); C NMR (151 MHz, CDCl ) δ
7
.46 (dd, J = 3.0, 1.6 Hz, 1H), 5.62 (ddd, J = 4.3, 2.9, 1.4
1
1
2
1
72.6, 147.7, 138.1, 133.7, 128.3 (2C), 128.1 (2C), 127.8,
10.2, 110.1, 83.4, 78.3, 78.0, 77.3, 74.9, 70.8, 68.7, 68.3,
Hz, 1H), 4.85 – 4.84 (m, 2H), 4.55 (dt, J = 5.3, 4.4 Hz, 1H),
4
2
.02 (dd, J = 8.8, 6.7 Hz, 1H), 3.82 (dd, J = 8.8, 5.3 Hz, 1H),
.01 (s, 3H), 1.42 (s, 3H), 1.22 (s, 3H); C NMR (151 MHz,
-1
7.1, 26.8, 26.3, 25.1; max (neat)/cm : 3479, 2987, 2934,
1
3
744, 1454, 1372, 1250, 1210, 1154, 1058, 1035, 844, 732,
+
3
CDCl ) δ 171.2, 169.9, 149.0, 130.6, 110.2, 74.9, 70.6, 68.5,
23 30 8
698; HRMS (ESI-TOF): calculated for C H O Na
[M+Na] 457.1833 found 457.1832; [α]
in CHCl ).
-
1
+
25
6
1
5.7, 26.2, 25.2, 21.0; max (neat)/cm : 2988, 2937, 1756,
448, 1373, 1226, 1156, 1067, 979, 838; HRMS (ESI-TOF):
Na+ [M+Na]+ 279.0839 found
D
= −4.7 (c = 1.0
3
16 6
calculated for C12H O
3
-((1R,2R)-2-(benzyloxy)-1-hydroxy-2-((4S,4'S)-2,2,2',2'-
2
79.0839.
tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)-ethyl)furan-
2
0
(5H)-one (17b). In the presence of Yb(OTf)
.077 mmol, 10 mol%) from TMS-furan 3 (0.143 ml, 0.85
3
(47.8 mg,
3
-((S)-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)(hydroxy)methyl)thiophen-2(5H)-one (15a). In the
presence of Yb(OTf) (47.8 mg, 0.077 mmol, 10 mol%)
mmol, 1.2 equiv.) and aldehyde 16 (249 mg, 0.71 mmol, 1.0
3
from TMS-thiophene 14 (146 mg, 0.85 mmol, 1.2 equiv.)
and aldehyde 8 (92.4 mg, 0.71 mmol, 1.0 equiv.) following
the general procedure described above, compound 15a (93.7
equiv.) following the general procedure described above,
compound 17b (46 mg, 0.11 mmol) was obtained in 15%
1
yield, as a colorless oil; H NMR (600 MHz, CDCl
3
) δ 7.53
mg, 0.4 mmol) was obtained in 48% yield, as a colorless oil;
(
(
1
dd, J = 3.2, 1.6 Hz, 1H), 7.37 – 7.30 (m, 5H), 4.94 – 4.93
m, 1H), 4.82 (dt, J = 6.8, 2.0 Hz, 2H), 4.78 (d, J = 11.5 Hz,
H), 4.63 (d, J = 11.6 Hz, 1H), 4.07 (dd, J = 8.7, 6.2 Hz,
1
3
H NMR (600 MHz, CDCl ) δ 7.53 (td, J = 2.8, 1.3 Hz, 1H),
4
7
.49 (m, 1H), 4.33 (td, J = 6.4, 4.0 Hz, 1H), 4.06 (dd, J =
.6, 5.8 Hz, 1H), 4.05 – 4.04 (m, 2H), 3.96 (dd, J = 8.5, 6.1
Hz, 1H), 2.79 (d, J = 6.9 Hz, 1H), 1.47 (s, 3H), 1.36 (s, 3H);
C NMR (151 MHz, CDCl ) δ 199.3, 150.3, 145.0, 109.8,
3
1H), 4.04 (dd, J = 7.5, 1.7 Hz, 1H), 4.03 – 4.00 (m, 2H),
3.96 (dd, J = 9.6, 3.5 Hz, 1H), 3.87 (d, J = 7.1 Hz, 1H), 3.77
13
-
1
7
2
7
6.9, 68.1, 66.0, 35.8, 26.3, 24.9; max (neat)/cm : 3300,
(
dd, J = 8.7, 5.4 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H), 1.32 (s,
972, 2945, 1693, 1600, 1464, 1339, 1210, 1138, 1072, 833,
H), 1.30 (s, 3H); 13C NMR (151 MHz, CDCl
3
1
1
2
3
) δ 172.5,
14 4
96; HRMS (ESI-TOF): calculated for C10H O
SNa+
47.7, 137.7, 134.3, 128.5 (2C), 127.9 (2C), 127.8, 110.3,
09.8, 79.6, 77.3, 76.9, 76.3, 72.4, 70.8, 68.1, 67.7, 27.3,
+
25
[
M+Na] 253.0505 found 253.0503; [α]
D
= −15.4 (c = 1.0
in CHCl ).
3
-
1
6.5, 26.4, 25.1; max (neat)/cm : 3484, 2986, 2934, 1749,
6
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901218
1
455, 1371, 1210, 1155, 1059, 843, 734, 698; HRMS (ESI-
1.0 equiv.) following the general procedure described
Na+ [M+Na]+ 457.1833
= +36.9 (c = 1.0 in CHCl ).
above, compound 24a (124 mg, 0.39 mmol) was obtained in
30 8
TOF): calculated for C23H O
found 457.1832; [α]25
1
54% yield, as a colorless oil; H NMR (600 MHz, CDCl
3
) δ
D
3
1
3
H NMR (600 MHz, CDCl ) δ 7.31 (dd, J = 2.9, 1.5 Hz, 1H),
5
1
–
.44 (brs, 1H), 4.83 (t, J = 1.6 Hz, 2H), 4.59 (d, J = 8.2 Hz,
H), 2.40 (brs, 1H), 2.10 (brs, 1H), 2.01-1.98 (m, 1H), 1.90
1.87 (m, 1H), 1.85-1.83 (m, 1H), 1.75 (s, 3H), 1.69 – 1.66
3
-((1R)-1-hydroxy-2-((1S,8aS)-5,5,8a-trimethyl-2-
methylenedecahydronaphthalen-1-yl)ethyl)-furan-2(5H)-
one - Curcucomosin C (2).
[9,11a]
In the presence of Yb(OTf)
3
(
1
m, 2H), 1.55 – 1.43 (m, 2H), 1.42 – 1.39 (m, 1H), 1.26 (m,
H), 1.18 (td, J = 13.2, 3.8 Hz, 1H), 1.05 (td, J = 12.8, 3.7
(
47.8 mg, 0.077 mmol, 10 mol%) from TMS-furan 3 (0.238
ml, 1.42 mmol, 2.0 equiv.) and aldehyde 21 (166.4 mg, 0.71
mmol, 1.0 equiv.) following the general procedure
described above, compound 2 (132 mg, 0.42 mmol) was
obtained in 58% yield, as a colorless oil. All data were in
13
Hz, 1H), 0.88 (s, 3H), 0.87 (s, 3H), 0.74 (s, 3H); C NMR
151 MHz, CDCl ) δ 173.1, 144.1, 137.3, 134.5, 123.0, 70.5,
7.7, 50.1, 49.8, 42.2, 39.2, 36.3, 33.9, 33.2, 33.0, 23.8,
(
3
6
2
1
6
-1
2.3, 21.9, 18.8, 13.7; max (neat)/cm : 3468, 2922, 2847,
1
excellent agreement with previously reported.; H NMR
739, 1446, 1345, 1205, 1156, 1092, 1034, 944, 879, 809,
(
600 MHz, CDCl
3
) δ 7.31 (q, J = 1.5 Hz, 1H), 4.88 (dd, J =
+
30 3
73; HRMS (ESI-TOF): calculated for C20H O Na
2
1
1
1
.7, 1.3 Hz, 1H), 4.81 (t, J = 1.7 Hz, 2H), 4.71 (dd, J = 2.7,
+
25
[
M+Na] 341.2087 found 341.2085; [α]
D
= +22.4 (c = 1.0
.4 Hz 1H), 4.54 (d, J = 9.5 Hz, 1H), 2.48 (d, J = 5.0 Hz,
H), 2.41 (ddd, J = 12.7, 4.1, 2.4 Hz, 1H), 2.06 (brd, J =
1.3 Hz, 1H), 2.01 (dd, J = 13.0, 5.0 Hz, 1H), 1.88 (ddd, J
in CHCl ).
3
3
1
2
0
-((1S)-1-hydroxy-2-((1S,8aS)-2,5,5,8a-tetramethyl-
,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-ethyl)furan-
=
13.7, 11.4, 2.0 Hz, 1H), 1.74 (ddt, J = 12.7, 4.9, 2.3 Hz,
1
1
1
3
H), 1.71 – 1.66 (m, 2H), 1.58 – 1.51 (m, 1H), 1.50-1.47 (m,
H), 1.41 – 1.37 (m, 1H), 1.34 (qd, J = 12.9, 4.2 Hz, 1H),
.21 – 1.16 (m, 2H), 1.06 (td, J = 12.9, 3.9 Hz, 1H), 0.87 (s,
(5H)-one (24b). In the presence of Yb(OTf)
3
(47.8 mg,
.077 mmol, 10 mol%) from TMS-furan 3 (0.238 ml, 1.42
1
3
H), 0.80 (s, 3H), 0.68 (s, 3H); C NMR (151 MHz, CDCl
3
)
mmol, 2.0 equiv.) and aldehyde 22 (166.4 mg, 0.71 mmol,
1.0 equiv.) following the general procedure described above,
compound 24a (24.9 mg, 0.08 mmol) was obtained in 11%
δ 173.2, 148.3, 144.1, 137.7, 107.2, 70.5, 65.8, 55.5, 51.9,
4

1
2.1, 39.3, 39.0, 38.3, 33.6 (2C), 30.3, 24.4, 21.7, 19.3, 14.6;
-
1
1
max (neat)/cm : 3440, 3078, 2930, 2845, 1742, 1642, 1449,
yield, as a colorless oil; H NMR (600 MHz, CDCl ) δ 7.31
3
390, 1345, 1214, 1039, 908, 890, 830, 732; HRMS (ESI-
(
dd, J = 2.5, 1.6 Hz, 1H), 5.46 – 5.45 (m, 1H), 4.86-4.85 (m,
Na [M+Na]+ 341.2087
+
TOF): calculated for C20
found 341.2088; [α]
H
30
O
3
2
2
1
1
H), 4.58 – 4.56 (m, 1H), 2.67 (brs, 1H), 1.97 – 1.91 (m,
H), 1.89 – 1.82 (m, 2H), 1.75 (s, 3H), 1.73 – 1.70 (m, 2H),
.52 – 1.46 (m, 1H), 1.42 – 1.38 (m, 2H), 1.29 – 1.27 (m,
H), 1.17 (dd, J = 12.1, 4.8 Hz, 1H), 1.10 (m, 1H), 0.87 (s,
2
5
D 3
= +46.5 (c = 1.0 in CHCl ).
3
-((1S)-1-hydroxy-2-((1S,8aS)-5,5,8a-trimethyl-2-
methylenedecahydronaphthalen-1-yl)ethyl)-furan-2(5H)-
13
[9a]
3H), 0.84 (s, 3H), 0.77 (s, 3H); C NMR (151 MHz, CDCl
δ 173.2, 145.4, 135.8, 134.1, 70.5, 68.8, 50.6, 50.1, 42.2,
9.3, 36.9, 33.4, 33.1, 33.0, 29.7, 23.8, 22.6, 21.8, 18.7,
3
)
one - Vitexolide D (1). In the presence of Yb(OTf)
mg, 0.077 mmol, 10 mol%) from TMS-furan 3 (0.238 ml,
.42 mmol, 2.0 equiv.) and aldehyde 21 (166.4 mg, 0.71
3
(47.8
3
1
-
1
mmol, 1.0 equiv.) following the general procedure
described above, compound 1 (26 mg, 0.08 mmol) was
obtained in 12% yield, as a colorless oil. All data were in
13.5; max (neat)/cm : 3470, 2926, 2846, 1740, 1442, 1348,
1209, 1156, 1095, 1037, 945, 880, 809, 674; HRMS (ESI-
TOF): calculated for C20
found 341.2088; [α]
Na [M+Na]+ 341.2087
+
H
30
O
3
1
25
excellent agreement with previously reported.; H NMR
D
= +5.1 (c = 1.0 in CHCl3).
(
(
600 MHz, CDCl
dd, J = 2.8, 1.3 Hz, 1H), 4.84 (t, J = 1.8 Hz, 2H), 4.72 (m,
3
) δ 7.27 (dd, J = 2.7, 1.6 Hz, 1H), 4.90
3
3
2
0
-((1R)-1-hydroxy-2-((8aS)-2,5,5,8a-tetramethyl-
,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-ethyl)furan-
(5H)-one (25a). In the presence of Yb(OTf) (47.8 mg,
.077 mmol, 10 mol%) from TMS-furan 3 (0.238 ml, 1.42
1
1
1
H), 4.53 (m, 1H), 2.61 (d, J = 4.7 Hz, 1H), 2.41 (ddd, J =
2.7, 4.1, 2.5 Hz, 1H), 2.07 (ddd, J = 14.1, 8.0, 1.7 Hz, 1H),
.96 (td, J = 13.0, 5.1 Hz, 1H), 1.86 (ddd, J = 14.1, 10.6, 5.9
3
Hz, 1H), 1H), 1.78 – 1.73 (m, 2H), 1.60 (d, J = 10.5 Hz,
1
1
mmol, 2.0 equiv.) and aldehyde 23 (166.4 mg, 0.71 mmol,
.0 equiv.) following the general procedure described above,
compound 25a (135.7 mg, 0.4 mmol) was obtained in 60%
H), 1.56 – 1.50 (m, 2H), 1.40 – 1.38 (m, 1H), 1.32 (dd, J =
2.9, 4.3 Hz, 1H), 1.16 (td, J = 13.3, 4.1 Hz, 1H), 1.07 (dd,
1
J = 12.6, 2.7 Hz, 1H), 0.95 (td, , J = 12.8, 3.9 4.5 Hz 1H),
1
1
yield, as a colorless oil; H NMR (600 MHz, CDCl
NMR (600 MHz, CDCl ) δ 7.38 (dd, J = 3.3, 1.6 Hz, 1H),
3
) δ H
1
3
0
.86 (s, 3H), 0.79 (s, 3H), 0.69 (s, 3H); C NMR (151 MHz,
CDCl ) δ 173.1, 149.3, 145.1, 136.1, 107.1, 70.4, 67.7, 55.6,
3.6, 42.0, 39.9, 39.0, 38.3, 33.6, 33.5, 30.0, 24.4, 21.7,
3
3
4
1
2
1
1
3
.84 (t, J = 1.8 Hz, 2H), 4.61 – 4.59 (m, 1H), 2.65 (dd, J =
4.3, 3.7 Hz, 1H), 2.32 (dd, J = 14.1, 11.0 Hz, 2H), 2.19 –
.12 (m, 1H), 2.03 (dd, J = 17.9, 6.6 Hz, 1H), 1.99-1.97 (m,
H), 1.67 (s, 3H), 1.62 – 1.56 (m, 1H), 1.53 – 1.40 (m, 4H),
5
1
1
-
1
9.3, 14.5; max (neat)/cm : 3340, 3080, 2940, 2862, 2850,
642, 1500, 1450, 1390, 1162, 1025, 877, 790, 730; HRMS
+
+
(
ESI-TOF): calculated for C20
H
30
O
3
Na [M+Na] 341.2087
.20 (dd, J = 12.8, 2.0 Hz, 1H), 1.18 – 1.12 (m, 2H), 0.99 (s,
2
5
found 341.2089; [α]
D
= +5.2 (c = 1.0 in CHCl ).
3
13
H), 0.90 (s, 3H), 0.84 (s, 3H); C NMR (151 MHz, CDCl
3
)
δ 172.8, 144.0, 137.4, 135.8, 132.2, 70.6, 67.2, 51.5, 41.7,
3
1
2
0
-((1R)-1-hydroxy-2-((1S,8aS)-2,5,5,8a-tetramethyl-
,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-ethyl)furan-
(5H)-one (24a). In the presence of Yb(OTf) (47.8 mg,
.077 mmol, 10 mol%) from TMS-furan 3 (0.238 ml, 1.42
39.4, 37.4, 34.1, 33.8, 33.4, 33.3, 21.7, 21.1, 20.1, 19.0,
-
1
18.9; max (neat)/cm : 3500, 2931, 1739, 1456, 1352, 1307,
3
1176, 1099, 1063, 1032, 942, 831, 753 714, 730; HRMS
+
+
(ESI-TOF): calculated for C H O Na [M+Na] 341.2087
2
0
30
3
found 341.2089; [α]25 = −2.7 (c = 1.0 in CHCl3).
mmol, 2.0 equiv.) and aldehyde 22 (166.4 mg, 0.71 mmol,
D
7
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
MHz, CDCl
3
) δ 7.16 (dd, J = 1.9 Hz, 1H), 6.65 (dd, J = 15.8,
1
(
1
(
1
1
0.6 Hz, 1H), 6.13 (d, J = 15.8 Hz, 1H), 5.52 (br s, 1H), 4.81
br s, 2H), 2.44 (d, J = 9.8 Hz, 1H), 2.05 – 1.98 (m, 1H),
.95 – 1.88 (m, 1H), 1.57 (br d, J = 13.2, 1H), 1.52 – 1.51
m, 4H), 1.43 – 1.38 (m, 2H), 1.20 (dd, J = 12.1, 4.7 Hz, 1H),
3
3
2
0
-((1S)-1-hydroxy-2-((8aS)-2,5,5,8a-tetramethyl-
,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-ethyl)furan-
(5H)-one (25b). In the presence of Yb(OTf)
3
(47.8 mg,
.077 mmol, 10 mol%) from TMS-furan 3 (0.238 ml, 1.42
.15 (dd, J = 14.2, 4.4 Hz, 1H), 0.99 (td, J = 13.2, 3.4 Hz,
mmol, 2.0 equiv.) and aldehyde 23 (166.4 mg, 0.71 mmol,
.0 equiv.) following the general procedure described above,
compound 25b (22 mg, 0.07 mmol) was obtained in 10%
H), 0.90 (s, 3H), 0.88 (s, 3H), 0.87 (s, 3H); 13C NMR (151
1
MHz, CDCl
1
2
1
3
) δ 172.4, 142.1, 138.6, 132.6, 129.5, 122.4,
21.0, 69.6, 60.8, 49.7, 42.4, 40.4, 36.5, 33.3, 33.1, 23.7,
1
yield, as a colorless oil; H NMR (600 MHz, CDCl
3
) δ 7.34
-1
2.6, 22.0, 18.7, 14.9; max (neat)/cm : 2930, 1754, 1658,
(
(
(
(
dd, J = 3.1, 1.5 Hz, 1H), 4.83 – 4.82 (m, 2H), 4.67 – 4.64
090, 1047, 946, 885, 890; HRMS (ESI-TOF): calculated
+
+
m, 1H), 2.75 (dd, J = 14.4, 4.5 Hz, 1H), 2.43 (brs, 1H), 2.33
dd, J = 14.4, 10.2 Hz, 1H), 2.10-2.08 (m, 2H), 1.95 – 1.93
m, 1H), 1.62 (s, 3H), 1.58 – 1.50 (m, 4H), 1.43 – 1.40 (m,
28 2
for C20H O Na [M+Na] 323.1981 found 323.1984.
Synthesis of chinensine C (5).[9d] To a solution of villosin 4
(85 mg, 0.28 mmol, 1.0 equiv) in dry CH Cl (2 mL) at
78 °C DIBAL-H (1.0 M in hexane, 492 μL, 0.50 mmol, 1.8
1
3
H), 1.18 – 1.16 (m, 3H), 1.04 (s, 3H), 0.89 (s, 3H), 0.86 (s,
2
2
13
−
H); C NMR (151 MHz, CDCl
3
) δ 172.9, 144.2, 136.9,
equiv) was added dropwise over a period of 15 min. The
reaction was stirred for a further 30 min at −78 °C and
quenched at the same temperature by adding MeOH (3 mL).
The homogeneous mixture was allowed to warm to room
temperature over a period of 1 h until a white precipitate
appeared. The cloudy solution was filtered through a pad of
1
3
3
1
36.2, 131.4, 70.6, 67.0, 51.4, 41.7, 38.3, 38.0, 34.5, 33.7,
-
1
3.5, 33.4, 21.8, 21.6, 20.8, 19.1, 19.0; max (neat)/cm :
505, 2931, 1740, 1452, 1350, 1307, 1179, 1099, 1066,
037, 944, 831, 753 714, 730; HRMS (ESI-TOF):
+
+
calculated for C20
3
H
30
O
3
Na [M+Na] 341.2087 found
41.2088; [α]25
= −1.8 (c = 1.0 in CHCl ).
D 3
2
celite that was washed with Et O (3 × 5 mL). The filtrate
was concentrated under reduced pressure to give pure
Synthesis of villosin (4) and (E)-labda-7,11,13-trien-
6,15-olide (7). Al (1.5 equiv.) was added to the α-
butenolide (1.0 equiv.) in dry pyridine (3 mL). The mixture
was refluxed for 12 h, allowed to room temperature and then
diastereomeric lactols 5 in 1:1 ratio as colorless oil (65 mg,
1
7
3
6%); H NMR (300 MHz, CDCl
H for each diastereomer), 5.91 (br s, 2H, 1H for each
3
) δ 6.22 – 5.97 (m, 6H,
1
2 3
O
diastereomer), 4.79 (ddd, J = 6.8, 4.4, 2.4 Hz, 2H, 1H for
each diastereomer), 4.74 (dd, J = 3.5, 1.7 Hz, 2H, 1H for
each diastereomer), 4.61 – 4.52 (m, 2H, 1H for each
diastereomer), 4.51 (dd, J = 3.6, 1.8 Hz, 1H), 4.45 (q, J =
1.8 Hz, 1H), 2.79 (dd, J = 9.0, 5.0 Hz, 2H, 1H for each
diastereomer), 2.44 (ddd, J = 13.5, 4.3, 2.2 Hz, 2H, 1H for
each diastereomer), 2.34 (d, J = 8.3 Hz, 2H, 1H for each
diastereomer), 2.15 – 2.03 (m, 2H, 1H for each
diastereomer), 1.70 (ddd, J = 10.3, 5.4, 2.6 Hz, 2H, 1H for
each diastereomer), 1.53 – 1.36 (m, 10H, 5H for each
diastereomer), 1.23 – 1.17 (m, 2H, 1H for each
diastereomer), 1.08 (dd, J = 12.6, 2.6 Hz, 2H, 1H for each
diastereomer), 1.00 (dd, J = 12.8, 9.4 Hz, 2H, 1H for each
diastereomer), 0.89 (s, 6H, 3H for each diastereomer), 0.83
2 3
filtrated to remove the Al O . The filter cake was washed
with chloroform (20 mL). The solvent was removed from
the filtrate under reduced pressure. The crude was purified
by column chromatography using hexane/ethyl acetate (3:2,
v/v) as eluent. The volatiles were removed under reduced
pressure to give pure product.
Villosin (4).[9e] From the mixture of diastereomers 1 and 2
(
2 3
110 mg, 0.35 mmol, 1.0 equiv.) and Al O (52 mg, 0.53
mmol, 1.5 equiv.) following the general procedure
described above, compound 4 (87 mg, 0.29 mmol) was
1
obtained in 84% yield, as a white solid; H NMR (600 MHz,
(
s, 6H, 3H for each diastereomer), 0.82 (s, 6H, 3H for each
3
CDCl ) δ 7.15 (s, 1H), 6.90 (dd, J = 15.8, 10.1 Hz, 1H), 6.11
13
diastereomer); C NMR (75 MHz, CDCl
3
) δ 150.4, 150.3,
(
d, J = 15.8 Hz, 1H), 4.80 (d, J = 1.3 Hz, 2H), 4.76 (q, J =
1
1
4
3
39.6, 139.5, 134.2, 134.0, 125.93, 125.90, 124.4, 124.3,
1
4
1
1
1
1
.6 Hz, 1H), 4.50 (q, J = 1.6 Hz, 1H), 2.44 (ddd, J = 13.5,
.3, 2.2 Hz, 1H), 2.37 (d, J = 10.1 Hz, 1H), 2.08 (ddd, J =
3.4, 9.3, 3.8 Hz, 1H), 1.70 (ddt, J = 12.9, 5.2, 2.5 Hz, 1H),
.55 1.51 (m, 1H), 1.49-1.45 (m, 1H), 1.44 – 1.36 (m, 3H),
.18 (dt, J = 13.3, 3.5 Hz, 1H), 1.09 (dd, J = 12.6, 2.7 Hz,
H), 1.03 – 0.96 (td, J = 13.3, 3.2 Hz, 1H), 0.89 (s, 3H), 0.87
09.0, 108.6, 103.3 (2C), 74.2 (2C), 62.5 (2C), 55.4 (2C),
2.9 (2C), 41.5, 41.4, 39.9, 39.7, 37.33 (2C), 34.2 (2C), 30.9,
0.3, 24.0 (2C), 22.6 (2C), 19.7, 19.5, 15.64 (2C); max
-
1
(
neat)/cm : 3618, 3430, 3010, 2910, 2860, 1685, 1642;
+
+
30 2
HRMS (ESI-TOF): calculated for C20H O Na [M+Na]
3
25.2138 found 325.2138; [α]25
= +22.1 (c = 1.0 in CHCl ).
D 3
1
3
(
s, 3H), 0.83 (s, 3H); C NMR (151 MHz, CDCl
3
) δ 172.4,
49.4, 142.5, 136.8, 129.5, 120.7, 108.4, 69.6, 62.2, 54.7,
2.3, 40.8, 39.3 , 36.7, 33.6 (2C), 23.4, 21.9, 19.1, 15.1; max
1
4
Synthesis of coronarin E (6).[9g,h] To a solution of villosin 4
(70 mg, 0.23 mmol, 1.0 equiv) in dry THF (10 mL) at
−78 °C dropwise DIBAL-H (1.0 M in toluene, 1.1 mL, 1.1
mmol, 4.5 equiv) was added dropwise over a period of 30
min. The reaction was stirred for a further 4 h at −78 °C and
quenched at the same temperature by adding 10% HCl (15
mL). The homogeneous mixture was allowed to warm to
room temperature over a period of 1 h and stirred at this
temperature over 20 min. The organic layer was separated.
-
1
(
neat)/cm : 3079, 2925, 1757, 1642, 1085, 1050, 948, 900,
+
8
91; HRMS (ESI-TOF): calculated for C20
H
28
O
2
Na
+
25
[
M+Na] 323.1981 found 323.1982; [α]
D
= −7.8 (c = 1.0
in CHCl ).
3
(
E)-labda-7,11,13-trien-16,15-olide (7).[9i] From α-
butenolide 24 (50 mg, 0.16 mmol, 1.0 equiv.) and Al
26.5 mg, 0.24 mmol, 1.5 equiv.) following the general
2
O
3
(
The aqueous phase was extracted with Et O (3 × 20 mL) and
2
procedure described above, compound 7 (7 mg, 0.12 mmol)
dried over MgSO . The residue obtained after evaporation
4
1
was obtained in 78 % yield, as a colorless oil. H NMR (600
of the solvent under reduced pressure was purified by silica
8
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Advanced Synthesis & Catalysis
10.1002/adsc.201901218
gel chromatography, eluted with hexanes-ethyl acetate (9:1
1640, 1468, 1440, 1390, 1370, 1160, 1070, 1027, 970, 890,
→
1:1, v/v) to provide pure product 6 as colorless oil (53
598; HRMS (ESI-TOF): calculated for C20H
28ONa+
1
+
25
mg, 80%); H NMR (600 MHz, CDCl
3
) δ 7.36 (s, 1H), 7.35
[M+Na] 307.2032 found 307.2036; [α]
in CHCl ).
D
= +21.4 (c = 1.0
(
s, 1H), 6.55 (s, 1H), 6.20 (d, J = 15.8 Hz, 1H), 5.98 (dd, J
3
=
15.7, 9.8 Hz, 1H), 4.76 (d, J = 1.8 Hz, 1H), 4.54 (d, J =
1
.8 Hz, 1H), 2.46 (ddd, J = 13.5, 4.4, 2.3 Hz, 1H), 2.41 (d, Acknowledgment
J = 9.8 Hz, 1H), 2.11 (td, J = 13.4, 5.5 Hz, 1H), 1.74 – 1.68
m, 1H), 1.54 – 1.40 (m, 5H), 1.20 (dt, J = 13.9, 4.0 Hz, 1H),
Financial support from the Polish National Science Centre
PRELUDIUM Grant No. NCN 2016/21/N/ST5/00875) is
(
1
1
(
.12 (dd, J = 12.6, 2.7 Hz, 1H), 1.03 (td, J = 13.8, 3.4 Hz,
gratefully acknowledged. IW and JM also thank Polish
National Science Centre (OPUS Grant No. NCN
1
3
H), 0.90 (s, 3H), 0.85 (s, 3H), 0.85 (s, 3H); C NMR (151
) δ 150.3, 143.3, 139.6, 128.3, 124.5, 121.8,
08.0, 107.7, 61.5, 54.8, 42.3, 40.8, 39.2, 36.8, 33.6 (2C),
MHz, CDCl
1
2
3
2
017/27/B/ST5/01111) for financial support. AB thanks
PLGrid Infrastructure for the computer time.
-
1
3.4, 22.0, 19.1, 15.0; max (neat)/cm : 3070, 2945, 2860,
and J. Boukouvalas, J. Chem. Soc., Chem. Commun. 1988,
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UPDATE
Lewis Acid-Catalyzed Stereoselective α-Addition
of Chiral Aldehydes to Cyclic Dienol Silanes:
Aqueous Synthesis of Chiral Butenolides
Adv. Synth. Catal. Year, Volume, Page – Page
Anna Adamkiewicz, Izabela Węglarz, Aleksandra
Butkiewicz, Marta Woyciechowska, Jacek
Mlynarski*
1
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