Synthetic Access to Noncanonical Strigolactones: Syntheses of Carlactonic Acid and Methyl Carlactonoate

Article abstract of DOI:10.1021/acs.joc.7b02465

Strigolactones are plant hormones regulating essential stages of a plant's development. Their low natural abundance combined with a low chemical stability significantly hampered the detailed investigation of their biological activity. Noncanonical strigolactones lack the fused tricyclic ABC-ring system commonly present in canonical-type strigolactones but feature an open-chain unit linking structurally diverse A-ring moieties to the butenolide D-ring. We herein present an efficient synthetic access to enantiomerically pure noncanonical strigolactones by a Stille cross-coupling approach to forge the central diene moiety and demonstrate this strategy by syntheses of natural products methyl carlactonoate and carlactonic acid. Furthermore, a synthetic access to deuterium-labeled analogues of these natural products has been developed.

Full text of DOI:10.1021/acs.joc.7b02465

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Article
Synthetic access to non-canonical strigolactones -
Syntheses of carlactonic acid and methyl carlactonoate
Michael Christian Dieckmann, Pierre-Yves Dakas, and Alain De Mesmaeker
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02465 • Publication Date (Web): 27 Nov 2017
Downloaded from http://pubs.acs.org on November 28, 2017
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Synthetic Access to NonꢀCanonical Strigolactones –
Syntheses of Carlactonic Acid and Methyl Carlactonoate
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Michael C. Dieckmann,† PierreꢀYves Dakas,‡ and Alain De Mesmaeker†,*
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstrasse 101, CH-4332 Stein,
Switzerland
alain.de_mesmaeker@syngenta.com
† Syngenta Crop Protection AG.
‡ Present address: Bayer AG, Animal Health Division, Wuppertal, Germany.
*To whom correspondence should be addressed.
ABSTRACT. Strigolactones are plant hormones regulating essential stages of a plants development.
Their low natural abundance combined with a low chemical stability significantly hampered the detailed
investigation of their biological activity. Nonꢀcanonical strigolactones lack the fused tricyclic ABCꢀring
system commonly present in canonicalꢀtype strigolactones, but feature an open chain unit linking
structurally diverse Aꢀring moieties to the butenolide Dꢀring.
We herein present an efficient synthetic access to enantiomerically pure nonꢀcanonical strigolactones by
a Stille crossꢀcoupling approach to forge the central diene moiety and demonstrate this strategy by
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syntheses of natural products methyl carlactonoate (MeCLA) and carlactonic acid (CLA). Furthermore,
a synthetic access to deuteriumꢀlabeled analogues of these natural products has been developed.
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- 3/ 4 steps syntheses
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- mild & versatile approach
A
- control of C11-stereocenter
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- deuterium labeling
R = OMe: MeCLA
R = OH: CLA
INTRODUCTION. Strigolactones are terpenoid derived natural products that have recently been
recognized as phytohormones involved in various stages of plant development. 1 After the first
characterization of a strigolactone, isolated from rootꢀexudates of cotton and named (+)ꢀstrigol (1,
Scheme 1) in 1966,2 more than 20 other strigolactones have been described in the following years.3
Land plants, including higher plants but also nonꢀvascular plants such as mosses, liverworts and
stoneworts have been found to produce a plant specific variety of strigolactones. The soꢀcalled
“canonical” strigolactones structurally consist of three fused rings (A, B, C) connected to a butenolide
ring (D) via an enol ether bridge. These canonical strigolactones are biologically investigated in detail
since the past decade and are involved in processes such as regulation of seed germination, seedling
establishment, plant architecture as well as in soil signaling with arbuscular mycorrhizal fungi (AM
fungi) and parasitic hosts. Several total syntheses and syntheses of analogues have been described which
have contributed to the further understanding of the complex biology of strigolactones.4,5
Recently, a novel subclass of strigolactones has been identified, that lack the canonical ABCꢀring
moiety, but feature an open chain unit linking structurally diverse Aꢀring moieties to the Dꢀring. The
structural and presumed biosynthetic “nonꢀcanonical” parent strigolactones are methyl carlactonoate 2
and carlactonic acid 3, containing a βꢀionone moiety as an Aꢀring (Scheme 1).6,7,10 First biological
studies show that they are potent inducers for germination6 and for hyphal branching in AM fungi.7
Further examples of nonꢀcanonical strigolactones are heliolactone (4)8 bearing an oxidized Aꢀring and
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zealactone 1a/b (5)9 containing an Aꢀring resulting from a formal oxidative rearrangement. Notably,
zealactone 1a/b (5) has been reported as the most abundant strigolactone in corn, with heliolactone (4)
being the most abundant in sunflower. These findings emphasize the potential high relevance of nonꢀ
canonical strigolactones in crops.9
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Scheme 1. Selected canonical and nonꢀcanonical strigolactones.
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C
A
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D
D
1
(+)-strigol
R = Me: methyl carlactonoate,
R = H: carlactonic acid,
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A
D
D
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heliolactone
zealactone 1a/b
The low natural abundance paired with the intrinsic instability of nonꢀcanonical strigolactones towards
acids and bases has so far hampered the investigation of these natural products. A single synthetic
strategy for methyl carlactonoate (2) and carlactonic acid (3) has been reported by Akiyama, Yoneyama,
Nomura and coworkers in 2014 (Scheme 2).10 Their strategy consisted of a formylation of methylꢀ (6) or
tertꢀbutyl homodienyl ester 7 and alkylation of intermediary formed enolate using a bromo butenolide
Dꢀring precursor 8, in analogy to described syntheses of canonical strigolactones.4 They were able to
obtain racemic methyl carlactonoate (MeCLA, 2) and racemic carlactonic acid (CLA, 3) in six to eight
steps and a low overall yield.
Scheme 2: Reported synthesis of MeCLA (2) and CLA (3).
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HCOOMe, NaH
then
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(6 steps, 0.7%)
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1. conditions
as above
2. TESOTf, lutidine
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3
7
(8 steps, 0.4%)
We sought for a more general approach towards nonꢀcanonical strigolactones and identified the C7ꢀ
C10 diene moiety to be possibly accessible by a Stille coupling of the known vinyl stannane 1011 with
the novel vinyl iodide 9 (Scheme 3). Vinyl iodide 9 would arise from a Michael addition of butenolide
alcohol 12 and methyl propynoate (11) and subsequent iodination. This strategy is shown in Scheme 3
for MeCLA (2) but could be generally applicable to nonꢀcanonicalꢀtype strigolactones employing vinyl
iodide 9 and suitable cross coupling partners. Furthermore, in contrast to reported syntheses of
strigolactones,4 control of the biologically relevant C11ꢀstereocenter could be feasible by this approach.
Scheme 3: Retrosynthetic approach toward MeCLA (2).
iodination
Michael addition
Stille coupling
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7
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10
11
9
2
12
10
RESULTS AND DISSCUSSION.
Synthesis of vinyl iodide 9 started with Michael addition of commercially available butenolide alcohol
12 and methyl propynoate (11) in presence of Nꢀmethyl morpholine (see Scheme 4).12 Notably, the Eꢀ
configured alkene 13 was obtained as the only stereoisomer in 77% yield. Iodination of olefin 13 was
achieved by treatment of 13 with a mixture of Nꢀiodosuccinimide (NIS) and acetic acid followed by
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triethylamine. This regioselective iodoacetoxylation and inꢀsitu base mediated acetateꢀelimination13
furnished the desired vinyl iodide 9 in high yield of 86% and as a pure Zꢀconfigured diastereomer as
confirmed by NMRꢀstudies and Xꢀray structure analysis. Racemic 9 was obtained as benchꢀstable
crystalline solid that could be readily separated into its C11ꢀenantiomers (R)ꢀ9 and (S)ꢀ9 on gramꢀscale
by HPLC on chiral stationary phase. The absolute configuration of the C11ꢀstereocenter of both
enantiomers (R)ꢀ9 and (S)ꢀ9 was elucidated via CDꢀanalysis. Independently, a germination assay on
Orobanche Cumana, known to highly favor strigolactoneꢀtype compounds containing the naturally
occuring (R)ꢀconfigured butenolide Dꢀring confirmed the absolute configuration.5e
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Scheme 4: Synthesis of vinyl iodide 9.
THF, rt, 18h
77%
11
12
13
NIS, AcOH
DCM, rt, 36h
then NEt3, 8h
11
86%
9
separation of C11-enantio-
mers via chiral HPLC
X-ray
Synthesis of the vinyl stannane 10 proceeded by known alkynylation of βꢀcyclocitral (14)14 using
Colvin’s procedure and hydrostannylation under modified radical conditions described by de Lera and
coworkers (Scheme 5).11 Vinyl stannane 10 decomposed upon attempted purification on silica gel, but
was obtained in high purity by adding equimolar amounts of tributyl stannane to alkyne 15 under neat
conditions with subsequent filtration over Celite.
Scheme 5: Synthesis of vinyl stannane 10.
TMSCHN2
HSnBu3
LDA, THF
-78°C, 6h
AIBN
80°C, 24h
92%
99%
10
14
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With both building blocks 9 and 10 in hand, we investigated suitable cross coupling conditions to
build up the central C7ꢀC10 dieneꢀmoiety as a common motif present in nonꢀcanonical strigolactones.
Due to the pronounced lability of strigolactones under basic conditions, we focused on neutral Stille
coupling conditions. Different catalytic systems were evaluated (entries 1ꢀ3, Table 1) showing that
Pd2dba3/ AsPh3 gave the most promising conversion and 30% isolated yield of the desired coupling
product 2. By employing an excess of stannane 10 (2.5 eq), the previously observed
protiodehalogenation of vinyl iodide 9 could be suppressed. Further experimentation regarding catalyst
loading, concentration, reaction time and temperature finally led to the optimized conditions to give
racemic 2 in 75% yield (entry 4). Notably, the bromoꢀanalogue 16 proved to be almost unreactive and
gave only traces (<0.1%) of 2 (entry 5), presumably due to its lower reactivity towards oxidative
addition with Pd(0). Enantiomerically pure vinyl iodides (R)ꢀ9 and (S)ꢀ9 gave natural product (+)ꢀ(R)ꢀ
MeCLA and its enantiomer (−)ꢀ(S)ꢀMeCLA without any observed C11ꢀracemization.
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Table 1.
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10
9/16
2
entry
'PdLn'
X
conditions
Conversion
/ yield of 2
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2
3
Pd(PPh3)4
(20 mol%)
I
toluene, 100°C
60min
5% / traces
PdCl2(PPh3)2
(20 mol%)
I
I
CuI, DMF 100°C
60min
full conv./
10%
Pd2(dba)3 (10
mol%), AsPh3
(40 mol%)
dioxane, 100°C
60min
full conv./
30%
4
Pd2(dba)3 (7.5
I
dioxane, 90°C
45min
full conv./
75%
mol%), AsPh3
(30 mol%)
5
Pd2(dba)3 (10
mol%), AsPh3
(40 mol%)
Br
dioxane, 100°C
60min
30% /
traces
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This developed route led to racemic methyl carlactonate (MeCLA, 2) in three steps and an overall
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yield of 50% (longest linear sequence). Stability studies of MeCLA (2) either stored as neat product or
in solution at different temperatures revealed a halflifeꢀtime of t1/2 ~ 30 d when stored as neat product or
as solution in dichloromethane at ꢀ80 °C in the dark under argon.
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Isotopeꢀlabeled nonꢀcanonical strigolactones are valuable tools to study various biochemical processes
such as biosynthetic pathways, metabolic behavior or transport processes. We thus sought for possible
isotopes at optimal positions for MeCLA (2) and identified deuterated analogues 17 & 18 (Scheme 6)
that should be metabolically suitable and accessible by using our developed synthetic strategy.
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Scheme 6: Deuterium labeled MeCLA.
or
biosynthesis
metabolism
2H
etc.
2H
7
10
deutero-derivates
HPLC-MS analysis
7-2H-MeCLA, 17
10-2H-MeCLA, 18
MeCLA (18) deuterated at the C10ꢀposition was synthesized as outlined in Scheme 7. Deutero methyl
propynoate (19, 98% deuteration) could be synthesized under basic phaseꢀtransfer conditions using
catalytic amounts of tetrabutylammonium iodide (TBAI) in a dichloromethane/ D2O mixture. 15
Following the same procedure, we obtained deuterated butenolide alcohol 20 (50% deuteration).
Deuteration of the latter was necessary due to significant H/Dꢀexchange at propynoate 19 when nonꢀ
deuterated butenolide alcohol 12 was employed in the Michael reaction. The Michael addition gave (E)ꢀ
olefin 21 in 63% yield with 92% C10ꢀdeuteration accompanied by 78% of C9ꢀdeuteration. Iodination of
21 furnished vinyl iodide 22 (91% C10ꢀdeuteration), that could be coupled with vinyl stannane 10 to
give MeCLA 18 with 91% C10ꢀdeuteration as measured by 1HꢀNMR.
Scheme 7.
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2H
1
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6
2H
10
2H
K2CO3, TBAI
9
19
THF, rt, 24h
63%
11
12
DCM/ D2O
rt, 18h
2HO
21
20
7
8
9
10, Pd2dba3
NIS, AcOH
then NEt3
2H
10
2H
AsPh3, dioxane
100°C, 45min
DCM, rt, 36h
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44%
51%
18
91% deuteration
22
C7ꢀdeuterated MeCLA 17 could be obtained by using a deuteroꢀstannylation of enyne 15 with deutero
tributylstannane and subsequent Stille coupling with vinyl iodide 9 (Scheme 8). Both described
approaches to deuteriumꢀlabeled MeCLA resulting in the deuterium label at C7 or C10 of the molecule
should be applicable as well for other nonꢀcanonical strigolactones in a complementary fashion.
Scheme 8.
2H
2H
SnBu3, AIBN
80°C, 22h
7
99%
23
15
>99% deuteration
9, Pd2dba3, AsPh3
2H
dioxane, 100°C
45min
7
23%
17
>99% deuteration
Carlactonic acid (CLA) biosynthetically derives from βꢀcarotene that is oxidatively cleaved and
cyclized to carlactone (CL), followed by further C19ꢀoxidation delivering CLA (Scheme 9).6 CLA has
been shown to be the biosynthetic precursor for canonical strigolactones belonging to the strigolꢀ and the
orobancholꢀsubclass6 and has also been hypothesized to be also the precursor for nonꢀcanonical
strigolactones.10
Scheme 9: Pivotal role of carlactonic acid (CLA) in strigolactone biosynthesis.
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19
1
2
-carotene
β
3
4
carlactone (CL)
carlactonic acid (CLA)
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9
C
C
B
A
B
A
A
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D
5
11
2'
2'
D
D
methyl carlactonoate (MeCLA)
5-deoxystrigol
4-deoxyorobanchol
strigol
fabacyl acetate
orobanchol
(and others)
orobanchol subclass
sorgomol
heliolactone
(and others)
zealactone 1a/b
(and others)
strigol subclass
canonical SLs
non-canonical SLs
We planned to synthesize carlactonic acid (CLA, 3) from methyl carlactonoate (MeCLA, 2) by ester
cleavage. Basic aqueous conditions led, as expected, to decomposition of the material (Table 2, entry 1,
2). Neutral conditions using (Bu3Sn)2O16 in toluene at room temperature gave low conversion with only
traces of desired CLA (3) observed by LCMS analysis. The same conditions at 50 °C led to
decomposition and again only traces of 3 were obtained as mixtures with various decomposition side
products (entry 3). Enzymatic methyl ester hydrolyses were investigated using five different enzymes. In
each case, acid 3 was detected in the reaction mixture but only traces of 3 accompanied by several
unidentified side products were obtained. Furthermore, deactivation of the enzymes seemed to occur
after initial partial conversion of MeCLA (2) to small amounts of desired CLA (3) (entries 4ꢀ8).
Table 2.
2
3
entry conditions
conv./ yield of 3
1
Ba(OH)2*8H2O, MeOH
rt, 18h
full decomp.
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2
3
4
LiOH*H2O, THF/MeOH/H2O
rt, 18h
90% conv./ --
1
2
3
4
5
6
7
8
(Bu3Sn)2O, toluene, 24h
rt or 50°C
full conv./
traces of 3
Candida rugosa lipasea
80-90% conv./
traces of 3
9
5
6
7
8
Cal B lypozymeb
“ / “
“ / “
“ / “
“ / “
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Lipolase 100Lb
Novocor ADLb
Burkholderia cepacia lipaseb
a) toluene/phosphate buffer (aq, pH = 7, 0.05M), 24h;
b) cyclohexane/phosphate buffer (aq, pH = 7, 0.05M), 24h.
We thus decided to use other protecting groups instead of a methyl ester to synthesize acid 3. In
analogy to the developed synthesis of methyl ester 2, the corresponding benzylꢀ (24), 2,2,2ꢀ
trichloroethylꢀ (TCE) (25), and tertꢀbutylꢀ (26) protected compounds were synthesized in three to four
steps. We subsequently investigated potential protective group cleavage conditions as summarized in
Table 3.
Table 3.
3-4 steps
PG = Bn: 24
TCE: 25
3
tBu:
26
entry PG
conditions
conv./ yield of 3
1
Bn
10% Pd/C, H2 (1 and 3 barb), full conv./ --
EtOAc, rt, 24h
2
3
4
Bn
Bn
Bn
5% Pd/C, H2, THF, rt, 24h
5% Pd/C, H2, EtOH, rt, 24h
80-90% conv./ --
full conv./ --
5% Pd/C, cyclohexa-1,4-
diene, EtOAc, rt, 24h
80-90% conv./--a
5
Bn
20% Pd(OH)2/C, H2, EtOAc,
rt, 24h
80-90% conv./--a
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6
7
Bn
Bn
Raney-Ni, H2 (1 bar),
EtOH/H2O, rt, 48h
50% conv. / --
1
2
3
4
Raney-Ni, H2 (10 bar)b,
EtOAc, rt
full conv./ --
5
6
7
8
9
10
11
12
13
14
15
16
8
TCE
TCE
tBu
Zn, AcOH, 0°C, 1h
full conv./ --
9
Zn, NH4OAc, THF, rt, 1h
20-30% conv. /--
full conv./ 5%
10
TESOTf, 2,6-lutidine, DCM,
0°C, 3h
TCE = 2,2,2-trichloroethyl; a) hydrolysis of butenolide D-ring, 12 obtained as
major side-product; b) H-cube® apparatus was used.
Hydrogenolyses of benzylꢀcompound 24 was investigated with 5ꢀ10% Pd/C in ethyl acetate, THF and
ethanol as solvent. In addition, flowꢀconditions using an Hꢀcube® apparatus at different H2ꢀpressures
were probed. All of these conditions, however, led to decomposition of the material (entries 1ꢀ3, Table
3). Under transfer hydrogenolysis conditions using 1,4ꢀcyclohexadiene as reductant, 80ꢀ90% conversion
was obtained, with hydrolysed butenolide Dꢀring alcohol 12 as major side product (entry 4). A similar
result was obtained when Pearlman’s catalyst was employed (entry 5). Raneyꢀnickel proved to be rather
unreactive and led to decomposition at higher pressure (10 bar) under flow conditions (entries 6, 7). The
attempted synthesis of a benzhydrylꢀanalogue of 24 was not successful17 and we decided to not further
follow up a hydrogenolytic cleavage strategy due to the instability of the trieneꢀmoiety under such
conditions. According to preliminary stability tests of 24 under common deprotection conditions such as
tetrabutylammonium fluoride (TBAF), zinc/ acetic acid and TFA, we assumed that a 2,2,2ꢀtrichloroethyl
(TCE)ꢀester could be a suitable protective group to synthesize acid 3 under mild reductive conditions.
Unfortunately, also TCEꢀester 25 could not be converted to 3, when zinc/ acetic acid or zinc/ ammonium
acetate18 combinations were employed (entries 8, 9).
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Akiyama, Yoneyama, Nomura and coworkers were able to synthesize carlactonic acid 3 by deprotection
of the corresponding tertꢀbutyl ester 26.10 They did not specify the yield for this transformation and
described 26 as an unstable compound that was not isolated and directly submitted to deprotection
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conditions using an excess of TESꢀtriflate and 2,6ꢀlutidine. In our hands, these conditions furnished 3
1
2
3
but resulted in a very low isolated yield of 5% (entry 10).
4
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7
8
Reviewing the results of attempted deprotection reactions, methyl and especially tertꢀbutyl esters could
be cleaved, however, in only very low yield. The instability of compounds 2 and 26 presumably arises
from the relative electronꢀrich triene moiety. Benzylꢀ and trichloroethylꢀanalogues 24 and 25 showed a
higher hydrolytic stability, but also decomposed under reductive conditions and not even traces of
deprotected acid 3 were detected. We thus modified our strategy aiming for an efficient synthesis of
carlactonic acid 3 and investigated an approach without protecting groups. To test this strategy we
focused on a free aldehydeꢀfunctionality that could be oxidized at a suitable stage to the carboxylic acid.
9
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This modified route started with Michaelꢀaddition of butenolide alcohol 12 to propyneꢀaldehyde (27)
(Scheme 10). Due to the increased electrophilicity of Michaelꢀacceptor 27 compared to methyl
propynoate (11) the reactionꢀtime and ꢀtemperature were reduced. (E)ꢀOlefin 28 was obtained in
excellent yield and subjected to iodination under slightly modified conditions. Iodide 29 proved to be
more labile in the presence of triethylamine and the iodoacetoxyꢀintermediate of 29 had to be treated
with triethyl amine for short reaction times of 10 minutes at 0 °C in order to obtain 80% yield of desired
vinyl iodide 29. Racemic product racꢀ29 was obtained as crystalline solid that in similarity to methyl
ester 9 could be separated by HPLC on gramꢀscale to give pure C11ꢀenantiomers (R)ꢀ29 and (S)ꢀ29.
Determination of stereochemistry by CDꢀanalysis revealed the absolute configuration of both
compounds.
Scheme 10: Protectiveꢀgroup free approach – synthesis of vinyl iodide 29.
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The Journal of Organic Chemistry
1
2
THF, 0°C, 15min
3
4
5
92%
27
12
28
6
7
8
NIS, AcOH
DCM, rt, 18h
then NEt3
0°C, 10min
11
9
80%
10
11
12
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14
29
separation of C11-enantio-
mers via chiral HPLC
X-ray
With aldehyde 29 in hand we envisaged two possibilities to synthesize carlactonic acid (3). On the one
hand, by first performing a Stille crossꢀcoupling with vinyl stannane 10 and oxidizing the aldehyde
moiety under “mild” conditions; on the other hand, by oxidation of 29 and by crossꢀcoupling of the
obtained free carboxylic acid building block with stannane 10 to give 3.
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As shown in Scheme 11, vinyl iodide 29 could be coupled with stannane 10 to give 30 in moderate yield.
Thereafter a variety of oxidation methods, including Pinnickꢀoxidation and Ag(I)ꢀoxidation,19 proved
unsuitable. Oxidation methods described by Chakraborty and coworkers using tertꢀbutyl hydroperoxide
in combination with Fe(II)ꢀ or Cu(II)ꢀsalts20 gave excellent results when aldehyde 28 was used as a
modelꢀsystem but resulted in only traces of carlactonic acid 3 when applied to aldehyde 30. However, by
this route we were able to synthesize “19ꢀoxoꢀcarlactone” 30 that has been hypothesized to be an
intermediate in strigolactone biosynthesis but until now could not be synthesized successfully.10 Our
second option of inverting the Stilleꢀcoupling and the oxidation steps finally proved to be successful.
Aldehyde 29 could be oxidized to acid 31 in excellent yield using tertꢀbutyl hydroperoxide in the
presence of a catalytic amount of CuBr2. No racemization of the C11ꢀstereocenter was observed when
optically pure aldehydes (R)ꢀ29 and (S)ꢀ29 were submitted to these conditions. To our delight, Stilleꢀ
coupling of the free carboxylic acid 31 with an excess of five equivalents of stannane 10 furnished
carlactonic acid (3) in 51% yield. A lower amount of stannane 10 led to an increased protiodeiodination
of vinyl iodide 30 and a lower yield of desired crossꢀcoupling product 3. Optically pure acids (R)ꢀ31 and
(S)ꢀ31, obtained from oxidation of (R)ꢀ29 and (S)ꢀ29, applied within this crossꢀcoupling, gave (R)ꢀ and
(S)ꢀcarlactonic acid as stereochemically pure samples. This protectingꢀgroupꢀfree route circumvents the
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stability issues that we faced under a variety of tested deprotection conditions and gave access to
carlactonic acid (3) in four linear steps with an overall yield of 36%. Carlactonic acid (3) shows an
increased stability compared to methyl carlactonoate (2) and could be stored at ꢀ80 °C under argon for
month without any significant decomposition.
1
2
3
4
5
6
7
8
9
Scheme 11: Synthesis of carlactonic acid (3) and 19ꢀoxoꢀcarlactone (30).
10
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Pd2dba3 (7.5 mol%)
AsPh3 (30 mol%)
CuBr2 (5 mol%)
TBHP (10 eq)
CH3CN, 0°C, 60min
dioxane, 90°C, 45min
traces
of 3
18%
30
"19-oxo-CL"
10 (2.5 eq)
29
Pd2dba3 (7.5 mol%)
CuBr2 (5 mol%)
AsPh3 (30 mol%)
TBHP (5 eq)
CH3CN, rt, 18h
10 (5 eq), dioxane
90°C, 45min
95%
51%
11
3
31
4 steps (36% overall)
In summary, we have developed a synthetic access to natural products methyl carlactonoate, carlactonic
acid and hypothesized 19ꢀoxoꢀcarlactone that should also be applicable to a broad variety of natural and
nonꢀnatural nonꢀcanonical strigolactones. Furthermore, vinyl iodides as keyꢀintermediates have been
identified, allowing for the control of the C11ꢀstereochemistry and two complementary approaches were
found to introduce a deuteriumꢀlabel. Key features of this synthetic strategy are a diastereoselective
Michaelꢀadditionꢀiodination sequence and
a
Stille crossꢀcoupling furnishing nonꢀcanonical
strigolactones in a rapid and highly versatile fashion. These findings provide valuable tools for further
biological investigations of strigolactones and may stimulate related syntheses of naturalꢀ as well as nonꢀ
natural related bioactive compounds.
Experimental Section.
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The Journal of Organic Chemistry
General Experimental Procedures
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9
All chemicals and solvents were purchased from common suppliers and used as received.
Chromatographic purifications were done on Rfꢀmachine CombiFlash Rf 200i Teledyne ISCO equipped
with standard silica columns or via flash column chromatography over silica gel (silica gel 60, 0.040ꢀ
0.063 mm). Thin layer chromatography was performed on precoated TLC glass plates SIL Gꢀ25 with
fluorescence indicator UV254. Staining agents were either KMnO4 (40 g of K2CO3 + 6g of KMnO4 in
10
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.
600 mL of water, then 5 mL of 10% NaOH added) or CAM (2 g Ce(SO4)2 + 60 g (NH4)6Mo7O24 4H2O
in 360 mL of water, then 40 mL of H2SO4 conc. added) and subsequent heating of TLC plates treated
with these staining solutions. 1H and 13C NMR spectra were recorder on Brucker spectrometer operating
at 400 MHz and 100 MHz respectively unless otherwise stated. Chemical shifts are given in ppm.
Tetramethyl silane was used as external reference. Following abbreviations describe the multiplets: s ꢀ
singlet, d ꢀ doublet, tꢀ triplet, q ꢀquadruplet, m –multiplet, virt. ꢀ virtuell. Mass spectra were recorded on
a High Resolution Mass Spectrometer (QꢀExactive, Orbitrap analyzer) from Thermofischer equipped
with an electrospray source, (Polarity: positive mode, Capillary: 3.8 kV, Capillary temperature: 320°C,
Sꢀlens RF level: 55, Sheath gas flow rate: 40, Mass range: 100 to 1000 m/z) coupled to a 1200 Infinity
series UPLC from Agilent: Solvent degasser, binary pump, heated column compartment and diodeꢀarray
detector (DAD). DAD Wavelength range (nm): 190 to 400. Column: Waters Acquity UPLC BEH C18,
1.7 µm, 50 x 2.1 mm, Temp: 60 °C. Solvent Gradient: A = water + 5% MeOH + 0.05 % HCOOH, B=
Acetonitrile + 0.05 % HCOOH. Infrared spectra were recorded on a Perkin Elmer UATR two FIꢀTR
spectrometer. Melting points were measured on a Büchi Melting Point Bꢀ540 apparatus. Circular
dichroism spectra were recorded on a Jasco Jꢀ815 apparatus.
rac-Methyl (E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate (13): To a solution of 2ꢀ
hydroxyꢀ4ꢀmethylꢀ2Hꢀfuranꢀ5ꢀone (12) (5.50 g, 48.0 mmol, 2.0 equiv.) in THF (50 mL) was added
subsequently methyl propꢀ2ꢀynoate (11) (2.00 mL, 24.0 mmol, 1.0 equiv.) and 4ꢀmethylmorpholine
(1.90 g, 19.0 mmol, 0.8 equiv.) at 0 °C. The clear orange solution was allowed to warm to ambient
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temperature and was stirred for 18 h. An aqueous saturated solution of NH4Cl (100 mL) was added, the
mixture was extracted with diethyl ether (3 x 100 mL), combined organic layers were dried over MgSO4
and concentrated in vacuo. Purification by flash column chromatography (SiO2, cyclohexane/ ethyl
acetate = 2/1) gave the title compound as white solid (3.64 g, 18.4 mmol, 77%). Rf = 0.30 (cyclohexane/
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3
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5
6
7
8
9
1
ethyl acetate = 2/1); mp = 67ꢀ69 °C; H NMR (400 MHz, CDCl3) δ ppm 7.47 ꢀ 7.63 (m, 1 H), 7.55 (d,
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J=12.5 Hz, 1 H), 6.87 ꢀ 6.95 (m, 1 H), 6.04 ꢀ 6.14 (m, 1 H), 5.48 ꢀ 5.62 (m, 1 H), 3.66 ꢀ 3.75 (m, 3 H),
1.98 ꢀ 2.04 (m, 3 H); 13C NMR (101 MHz, CDCl3) δ ppm 170.4, 166.9, 157.7, 141.0, 135.4, 102.2, 99.2,
51.4, 10.6; HRMS: calc. for C9H11O5 [M+H]+: 199.0600, found: 199.0603; IR (cmꢀ1): 1778, 1712, 1651,
1631, 1437, 1367, 1326, 1289, 1171, 1131, 1095, 999, 952, 861, 846.
rac-/ (R)-/ (S)- Methyl (Z)-2-iodo-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate (9): To a
solution of 13 (1.00 g, 5.05 mmol, 1.00 equiv.) obtained from above in dichloromethane (10 mL) was
added Nꢀiodosuccinimide (1.59 g, 6.86 mmol, 1.36 equiv.) and glacial acetic acid (520 ꢀL, 9.08 mmol,
1.80 equiv.) subsequently at room temperature. The red suspension was stirred for 8 h, afterwards
further Nꢀiodosuccinimide (0.80 g, 3.43 mmol, 0.68 equiv.) and glacial acetic acid (260 ꢀL, 4.54 mmol,
0.90 equiv.) was added and the mixture was further stirred for 18 h until no starting material could be
detected anymore by NMRꢀanalysis. Triethylamine (2.28 mL, 16.3 mmol, 3.24 equiv.) was added and
the dark solution was stirred for 6 h. An aqueous saturated solution of NH4Cl (30 mL) and
dichloromethane (20 mL) was added, the mixture was extracted with dichloromethane (3 x 30 mL),
combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash
column chromatography (SiO2, cyclohexane/ ethyl acetate = 2/1) gave the title compound 9a/b as white
1
solid (1.41 g, 4.35 mmol, 86%). Rf = 0.30 (cyclohexane/ ethyl acetate = 2/1); mp = 126ꢀ128 °C; H
NMR (400 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.00 (s, 1 H), 6.26 (s, 1 H), 3.83 (s, 3 H), 2.05 (s, 3 H);
13C NMR (101 MHz, CDCl3) δ ppm 170.1, 163.6, 158.2, 141.0, 135.9, 100.0, 70.5, 53.3, 10.8; HRMS:
calc. for C9H10IO5 [M+H]+: 324.9567, found: 324.9567; IR (cmꢀ1): 1783, 1718, 1624, 1434, 1364, 1267,
1175, 1074, 1000, 955, 753. Xꢀray analysis was performed for racemic racꢀ9. Separation of enantiomers
(R)ꢀ9 and (S)ꢀ9 via chiral HPLC: Daicel CHIRALPAK ® IF, Hept/EtOH = 70/30; Rꢀstereoisomer (R)ꢀ9:
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Rt = 5.32 min; [α] 20 = +69.1° (c = 1.28, CHCl3, 20 °C), stereochemical assignment: CDꢀanalysis and
D
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3
Orobanche cumana germination assay; Sꢀstereoisomer (S)ꢀ9: Rt = 8.61 min; [α] 20 = −74.5° (c = 1.07,
D
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CHCl3, 20 °C), stereochemical assignment: CDꢀanalysis and Orobanche cumana germination assay. For
7
8
further details see supporting information.
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Methyl-(Z)-2-bromo-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate (16): To a solution of 13
(100 mg, 505 ꢀmol, 1.00 equiv.) in dichloromethane (2.5 mL) was added Nꢀbromosuccinimide (122 mg,
686 ꢀmol, 1.36 equiv.) and glacial acetic acid (52.0 ꢀL, 908 ꢀmol, 1.80 equiv.) subsequently at room
temperature. The colorless suspension was stirred for 24 h, afterwards further Nꢀbromosuccinimide (122
mg, 686 ꢀmol, 1.36 equiv.) and glacial acetic acid (52.0 ꢀL, 908 ꢀmol, 1.80 equiv.) subsequently were
added at room temperature. The colorless suspension was stirred 24 h until no starting material could be
detected anymore by NMRꢀanalysis. Triethylamine (228 ꢀL, 1.64 mmol, 3.24 equiv.) was added and the
solution was stirred for 6 h. An aqueous saturated solution of NH4Cl (7 mL) and dichloromethane (10
mL) was added, the mixture was extracted with dichloromethane (3 x 10 mL), combined organic layers
were dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2,
cyclohexane/ ethyl acetate = 2/1) gave the title compound as yellowish solid (48.0 mg, 173 ꢀmol, 34%).
Rf = 0.24 (cyclohexane/ ethyl acetate = 2/1); mp = 104ꢀ106 °C; 1H NMR (400 MHz, CDCl3) δ ppm 8.06
13
(s, 1 H), 7.03 (s, 1 H), 6.25 (s, 1 H), 3.85 (s, 3 H), 2.06 (s, 3 H); C NMR (101 MHz, CDCl3) δ ppm
170.0, 163.0, 153.3, 140.9, 135.9, 100.1, 53.0, 26.9, 10.7; HRMS: calc. for C9H1079BrO5 [M+H]+:
276.9706, found: 276.9709; IR (cmꢀ1): 1784, 1723, 1638, 1437, 1365, 1278, 1178, 1081, 1051, 1001,
957, 754.
Tributyl-[(E)-2-(2,6,6-trimethylcyclohexen-1-yl)vinyl]stannane (10): In a 10 mL microwave tube
was added 2ꢀethynylꢀ1,3,3ꢀtrimethylꢀcyclohexene (15)14 (593 mg, 4.00 mmol, 1.0 equiv.), tributyl
stannane (1.06 mL, 4.00 mmol, 1.0 equiv.) and AIBN (67.0 mg, 400 ꢀmol, 0.1 equiv.) under argon. The
vial was sealed and the mixture was stirred and heated to 80 °C for 24 h. The solution was allowed to
cool to rt and was filtered over Celite (wash with cyclohexane, 15 mL). The solvent was removed in
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vacuo to give the title compound 1.80 g, 4.00 mmol, 99%) as colorless oil. 1H NMR (400 MHz, CD2Cl2)
δ ppm 6.36 (d, J = 19.4 Hz, 1 H), 5.87 (d, J = 19.4 Hz, 1 H), 1.97 (virt. t, J = 6.2 Hz, 2 H), 1.67 (d, J =
0.7 Hz, 3 H), 1.62ꢀ1.57 (m, 2 H), 1.56ꢀ1.50 (m, 6 H), 1.45ꢀ1.42 (m, 2 H), 1.32 (sext., J = 7.3 Hz, 6 H),
1.00 (s, 6 H), 0.93ꢀ0.88 (m, 6 H), 0.89 (t, J = 7.3 Hz, 9 H); 13C NMR (101 MHz, CD2Cl2) δ ppm 146.5,
141.9, 132.9, 127.9, 40.0, 34.2, 33.1, 29.8, 29.1, 27.8, 21.9, 19.9, 14.1, 10.1; IR (cmꢀ1): 2956, 2924,
2870, 2853, 1457, 991, 689, 664, 592, 504.
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rac-/
(R)-/
(S)-Methyl
(E,2E)-2-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-4-(2,6,6-
trimethylcyclohexen-1-yl)but-3-enoate (2, methyl carlactonoate, Me-CLA): To a solution of vinyl
iodide rac-9 (20.0 mg, 61.7 ꢀmol, 1.00 equiv.) and triphenylarsane (5.7 mg, 18.5 ꢀmol, 0.30 equiv.) in
dioxane (620 ꢀL) was added vinylstannane 10 (67.8 mg, 154 ꢀmol, 2.50 equiv.) under argon
atmosphere. The solution was degassed by bubbling argon through the solution for 10 min. Pd2dba3 (4.2
mg, 4.63 ꢀmol, 0.075 equiv.) was added, the reaction vial was sealed and heated to 90 °C for 45 min.
The clear yellow mixture was allowed to cool to rt and was filtered over Celite (wash with CyH/EtOAc
= 2/1, 20 mL). The solvent was removed in vacuo and the crude was purified by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 4/1). The title compound (MeꢀCLA) was obtained
as colorless oil (16.0 mg, 46.2 ꢀmol, 75%). Performing this procedure using enantiomerically pure
vinyliodides (R)ꢀ9 / (S)ꢀ9 obtained as described above delivered (R)ꢀMeꢀCLA ((R)ꢀ2) and (S)ꢀMeꢀCLA
1
((S)ꢀ2) in similar yields. Rf = 0.29 (cyclohexane/ ethyl acetate = 2/1); H NMR (400 MHz, CD2Cl2) δ
ppm 7.51 (s, 1 H), 6.98 ꢀ 6.96 (m, 1 H), 6.79 (d, J = 16.5 Hz, 1 H), 6.17 – 6.15 (m, 1 H), 6.08 (d, J =
16.5 Hz, 1 H), 3.73 (s, 3 H), 2.00 (virt. t, J = 6.2 Hz, 2 H), 1.98 (t, J = 1.5 Hz, 3 H), 1.69 (d, J = 0.7 Hz,
3 H), 1.62 – 1.57 (m, 2 H), 1.46 – 1.43 (m, 2 H), 0.99 (s, 6 H); 13C NMR (101 MHz, CD2Cl2) δ ppm
171.1, 167.5, 151.9, 141.9, 138.8, 135.9, 133.0, 129.7, 122.3, 113.4, 101.1, 52.0, 40.1, 34.6, 33.4, 29.2,
29.1, 21.9, 19.8, 11.0; HRMS: calc. for C20H27O5 [M+H]+: 347.1853, found: 347.1854; IR (cmꢀ1): 2930,
2869, 1769, 1603, 1438, 1345, 1249, 1206, 1091, 1010, 951, 864, 768, 746; [α] 20 ((R)ꢀMeꢀCLA, (R)ꢀ2)
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= +9.9° (c = 0.53, CH2Cl2, 20 °C), [α] 20 ((S)ꢀMeꢀCLA, (S)ꢀ2) = −30.4° (c = 0.57, CH2Cl2, 20 °C); see
D
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also supporting information.
4
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Methyl 3-deuterioprop-2-ynoate (19)15: In a round bottom flask K2CO3 (59.5 mg, 431 ꢀmol, 0.018
7
8
9
equiv.) and tetrabutylammonium iodide (106 mg, 431 ꢀmol, 0.012 equiv.) were placed as solids.
Dichloromethane (dry, 5.00 mL), deuterium oxide (5.00 mL) and methyl propꢀ2ꢀynoate (11) (2.00 mL,
23.9 mmol, 1.00 equiv.) were added subsequently and the clear yellowish suspension was stirred for
18 h at rt. The layers were separated, the aqueous layer was extracted with DCM (2 x 5.00 mL),
combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. 2nd cycle: The
obtained yellowish oil was dissolved in DCM (dry, 5.00 mL), deuterium oxide (5.00 mL), K2CO3 (59.5
mg) and tetrabutylammonium iodide (106 mg) were added and the mixture was stirred at rt for 5 h. The
layers were separated, the aqueous layer was extracted with DCM (2 x 5.00 mL), combined organic
layers were dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a
10
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yellowish oil (97.5% deuteration, 950 mg, 11.2 mmol, 47%). H NMR (400 MHz, CDCl3) δ ppm 3.81
(s, 3 H).
2-Deuteriooxy-4-methyl-2H-furan-5-one (20): In a round bottom flask K2CO3 (55.0 mg, 390 ꢀmol,
0.018 equiv.) and tetrabutylammonium iodide (97.0 mg, 260 ꢀmol, 0.012 equiv.) were placed as solids.
Dichloromethane (dry, 5.00 mL), deuterium oxide (5.00 mL) and 2ꢀhydroxyꢀ4ꢀmethylꢀ2Hꢀfuranꢀ5ꢀone
(2.50 g, 22.0 mmol, 1.00 equiv.) were added subsequently and the clear yellow suspension was stirred
for 48 h at rt. The layers were separated, the aqueous layer was extracted with DCM (2 x 5.00 mL),
combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. 2nd cycle: The
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obtained yellow solid (35% deuteration as judged by HꢀNMR) was dissolved in DCM (dry, 5.00 mL),
deuterium oxide (5.00 mL), K2CO3 (55.0 mg) and tetrabutylammonium iodide (97.0 mg) were added
and the mixture was stirred at rt for 48 h. The layers were separated, the aqueous layer was extracted
with DCM (2 x 5.00 mL), combined organic layers were dried over MgSO4, filtered and concentrated in
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vacuo to give the title compound as a yellow solid (50% deuteration, 400 mg, 3.49 mmol, 16%). H
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NMR (400 MHz, DMSOꢀd6) δ ppm 7.68 (broad s, 0.50 H), 7.06 (s, 1 H), 6.15 (s, 1 H), 1.81 (s, 3 H);
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HRMS: calc. for C5 HH6O3 [M+H]+: 116.0452, found: 116.0453.
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Methyl (E)-3-deuterio-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate (21): To a solution of
2ꢀdeuteriooxyꢀ4ꢀmethylꢀ2Hꢀfuranꢀ5ꢀone (20) (50.0 mg, 434 ꢀmol, 1.0 equiv.) in THF (1.00 mL) was
added methyl 3ꢀdeuteriopropꢀ2ꢀynoate (19) (148 mg, 1.73 mmol, 4.0 equiv.) and 4ꢀmethylmorpholine
(35.0 mg, 347 ꢀmol, 0.8 equiv.) subsequently at 0 °C. The clear orange solution was allowed to warm to
ambient temperature and was stirred for 24 h. An aqueous saturated solution of NH4Cl (5.0 mL) was
added, the mixture was extracted with diethyl ether (3 x 7.0 mL), combined organic layers were dried
over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2,
cyclohexane/ ethyl acetate = 2/1) gave the title compound as yellow oil (54.0 mg, 270 ꢀmol, 62%). 92%
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βꢀdeuteration, accompanied by 78% αꢀdeuteration was obtained as judged by HꢀNMR. Rf = 0.30
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(cyclohexane/ ethyl acetate = 2/1); H NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 0.08 H), 6.93 (s, 1 H),
6.11 (s, 1 H), 5.88 (s, 0.15 H), 3.74 (s, 3 H), 2.02 (s, 3 H); HRMS: calc. for C9 H2H9O5 [M+H]+:
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201.0726, found: 201.0727.
Methyl (Z)-3-deuterio-2-iodo-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate (22): To a
solution of 21 (100 mg, 500 ꢀmol, 1.00 equiv.) obtained from above in dichloromethane (5.00 mL) was
added Nꢀiodosuccinimide (158 mg, 679 ꢀmol, 1.36 equiv.) and glacial acetic acid (51.0 ꢀL, 899 ꢀmol,
1.80 equiv.) subsequently at room temperature. The red suspension was stirred for 18 h, afterwards
further Nꢀiodosuccinimide (79.0 mg, 340 ꢀmol, 0.68 equiv.) and glacial acetic acid (25.0 ꢀL, 450 ꢀmol,
0.90 equiv.) was added and the mixture was further stirred for 6 h until no starting material could be
detected anymore by NMRꢀanalysis. Triethylamine (226 ꢀL, 1.62 mmol, 3.24 equiv.) was added and the
dark solution was stirred for 14 h. An aqueous saturated solution of NH4Cl (7.0 mL) and
dichloromethane (7.0 mL) was added, the mixture was extracted with dichloromethane (2 x 10 mL),
combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash
column chromatography (SiO2, cyclohexane/ ethyl acetate = 2/1) gave the title compound as white solid
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(82.6 mg, 255 ꢀmol, 51%). 91% deuteration was obtained as judged by HꢀNMR. Rf = 0.30
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(cyclohexane/ ethyl acetate = 2/1); H NMR (400 MHz, CD2Cl2) δ ppm 7.93 (s, 0.09 H), 7.01 (s, 1 H),
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6.27 (s, 1 H), 3.78 (s, 3 H), 2.00 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ ppm 170.1, 163.6, 158.2,
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141.0, 135.9, 100.0, 70.3, 53.3, 10.8; HRMS: calc. for C9 HH9IO5 [M+H]+: 325.9630, found: 325.9629.
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rac-Methyl
(E,2E)-2-[deuterio-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]methylene]-4-(2,6,6-
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trimethylcyclohexen-1-yl)but-3-enoate (18, deutero-Me-CLA): To a solution of deutero vinyl iodide
22 (30.0 mg, 92.3 ꢀmol, 1.00 equiv.) and triphenylarsane (11.3 mg, 36.9 ꢀmol, 0.40 equiv.) in dioxane
(400 ꢀL) was added vinylstannane 10 (122 mg, 277 ꢀmol, 3.00 equiv.) under argon atmosphere. The
solution was degassed by bubbling argon through the solution for 10 min. Pd2dba3 (8.50 mg, 9.23 ꢀmol,
0.10 equiv.) was added, the reaction vial was sealed and heated to 100 °C for 45 min. The clear yellow
mixture was allowed to cool to rt and was filtered over Celite (wash with cyclohexane/ ethyl acetate =
2/1, 10 mL). The solvent was removed in vacuo and the crude was purified by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 4/1). The title compound (deuteronꢀMeꢀCLA) was
obtained as colorless oil (14.0 mg, 40.3 ꢀmol, 44%, 91% deuteration as judged by 1HꢀNMR). Rf = 0.29
(CyH/EA = 2/1); 1H NMR (400 MHz, CD2Cl2) δ ppm 7.51 (s, 0.09 H), 6.97 ꢀ 6.95 (m, 1 H), 6.79 (d, J =
16.9 Hz, 1 H), 6.17 – 6.15 (m, 1 H), 6.08 (d, J = 16.9 Hz, 1 H), 3.73 (s, 3 H), 2.00 (virt. t, J = 5.9 Hz, 2
H), 1.99ꢀ1.97 (m, 3 H), 1.69 (d, J = 0.7 Hz, 3 H), 1.62 – 1.58 (m, 2 H), 1.47 – 1.43 (m, 2 H), 0.99 (s, 6
2
H); HRMS: calc. for C20 HH26O5 [M+H]+: 348.1916, found: 348.1914.
Tributyl-[(E)-2-deuterio-2-(2,6,6-trimethylcyclohexen-1-yl)vinyl]stannane (23): In a 10 mL
microwave tube was added 2ꢀethynylꢀ1,3,3ꢀtrimethylꢀcyclohexene (15)14 (222 mg, 1.50 mmol, 1.0
equiv.), tributyl(deuterio)stannane (400 ꢀL, 1.50 mmol, 1.0 equiv.) and AIBN (25.1 mg, 150 ꢀmol, 0.1
equiv.) under argon. The vial was sealed and the mixture was stirred and heated to 80 °C for 22 h. The
solution was allowed to cool to rt and was filtered over Celite (wash with cyclohexane, 15 mL). The
solvent was removed in vacuo to give the title compound 660 mg, 1.50 mmol, 99%, deuteration >99%
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as judged by 1HꢀNMR) as colorless oil. H NMR (400 MHz, CDCl3) δ ppm 6.13 (s, 1 H), 1.94 (virt. t, J
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= 6.2 Hz, 2 H), 1.62 (s, 3 H), 1.52ꢀ1.49 (m, 2 H), 1.49ꢀ1.43 (m, 6 H), 1.36ꢀ1.31 (m, 2 H), 1.31 (sext., J
= 7.7 Hz, 6 H), 0.98 (s, 6 H), 0.93ꢀ0.88 (m, 6 H), 0.89 (t, J = 7.3 Hz, 9 H); HRMS: calc. for
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C23 HH44120Sn [M+H]+: 442.2600, mass not found.
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rac-Methyl
(E,2E)-4-deuterio-2-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-4-(2,6,6-
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trimethylcyclohexen-1-yl)but-3-enoate (17, deutero-Me-CLA): To a solution of vinyl iodide rac-9
(45.0 mg, 139 ꢀmol, 1.00 equiv.) and triphenylarsane (17.0 mg, 55.5 ꢀmol, 0.40 equiv.) in dioxane (1.50
mL) was added deuteroꢀvinylstannane 23 (183 mg, 417 ꢀmol, 3.00 equiv.) under argon atmosphere. The
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solution was degassed by bubbling argon through the solution for 10 min. Pd2dba3 (12.7 mg, 13.9 ꢀmol,
0.10 equiv.) was added, the reaction vial was sealed and heated to 100 °C for 60 min. The clear yellow
mixture was allowed to cool to rt and was filtered over Celite (wash with cyclohexane/ ethyl acetate =
2/1, 20 mL). The solvent was removed in vacuo and the crude was purified by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 4/1). The title compound (deuteroꢀMeꢀCLA) was
obtained as colorless oil (11.0 mg, 31.7 ꢀmol, 23%, >99% deuteration as judged by 1HꢀNMR). Rf = 0.29
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(cyclohexane/ ethyl acetate = 2/1); H NMR (400 MHz, CD2Cl2) δ ppm 7.51 (s, 1 H), 6.97 ꢀ 6.96 (m, 1
H), 6.17 – 6.15 (m, 1 H), 6.08 (bs, 1 H), 3.73 (s, 3 H), 2.00 (virt. t, J = 6.2 Hz, 2 H), 1.98 (t, J = 1.5 Hz,
3 H), 1.70 (s, 3 H), 1.62 – 1.58 (m, 2 H), 1.47 – 1.44 (m, 2 H), 0.99 (s, 6 H); HRMS: calc. for
2
C20 HH26O5 [M+H]+: 348.1916, found: 348.1919.
rac-Benzyl (E,2E)-2-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-4-(2,6,6-trimethylcyclohexen-
1-yl)but-3-enoate (24, benzyl carlactonate, Bn-CLA): To a solution of 2ꢀhydroxyꢀ4ꢀmethylꢀ2Hꢀfuranꢀ
5ꢀone (12) (2.07 g, 18.1 mmol, 2.0 equiv.) in THF (20.0 mL) was added subsequently benzyl propꢀ2ꢀ
ynoate (1.45 g, 9.05 mmol, 1.0 equiv.) and 4ꢀmethylmorpholine (733 mg, 7.24 mmol, 0.8 equiv.) at 0
°C. The clear yellowish solution was allowed to warm to ambient temperature and was stirred for 24 h.
An aqueous saturated solution of NH4Cl (25 mL) and dichloromethane (20 mL) was added. After
separation the aqueous layer was extracted with dichloromethane (3 x 30 mL), combined organic layers
were dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2,
cyclohexane/ ethyl acetate = 2/1) gave the Michael addition product as colorless oil (Rf = 0.25
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(cyclohexane/ ethyl acetate = 2/1), 1.80 g, 6.56 mmol). The obtained compound (1.80 g, 6.56 mmol, 1.0
equiv.) was dissolved in dichloromethane (30.0 mL), Nꢀiodosuccinimide (2.07 g, 8.93 mmol, 1.36
equiv.) and glacial acetic acid (676 ꢀL, 11.8 mmol, 1.80 equiv.) were added subsequently at room
temperature. The red suspension was stirred for 8 h, afterwards further Nꢀiodosuccinimide (1.04 g, 4.47
mmol, 0.68 equiv.) and glacial acetic acid (338 ꢀL, 5.90 mmol, 0.90 equiv.) was added and the mixture
was further stirred for 18 h until no starting material could be detected anymore by NMRꢀanalysis.
Triethylamine (2.96 mL, 21.3 mmol, 3.24 equiv.) was added and the dark solution was stirred for 6 h.
An aqueous saturated solution of NH4Cl (30 mL) and dichloromethane (20 mL) was added, layers were
separated, the aqueous layer was extracted with dichloromethane (3 x 30 mL), combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 4/1 to 2/1) gave the respective vinyl iodide
compound as yellowish solid (1.71 g, 4.27 mmol, 47%). Rf = 0.33 (cyclohexane/ ethyl acetate = 2/1); mp
= 85ꢀ87 °C; 1H NMR (400 MHz, CDCl3) δ ppm 7.97 (s, 1 H), 7.37 ꢀ 7.44 (m, 5 H), 6.95 ꢀ 7.04 (m, 1 H),
6.21 ꢀ 6.27 (m, 1 H), 5.27 (d, J = 15.0 Hz, 1 H), 5.23 (d, J = 15.0 Hz, 1 H), 2.01 ꢀ 2.06 (m, 3 H); 13C
NMR (101 MHz, CDCl3) δ ppm 170.0, 163.0, 158.5, 140.9, 135.9, 135.4, 128.6, 128.4, 128.2, 100.0,
70.9, 68.0, 10.7; HRMS: calc. for C15H14IO5 [M+H]+: 400.9881, found: 400.9880; IR (cmꢀ1): 1783,
1711, 1624, 1374, 1361, 1259, 1172, 1040, 1000, 954, 750. To a solution of vinyl iodide obtained from
above (200 mg, 500 ꢀmol, 1.00 equiv.) and triphenylarsane (45.9 mg, 150 ꢀmol, 0.30 equiv.) in dioxane
(5.00 mL) was added vinylstannane 10 (549 mg, 1.25 mmol, 2.50 equiv.) under argon atmosphere. The
solution was degassed by bubbling argon through the solution for 10 min. Pd2dba3 (34.3 mg, 37.5 ꢀmol,
0.075 equiv.) was added, the reaction vial was sealed and heated to 90 °C for 50 min. The clear yellow
mixture was allowed to cool to rt and was filtered over Celite (wash with cyclohexane/ ethyl acetate =
2/1, 20 mL). The solvent was removed in vacuo and the crude was purified by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 4/1). The title compound 24 (BnꢀCLA) was
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obtained as colorless oil (93.0 mg, 220 ꢀmol, 44%). Rf = 0.46 (cyclohexane/ ethyl acetate = 2/1); H
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NMR (400 MHz, CD2Cl2) δ ppm 7.55 (s, 1 H), 7.40 – 7.32 (m, 5 H), 6.96 ꢀ 6.94 (m, 1 H), 6.78 (d, J =
16.5 Hz, 1 H), 6.16 – 6.15 (m, 1 H), 6.09 (d, J = 16.5 Hz, 1 H), 5.21 (d, J = 14.7 Hz, 1 H), 5.18 (d, J =
16.5 Hz, 1 H), 1.99 (virt. t, J = 6.2 Hz, 2 H), 1.97 (t, J = 1.5 Hz, 3 H), 1.68 (s, 3 H), 1.63 – 1.56 (m, 2
H), 1.46 – 1.42 (m, 2 H), 0.97 (s, 6 H); 13C NMR (101 MHz, CD2Cl2) δ ppm 171.1, 166.9, 152.3, 141.9,
138.8, 136.9, 135.9, 133.1, 129.7, 129.1, 128.7, 122.3, 113.5, 101.2, 67.6, 66.7, 40.1, 34.6, 33.4, 29.1,
29.1, 21.9, 19.8, 11.0; HRMS: calc. for C26H31O5 [M+H]+: 423.2166, found: 423.2165; IR (cmꢀ1): 2957,
2928, 2866, 1784, 1713, 1456, 1351, 1249, 1186, 1112, 1015, 952, 864, 753.
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rac-2,2,2-trichloroethyl
(E,2E)-2-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-4-(2,6,6-
trimethylcyclohexen-1-yl)but-3-enoate (25, trichloroethyl carlactonoate, TCE-CLA): To a solution
of 2ꢀhydroxyꢀ4ꢀmethylꢀ2Hꢀfuranꢀ5ꢀone (12) (170 mg, 1.49 mmol, 2.0 equiv.) in THF (2.00 mL) was
added subsequently 2,2,2ꢀtrichloroethyl propꢀ2ꢀynoate (11) (150 mg, 745 ꢀmol, 1.0 equiv.) and 4ꢀ
methylmorpholine (66.0 ꢀL, 596 ꢀmol, 0.8 equiv.) at 0 °C. The clear yellowish solution was allowed to
warm to ambient temperature and was stirred for 18 h. An aqueous saturated solution of NH4Cl (25 mL)
and dichloromethane (20 mL) was added. After separation the aqueous layer was extracted with
dichloromethane (3 x 30 mL), combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by flash column chromatography (SiO2, cyclohexane/ ethyl acetate = 2/1) gave the
Michael addition product as colorless oil (Rf = 0.31 (cyclohexane/ ethyl acetate = 2/1), 96.0 mg, 304
ꢀmol). The obtained compound (96.0 mg, 304 ꢀmol, 1.0 equiv.) was dissolved in dichloromethane (2.90
mL), Nꢀiodosuccinimide (90.0 mg, 388 ꢀmol, 1.36 equiv.) and glacial acetic acid (29.4 ꢀL, 514 ꢀmol,
1.80 equiv.) were added subsequently at room temperature. The red suspension was stirred for 8 h,
afterwards further Nꢀiodosuccinimide (90.0 mg, 388 ꢀmol, 1.36 equiv.) and glacial acetic acid (29.4 ꢀL,
514 ꢀmol, 1.80 equiv.) was added and the mixture was further stirred for 18 h until no starting material
could be detected anymore by NMRꢀanalysis. Triethylamine (129 ꢀL, 924 ꢀmol, 3.24 equiv.) was added
and the dark solution was stirred for 6 h. An aqueous saturated solution of NH4Cl (30 mL) and
dichloromethane (20 mL) was added, layers were separated, the aqueous layer was extracted with
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dichloromethane (3 x 30 mL), combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. Purification by flash column chromatography (SiO2, cyclohexane/ ethyl acetate
= 4/1 to 2/1) gave the respective vinyl iodide as yellow oil (45.0 mg, 102 ꢀmol, 14%). Rf = 0.41
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(cyclohexane/ ethyl acetate = 2/1); H NMR (400 MHz, CDCl3) δ ppm 8.07 (s, 1 H), 7.04 ꢀ 7.02 (m, 1
9
H), 6.31 – 6.30 (m, 1 H), 4.88 (d, J = 11.7 Hz, 1 H), 4.83 (d, J = 11.7 Hz, 1 H), 2.06 (virt. t, J = 1.5 Hz,
3 H); 13C NMR (101 MHz, CDCl3) δ ppm 169.9, 161.6, 159.7, 140.8, 136.1, 100.1, 94.7, 75.3, 68.9,
10.8; HRMS: calc. for C10H9Cl3IO5 [M+H]+: 440.8555, found: 440.8553; IR (cmꢀ1): 1787, 1731, 1621,
1370, 1246, 1175, 1094, 1043, 1007, 956, 744, 712. To a solution of vinyl iodide obtained from above
(25.0 mg, 56.6 ꢀmol, 1.00 equiv.) and triphenylarsane (5.2 mg, 17.0 ꢀmol, 0.30 equiv.) in dioxane (1.00
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mL) was added vinylstannane 10 (74.6 mg, 170 ꢀmol, 2.50 equiv.) under argon atmosphere. The
solution was degassed by bubbling argon through the solution for 10 min. Pd2dba3 (3.9 mg, 4.25 ꢀmol,
0.075 equiv.) was added, the reaction vial was sealed and heated to 90 °C for 30 min. The clear yellow
mixture was allowed to cool to rt and was filtered over Celite (wash with cyclohexane/ ethyl acetate =
2/1, 15 mL). The solvent was removed in vacuo and the crude was purified by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 4/1). The title compound 25 (TCEꢀCLA) was
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obtained as colorless oil (15.0 mg, 32.3 ꢀmol, 57%). Rf = 0.37 (cyclohexane/ ethyl acetate = 4/1); H
NMR (400 MHz, CD2Cl2) δ ppm 7.65 (s, 1 H), 6.99 ꢀ 6.97 (m, 1 H), 6.84 (d, J = 16.5 Hz, 1 H), 6.22 –
6.21 (m, 1 H), 6.12 (d, J = 16.5 Hz, 1 H), 4.87 (d, J = 11.7 Hz, 1 H), 4.83 (d, J = 16.5 Hz, 1 H), 2.01
(virt. t, J = 6.5 Hz, 2 H), 1.99 (t, J = 1.5 Hz, 3 H), 1.71 (s, 3 H), 1.64 – 1.58 (m, 2 H), 1.48 – 1.45 (m, 2
H), 1.01 (s, 6 H); 13C NMR (101 MHz, CD2Cl2) δ ppm 170.7, 165.5, 153.2, 141.8, 136.2, 133.7, 130.0,
121.7, 112.5, 101.2, 95.9, 74.6, 40.1, 34.6, 33.5, 29.2, 27.5, 21.9, 19.8, 11.0; HRMS: calc. for
C21H26Cl3O5 [M+H]+: 463.0840, found: 463.0842; IR (cmꢀ1): 2957, 2929, 2867, 1787, 1728, 1606,
1449, 1371, 1241, 1190, 1107, 1048, 1014, 954, 716.
rac-tert-Butyl
(E,2E)-2-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-4-(2,6,6-
trimethylcyclohexen-1-yl)but-3-enoate (26, tert-butyl carlactonate, tBu-CLA): To a solution of 2ꢀ
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hydroxyꢀ4ꢀmethylꢀ2Hꢀfuranꢀ5ꢀone (12) (317 mg, 2.78 mmol, 2.0 equiv.) in THF (2.8 mL) was added
subsequently tert-butyl propꢀ2ꢀynoate (11) (176 mg, 1.39 mmol, 1.0 equiv.) and 4ꢀmethylmorpholine
(113 mg, 1.11 mmol, 0.8 equiv.) at 0 °C. The clear yellowish solution was allowed to warm to ambient
temperature and was stirred for 22 h. An aqueous saturated solution of NH4Cl (25 mL) and
dichloromethane (20 mL) was added. After separation the aqueous layer was extracted with
dichloromethane (3 x 30 mL), combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by flash column chromatography (SiO2, cyclohexane/ ethyl acetate = 2/1) gave the
Michael addition product as colorless oil (Rf = 0.35 (cyclohexane/ ethyl acetate = 2/1), 200 mg, 832
ꢀmol). The obtained compound (200 mg, 832 ꢀmol, 1.0 equiv.) was dissolved in dichloromethane (2.8
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mL), Nꢀiodosuccinimide (262 mg, 1.17 mmol, 1.40 equiv.) and glacial acetic acid (86 ꢀL, 1.50 mmol,
1.80 equiv.) were added subsequently at room temperature. The red suspension was stirred for 8 h until
no starting material could be detected anymore by NMRꢀanalysis. Triethylamine (376 ꢀL, 2.70 mmol,
3.24 equiv.) was added and the dark solution was stirred for 18 h. Further amount of triethylamine (376
ꢀL, 2.70 mmol, 3.24 equiv.) was added and the dark solution was stirred for another 24 h. An aqueous
saturated solution of NH4Cl (20 mL) and dichloromethane (20 mL) was added, layers were separated,
the aqueous layer was extracted with dichloromethane (3 x 30 mL), combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (SiO2,
cyclohexane/ ethyl acetate = 2/1) gave the respective vinyl iodide as yellowish oil (231 mg, 631 ꢀmol,
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45%). Rf = 0.36 (cyclohexane/ ethyl acetate = 2/1); H NMR (400 MHz, CD2Cl2) δ ppm 7.82 (s, 1 H),
7.00 – 6.99 (m, 1 H), 6.25 ꢀ 6.24 (m, 1 H), 1.98 (s, 3 H), 1.47 (s, 9 H); 13C NMR (101 MHz, CD2Cl2) δ
ppm 170.8, 162.4, 158.3, 141.7, 136.2, 100.9, 83.3, 74.4, 28.3, 11.0; HRMS: calc. for C12H16IO5
[M+H]+: 367.0037, found: 367.0039; IR (cmꢀ1): 2979, 1783, 1705, 1652, 1633, 1368, 1331, 1209, 1155,
1125, 1051, 1021, 978, 953, 847. To a solution of vinyl iodide obtained from above (50.0 mg, 137 ꢀmol,
1.00 equiv.) and triphenylarsane (12.5 mg, 41.0 ꢀmol, 0.30 equiv.) in dioxane (1.40 mL) was added
vinylstannane 10 (180 mg, 410 ꢀmol, 3.00 equiv.) under argon atmosphere. The solution was degassed
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by bubbling argon through the solution for 10 min. Pd2dba3 (9.4 mg, 10.2 ꢀmol, 0.075 equiv.) was
added, the reaction vial was sealed and heated to 90 °C for 45 min. The clear yellow mixture was
allowed to cool to rt and was filtered over Celite (wash with cyclohexane/ ethyl acetate = 2/1, 20 mL).
The solvent was removed in vacuo and the crude was purified by flash column chromatography (SiO2,
cyclohexane/ ethyl acetate = 4/1). The title compound 26 (tBuꢀCLA) was obtained as colorless oil (25.0
mg, 64.4 ꢀmol, 47%). Rf = 0.36 (cyclohexane/ ethyl acetate = 4/1); 1H NMR (400 MHz, CD2Cl2) δ ppm
7.41 (s, 1 H), 6.96 ꢀ 6.95 (m, 1 H), 6.72 (d, J = 16.5 Hz, 1 H), 6.15 – 6.14 (m, 1 H), 6.05 (d, J =
16.5 Hz, 1 H), 2.00 (virt. t, J = 6.2 Hz, 2 H), 1.97 (t, J = 1.5 Hz, 3 H), 1.70 (s, 3 H), 1.63 – 1.59 (m, 2
H), 1.49 (s, 9 H), 1.49 – 1.46 (m, 2 H), 0.99 (s, 6 H); 13C NMR (101 MHz, CD2Cl2) δ ppm 171.2, 166.4,
151.2, 141.9, 139.0, 135.8, 132.5, 130.1, 122.7, 115.0, 101.1, 40.1, 34.6, 33.5, 29.21, 29.18, 28.6, 21.9,
19.9, 17.1, 11.0; HRMS: calc. for C23H33O5 [M+H]+: 389.2322, found: 389.2323; IR (cmꢀ1): 2959, 2931,
2817, 1780, 1710, 1622, 1451, 1369, 1340, 1253, 1160, 1122, 1095, 1015, 953, 864, 768, 699.
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(E)-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enal (28): To a solution of 2ꢀhydroxyꢀ4ꢀmethylꢀ
2Hꢀfuranꢀ5ꢀone (12) (317 mg, 2.78 mmol, 1.5 equiv.) in THF (4.0 mL) was added subsequently methyl
propꢀ2ꢀynal (27) (100 mg, 1.85 mmol, 1.0 equiv.) and 4ꢀmethylmorpholine (150 mg, 1.48 mmol, 0.8
equiv.) at 0 °C. The clear yellow solution was stirred for 15 min at 0 °C. An aqueous saturated solution
of NH4Cl (10 mL) was added, the mixture was extracted with diethyl ether (3 x 15 mL), combined
organic layers were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 1/1) gave the title compound as colorless oil (285
mg, 1.69 mmol, 92%). Rf = 0.18 (cyclohexane/ ethyl acetate = 1/1); 1H NMR (400 MHz, CDCl3) δ ppm
9.46 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 12.5 Hz, 1 H), 6.98 6.97 (m, 1 H), 6.19 – 6.18 (m, 1 H), 5.91 (dd,
J = 12.5, 7.7 Hz, 1 H), 2.04 (t, J = 1.5 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ ppm 190.5, 170.1,
165.1, 140.8, 135.7, 114.6, 99.0, 10.7; HRMS: calc. for C8H9O4 [M+H]+: 169.0495, found: 169.0497;
IR (cmꢀ1): 1776, 1671, 1641, 1617, 1361, 1343, 1185, 1135, 1093, 1055, 991, 945, 864, 745.
(Z)-2-iodo-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enal (29): To a solution of 28 (260 mg,
1.31 mmol, 1.00 equiv.) obtained from above in dichloromethane (7.0 mL) was added Nꢀ
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iodosuccinimide (415 mg, 1.79 mmol, 1.36 equiv.) and glacial acetic acid (135 ꢀL, 2.37 mmol, 1.80
equiv.) subsequently at room temperature. The red suspension was stirred for 18 h until no starting
material could be detected anymore by NMRꢀanalysis. Triethylamine (366 ꢀL, 2.63 mmol, 2.00 equiv.)
was added slowly at 0 °C and the clear solution was stirred for 15 min at 0 °C. An aqueous saturated
solution of NH4Cl (25 mL) and dichloromethane (30 mL) and acetic acid (0.5 mL) was added, the
mixture was extracted with dichloromethane (3 x 30 mL), combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (SiO2,
cyclohexane/ ethyl acetate = 1/1) gave the title compound rac-29 as white solid (310 mg, 1.05 mmol,
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80%). Rf = 0.29 (cyclohexane/ ethyl acetate = 1/1); mp = 117ꢀ119 °C; H NMR (400 MHz, CDCl3) δ
ppm 8.77 (s, 1 H), 7.82 (s, 1 H), 7.08 (s, 1 H), 6.35 (s, 1 H), 2.08 (t, J = 1.5 Hz, 3 H); 13C NMR (101
MHz, CDCl3) δ ppm 185.2, 169.7, 165.3, 140.7, 136.3, 100.1, 87.8, 10.8; HRMS: calc. for C8H8IO4
[M+H]+: 294.9462, found: 294.9464; IR (cmꢀ1): 1782, 1669, 1616, 1358, 1210, 1170, 1149, 1093, 1055,
985, 954, 867. Xꢀray analysis was performed for racemic rac-29. Separation of enantiomers via chiral
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D
HPLC: SFC Daicel CHIRALPAK ® IB, CO2 /iPrOH; Rꢀstereoisomer (R)ꢀ29: Rt = 1.11 min; [α]
=
+119.1° (c = 1.00, CHCl3, 20 °C), stereochemical assignment: CDꢀanalysis; Sꢀstereoisomer (S)ꢀ29: Rt =
2.05 min; [α] 20 = −124.3° (c = 1.07, CHCl3, 20 °C), stereochemical assignment via CDꢀanalysis, see
D
supporting information.
(Z)-2-iodo-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoic acid (31): To a solution of rac-29
(85.0 mg, 289 ꢀmol, 1.00 equiv.) obtained from above in acetonitril (2.9 mL) was added CuBr2 (3.2 mg,
14.5 ꢀmol, 0.05 equiv.) and tert-butylhydroperoxide (5.5 mol/L solution in decane, 260 ꢀL, 1.45 mmol,
5.00 equiv.) subsequently at room temperature. The clear green solution was stirred for 24 h. An
aqueous solution of Na2S2O3 (10% (w/w), 10 mL), acetic acid (0.5 mL) and dichloromethane (10 mL)
was added, the mixture was extracted with dichloromethane (3 x 10 mL), combined organic layers were
dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography
(SiO2, cyclohexane/ ethyl acetate = 1/1 + 0.5% AcOH) gave the title compound as colorless oil (85.0
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mg, 274 ꢀmol, 95%). Performing this procedure using enantiomerically pure formyl vinyliodides (R)ꢀ29
/ (S)ꢀ29 obtained as described above delivered the corresponding (R)ꢀ31 and (S)ꢀ31 in similar yields. Rf
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= 0.28 (cyclohexane/ ethyl acetate = 1/1 + 0.5% AcOH); H NMR (400 MHz, CDCl3) δ ppm 8.06 (s, 1
H), 7.03 (s, 1 H), 6.29 (s, 1 H), 2.05 (t, J = 1.5 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ ppm 170.0,
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168.5, 160.3, 140.8, 136.1, 100.1, 69.7, 10.8; HRMS: calc. for C8H8IO5 [M+H]+: 310.9411, found:
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310.9410; IR (cmꢀ1) 3093, 1780, 1698, 1619, 1364, 1176, 1092, 1035, 949, 862, 735; [α] 20 ((R)ꢀ31) =
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+51.5° (c = 1.12, CHCl3, 20 °C), [α] 20 ((S)ꢀ31) = −54.1° (c = 0.99, CHCl3, 20 °C), see also supporting
D
information.
Benzhydryl (Z)-2-iodo-3-[(4-methyl-5-oxo-2H-furan-2-yl)oxy]prop-2-enoate (32): To a solution of
acid 31 (22.0 mg, 71.0 ꢀmol, 1.0 equiv.) and diphenylmethanol (17.0 mg, 92.2 ꢀmol, 1.3 equiv.) in
dichloromethane (500 ꢀL) was added a solution of DCC (17.6 mg, 85.2 ꢀmol, 1.2 equiv.) and DMAP
(0.9 mg, 7.10 ꢀmol, 0.1 equiv.) in dichloromethane (500 ꢀL). The mixture was stirred for 24 h. An
aqueous saturated solution of NH4Cl (7.0 mL) and dichloromethane (15 mL) was added. After
separation the aqueous layer was extracted with dichloromethane (3 x 15 mL), combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column
chromatography (SiO2, cyclohexane/ ethyl acetate = 2/1) gave benzhydryl compound 32 as yellowish oil
(19.0 mg, 39.9 ꢀmol, 56%). Rf = 0.31 (cyclohexane/ ethyl acetate = 2/1); 1H NMR (400 MHz, CD2Cl2) δ
ppm 8.02 (s, 1 H), 7.41ꢀ7.30 (m, 10 H), 7.00 (s, 1 H), 6.89 (s, 1 H), 6.28 (s, 1 H), 2.00 (t, J = 1.5 Hz, 3
H); 13C NMR (101 MHz, CD2Cl2) δ ppm 170.7, 162.7, 159.5, 141.6, 140.6, 136.4, 129.2, 129.0, 128.6,
127.5, 127.4, 127.0, 101.0, 79.6, 70.7, 11.5; HRMS: calc. for C21H18IO5 [M+H]+: 477.0199, found:
477.0197; IR (cmꢀ1): 1785, 1707, 1623, 1360, 1253, 1170, 1039, 990, 954, 748, 700.
rac-(E,2E)-2-[(4-methyl-5-oxo-2H-furan-2-yl)oxymethylene]-4-(2,6,6-trimethylcyclohexen-1-
yl)but-3-enal (30, 19-oxo-carlacton, 19-oxo-CL): To a solution of formyl vinyl iodide rac-29 (70.0
mg, 238 ꢀmol, 1.00 equiv.) and triphenylarsane (21.9 mg, 71.4 ꢀmol, 0.30 equiv.) in dioxane (4.80 mL)
was added vinylstannane 10 (262 mg, 595 ꢀmol, 2.50 equiv.) under argon atmosphere. The solution was
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