Synthesis of the core framework of the cornexistins by intramolecular Nozaki-Hiyama-Kishi coupling

Article abstract of DOI:10.3390/molecules24142654

A new and direct approach to the construction of the core framework of the herbicidal natural products cornexistin and hydroxycornexistin has been developed. Formation of the nine-membered carbocycle found in the natural products has been accomplished by an intramolecular Nozaki-Hiyama-Kishi reaction between a vinylic iodide and an aldehyde. Good yields of carbocyclic products were obtained from the reaction, but diastereomeric mixtures of allylic alcohols were produced. The cyclisation reaction was successful irrespective of the relative configuration of the stereogenic centres in the cyclisation precursor.

Full text of DOI:10.3390/molecules24142654

molecules
Article
Synthesis of the Core Framework of the Cornexistins
by Intramolecular Nozaki-Hiyama-Kishi Coupling
Anthony Aimon , Louis J. Farrugia and J. Stephen Clark *
School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK
*
Correspondence: stephen.clark@glasgow.ac.uk; Tel.: +44-0141-330-6296
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Ari Koskinen
Received: 28 June 2019; Accepted: 18 July 2019; Published: 22 July 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: A new and direct approach to the construction of the core framework of the herbicidal
natural products cornexistin and hydroxycornexistin has been developed. Formation of the
nine-membered carbocycle found in the natural products has been accomplished by an intramolecular
Nozaki-Hiyama-Kishi reaction between a vinylic iodide and an aldehyde. Good yields of carbocyclic
products were obtained from the reaction, but diastereomeric mixtures of allylic alcohols were
produced. The cyclisation reaction was successful irrespective of the relative configuration of the
stereogenic centres in the cyclisation precursor.
Keywords: cornexistins; nonadride; natural product; herbicide; nine-membered carbocycle;
Nozaki-Hiyama-Kishi reaction; cyclisation
1
. Introduction
1
.1. Isolation and Herbicial Activities of the Cornexistins
Cornexistin and hydroxycornexistin are structurally unique members of the nonadride family
of natural products (Figure 1) [1–5]. Cornexistin was first isolated from a culture of the fungus
Paecilomyces variotii Bainier (strain SANK 21086) by researchers at Sankyo Co. in 1987 and
hydroxycornexistin was isolated from the same strain of the fungus by workers at DowElanco
eight years later. Both compounds have attracted the interest of the agrochemical industry because
of the potent and selective herbicidal activities they possess and because they are prone to rapid
degradation on exposure to light or when treated with acid or base [6]. The cornexistins are unusual
members of the nonadride family of natural products because they possess a single maleic anhydride
unit embedded in their structures whereas most of the other nonadrides possess two [7].
HO
O
O
14 HO
O
HO
8
OH
OH
5
4
O
O
O
O
O
cornexistin
hydroxycornexistin
Figure 1. The cornexistin natural products.
Cornexistin and hydroxycornexistin both display potent herbicidal activity against grasses and
broadleaf weeds but are well tolerated by some crop plants [1
high activity and is effective against many types of broadleaf weeds [
cornexistins, or metabolised products thereof, exert their herbicidal activities by interfering with one or
−
5]. Hydroxycornexistin has particularly
4,5]. It has been suggested that the
more aspartate amino transferase enzymes [8], but their precise mode of action has yet to be elucidated
Molecules 2019, 24, 2654; doi:10.3390/molecules24142654
www.mdpi.com/journal/molecules

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fully. The selective and potent herbicidal activity of the cornexistins combined with their apparently
novel mode of action and non-persistence in the environment means that these natural products have
significant potential as lead compounds in the search for novel, biorational post-emergence weed
control agents that can be used in arable crop production.
1
.2. Previous Synthetic Studies on the Cornexistins
Although the cornexistins have significant potential as novel lead compounds in the search for
new herbicides, they have been the subject of few synthetic studies and very little has been published
concerning their total synthesis. Aside from our own previously published work (vide infra) [ 10],
9,
the only attempt to synthesise either cornexistin or hydroxycornexistin to have been reported is that of
Taylor and co-workers [11]. In this study, the oxidative ring opening of a hexahydroindene system
was used to create the fully functionalised nine-membered carbocyclic core structure. However, this
approach did not culminate in the total synthesis of either natural product.
Our interest in both cornexistin and hydroxycornexistin as targets for total synthesis was aroused
by the combination of the synthetic challenges presented by the natural products and their potent
herbicidal activities. Both compounds possess a relatively rare nine-membered carbocycle fused to
a highly reactive maleic anhydride unit, a combination of structural features that poses a formidable test
to conventional methods of ring construction. The cornexistins also present several interesting problems
concerning stereocontrol; control of the exocyclic alkene configuration is especially challenging.
We have already shown that a ring-closing metathesis (RCM) reaction can be used to construct
the core of the cornexistins from a relatively simple diene precursor [
9
]. Dihydroxylation of the
5
,6
resulting
∆
-cyclononene resulted in installation of hydroxyl groups at C-5 and C-6. Unfortunately,
the configuration at the hydroxyl-bearing carbon (C-5) was not that found in the natural products
and all attempts to invert the configuration at this stereogenic centre were unsuccessful. Ultimately,
a synthesis of 5-epi-hydroxycornexistin was completed instead of the natural product [10].
The failure of the original route motivated us to explore a completely new approach to the
synthesis of cornexistin and hydroxycornexistin. In this second-generation approach, we planned to
create the C-5 stereogenic centre with the correct configuration during the cyclisation reaction used
to assemble the nine-membered ring, instead of attempting to perform late-stage introduction of the
hydroxyl group after ring construction.
1
.3. Retrosynthetic Analysis of the Cornexistins and Synthesis Design
The synthetic strategy we chose to adopt in our second-generation approach to the synthesis of
the cornexistins was informed by the retrosynthetic analysis presented in Scheme 1. Conversion of
the C-6 carbonyl group into an exocyclic alkene and transformation of the maleic anhydride unit into
a furan suggested i as a late-stage intermediate. Tethering of the C-8 hydroxyl group and C-14 carbon
in the form of a butenolide and ring-opening of the C-5–C-6 bond by scission of the allylic alcohol then
led to the aldehyde ii. Subsequent functional group conversion of the iodoalkene into an alkyne and
the aldehyde into a hydroxyl group suggested the alcohol iii as intermediate. Finally, cleavage of the
C-9–C-10 bond resulted in the disconnection of the compound into two relatively simple fragments of
similar size and complexity: the halomethylfuran iv and the metallated butenolide v.
The key step in the synthetic route suggested by the retrosynthetic analysis presented in Scheme 1
was the intramolecular Nozaki-Hiyama-Kishi (NHK) reaction of a vinylic halide with an aldehyde [12].
At the outset of our synthetic studies there appeared to be no published examples of the use of this
reaction to construct a nine-membered carbocycle. However, after completion of the work described
in this paper [13], Hosokawa and co-workers reported the use of an intramolecular NHK reaction to
prepare a nine-membered carbocycle during their synthesis of the fused bicyclic core structure of the
marine natural product cristaxenicin A [14].

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Scheme 1. Retrosynthetic analysis of hydroxycornexistin.
. Results and Discussion
2
2
.1. Synthesis of the Butenolide Fragment 4
Synthetic work commenced with the four-step synthesis of the stannylated lactone
4
(corresponding
to intermediate
prepared by the condensation reaction of tetronic acid with pyrrolidine (Scheme 2) [15]. Deprotonation
of the lactone with t-butyl lithium and alkylation of the resulting anion with TIPS-protected propargyl
bromide [16] afforded the alkyne in high yield when an excess (typically five equivalents) of the
alkylating agent was employed. Enamine hydrolysis under acidic conditions and conversion of the
resulting enol into the stable enol triflate was followed by a palladium-catalysed reaction with
v in the retrosynthetic analysis) from the simple 4-aminobut-2-enolide 1, which was
1
2
3
hexamethyl ditin to produce the required stannane
reasonable yield [17].
4 (NMR spectra in Supplementary Material) in
Scheme 2. Synthesis of the stannylated crotonolactone 4.
2
.2. Synthesis of the Chloromethylfuran Fragment 12
Chloride 12 (corresponding to iv in the retrosynthetic analysis), the coupling partner required
for construction of the complete carbon skeleton of hydroxycornexistin, was synthesised from the
known aldehyde (available from a 3,4-furandicarboxylate diester) as shown in Scheme 3 [18].
Grignard addition of n-propylmagnesium bromide to the aldehyde delivered the alcohol and this
compound was oxidised with manganese (IV) oxide to produce the ketone . Wittig methylenation of
the ketone afforded the alkene and a subsequent hydroboration reaction provided the alcohol 9.
5
5
6
7
7
8
Protection of the alcohol as a t-butyldiphenylsilyl ether produced the furan 10 and selective cleavage
of the t-butyldimethylsilyl ether delivered the alcohol 11. The alcohol 11 was converted into the
chloride 12 (NMR spectra in Supplementary Material) directly and in high yield upon treatment with
methanesulfonyl chloride [19]. Thus, the aldehyde
5 was converted into the chloride 12 in 7 steps and
with an overall yield of 50% (an average yield of > 90% per step).

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Scheme 3. Synthesis of the chloromethylfuran 12. Reagents and conditions:
a
n-PrMgCl, THF,
Ph PCH Br, NaHMDS, THF, 0 C, 95%; (i) 9-BBN,
t-BuPh SiCl, Et N, DMAP, CH Cl ,
◦
◦
–
78 C
→
rt, 90%;
b
MnO , CH Cl , reflux, 90%;
c
d
2
2
2
3
3
◦
◦
◦
THF, 55 C, (ii) NaOH aq., EtOH, 0 C, (iii) 30% H O , 50 C, 89%;
rt, 91%; f PPTS, EtOH, 40 C, 94%; g MeSO Cl, Et N, CH Cl , rt, 90%.
e
2
2
2
3
2
2
◦
2
3
2
2
2
.3. Palladium-Mediated Coupling of the Stannane and Chloride to Complete the Skeleton of Hydroxycornexistin
2
3
The stannane
mediated by the combination of tris(dibenzylideneacetone)dipalladium(0) and triphenylarsine
Scheme 4) [20]. The resulting bicyclic compound 13 was then subjected to double desilylation
to reveal the alcohol 14. Palladium-mediated regioselective hydrostannylation of the alkyne followed
by tin-iodine exchange delivered the vinylic iodide 15 21]. A mixture of diastereomers had been
generated as a consequence of the coupling of two racemic fragments ( and 12), but the diastereomeric
4 and the chloride 12 were subjected to a high-yielding sp –sp coupling reaction
(
[
4
iodides 15a and 15b (NMR spectra in Supplementary Materials) were separable by standard silica
gel column chromatography, which allowed them to be characterized fully (vide infra) and the NHK
cyclisation reaction of each isomer to be explored separately.
Scheme 4. Assembly of the complete carbon backbone by Stille coupling of the vinylic stannane
the chloride 12.
4 and
2.4. Construction of the Nine-Membered Ring of Hydroxycornexistin by Use of the Nozaki-Hiyama-Kishi Reaction
Cyclisation of the aldehyde (corresponding to ii in Scheme 1) generated from the vinylic iodide 15a
,
the diastereomer that possesses incorrect relative stereochemistry (S*,S*), was explored first (Scheme 5).
Oxidation was performed using the Dess-Martin periodinane and treatment of the resulting aldehyde

Molecules 2019, 24, 2654
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with a large excess of chromium(II) chloride and a sub-stoichiometric amount (10 mol%) of nickel(II)
chloride in dry, degassed DMSO promoted an intramolecular NHK reaction to give the tricyclic
products 16a and 16b in yields of 49% and 13% respectively (NMR spectra in Supplementary Material).
The major isomer (16a) was a crystalline solid and crystals suitable for analysis by X-ray diffraction were
obtained [22]. X-ray diffraction data confirmed that the alcohol 16a has the relative stereochemistry
shown and by extension that 15a is the diastereomer shown in Scheme 5.
Scheme 5. Cyclisation of 15a to give the nine-membered ring by use of a Nozaki-Hiyama-Kishi reaction.
The cyclization reaction of the aldehyde derived from the alcohol 15b was also explored (Scheme 6).
Oxidation of the alcohol 15b proceeded in excellent yield and treatment of the resulting aldehyde
with a large excess of chromium(II) chloride and a sub-stoichiometric amount (13 mol%) of nickel(II)
chloride in dry, degassed DMSO produced an inseparable mixture (2.4:1 ratio, C-5 configuration not
established) of the diastereomeric alcohols 16c and 16d (NMR spectra in Supplementary Material)
in 43% yield. In an attempt to improve the diastereomeric ratio of the allylic alcohols, an oxidation
and reduction sequence was performed. Oxidation of the mixture of alcohols produced the enone 17
1
(
H-NMR spectrum in Supplementary Material) and subsequent Luche reduction returned a mixture
of the alcohols 16c and 16d with a similar diastereomeric ratio to that obtained from the original NHK
cyclization reaction.
Dess-Martin periodinane
I
CH Cl , rt
O
O
1. Dess-Martin
periodinane
O
O
2
2
O
O
OH
H
H
OH
H
O
CH Cl , rt 99%
2
2
2
. CrCl , NiCl (13 mol %)
2
2
DMSO, rt
50 °C
O
O
16c,d
O
17
43% (2.4:1)
NaBH , CeCl 7H O
4 3 2
1
5b
MeOH, –78 °C
99% (3:1)
Scheme 6. Cyclisation of 15a to give the nine-membered ring by use of a Nozaki-Hiyama-Kishi
reaction and an attempt to improve the diastereomeric ratio by sequential alcohol oxidation and
ketone reduction.
3
. Conclusions
We have shown that it is possible to assemble the core structure of the cornexistins by a short
2
3
and convergent route. Palladium-mediated sp –sp coupling of the vinylic stannane
4 with the
chloromethylfuran 12, conversion of the coupled product 13 into the vinylic iodides 15 and subsequent
sequential oxidation and intramolecular Nozaki-Hiyama-Kishi (NHK) reaction was used to construct
the nine-membered ring. The intramolecular NHK reactions of aldehydes derived from alcohols
1
5a and 15b have been accomplished in reasonable yield, which demonstrates that cyclisation is
successful irrespective of the relative configuration of the stereogenic centres present in the vinylic
iodide. This finding means that either diastereomer can be used as a cyclisation precursor, which should
permit greater flexibility in latter stages of the synthetic route.

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4
. Materials and Methods
Air and/or moisture sensitive reactions were performed under an atmosphere of Argon in
flame-dried apparatus. When necessary, solvents were dried and purified using a Pure Solv solvent
™
purification system (SPS). IR spectra were recorded using a type IIa diamond single reflection element
on a Shimadzu FTIR-8400 instrument. The IR spectrum of the compound (solid or liquid) was obtained
1
13
by analysis of a thin layer at ambient temperature. H and C-NMR spectra were recorded using
either a Bruker 400 MHz or 500 MHz Spectrospin spectrometer at ambient temperature; 13C-NMR
NMR spectra were recorded at 101 MHz or 126 MHz. Mass spectra were obtained by ionisation under
EI, FAB, CI and ESI conditions on a Jeol MStation JMS-700 instrument. Elemental analyses were
performed on an Exeter Analytical Elemental Analyser EA 440 by technical staff at the University of
Glasgow. Melting points were recorded with an Electrothermal IA 9100 apparatus.
4
.1. Synthesis of 4-(pyrrolidin-1-yl)-5-(3-triisopropylsilylprop-2-ynyl)furan-2(5H)-one (2)
◦
To a solution of
1
(653 mg, 4.26 mmol) in THF (6 mL) at
−
78 C was added carefully a solution of
t-BuLi (4.0 mL of a 1.6 m solution in hexane, 6.4 mmol, 1.5 equiv.). The mixture was stirred for 30 min
before a solution of 3-bromo-1-(triisopropylsilyl)-1-propyne (5.88 g, 21.4 mmol, 5.0 equiv.) in THF
◦
(
8 mL) cooled to
−
78 C was added carefully. After 3 h, the mixture was allowed to warm to room
temperature over 45 min, and the reaction was quenched by the addition of saturated aqueous NH Cl
4
solution (10 mL). The mixture was diluted with ethyl acetate (20 mL) and the phases were separated.
The aqueous phase was extracted with ethyl acetate (2
×
10 mL) and the combined organic extracts
were washed with brine (20 mL), then dried over MgSO , filtered and concentrated in vacuo. The crude
4
material was purified by flash column chromatography (PE-EtOAc, 7:3) to give the desired alkyne
2
◦
(
1.34 g, 90%) as a colourless solid. M.p. 122
−
125 C; R = 0.23 (PE-EtOAc, 1:1); IR νmax 2942, 2928, 2888,
f
−1 1
2
865, 2180, 1722, 1610, 994, 920, 901, 882, 853, 839, 773 cm ; H-NMR (400 MHz, CDCl3)
δ 4.95 (1H, dd,
J = 4.5, 3.5 Hz), 4.55 (1H, s), 3.32 (4H, br s), 3.00 (1H, dd, J = 17.8, 3.5 Hz), 2.80 (1H, dd, J = 17.8, 4.5 Hz),
2
8
8
.12
−
2.02 (2H, m), 1.99
−
1.90 (2H, m), 1.03 (21H, s); 13C-NMR (101 MHz, CDCl3)
δ 173.9, 167.1, 100.6,
4.5, 83.3, 76.0 (CH-C5), 24.2, 18.7, 11.3; LRMS (CI, isobutane): m/z (int) 348 (98), 137 (61), 121 (51),
9 (94); HRMS (CI, isobutane) calculated for C H NO Si [M + H] : 348.2359; found 348.2364. Anal.
+
20
34
2
calculated for C H NO Si: C, 69.11; H, 9.57; N, 4.03. Found: C, 69.07; H, 9.65; N, 4.09.
20
33
2
4.2. Synthesis of 5-oxo-2-(3-triisopropylsilylprop-2-ynyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (
3)
A solution of the lactone (1.83 g, 5.27 mmol) was added to a solution of hydrochloric acid in
2
◦
EtOH (30 mL of a 1.2 m solution, 38 mmol, 7.1 equiv.) at 0 C followed by water (3.0 mL). The mixture
was heated at 78 C for 5 h, cooled to room temperature and diluted with water (10 mL) and Et O
◦
2
(
40 mL). The phases were separated and the aqueous phase was extracted with Et O (2
×
20 mL).
2
The organic extracts were combined and washed with brine (20 mL), then dried over MgSO , filtered
4
and concentrated in vacuo. Azeotropic removal of water with toluene (3
×
50 mL) provided an orange
residue that was used directly in the next step.
◦
To a solution of the crude acid in CH Cl (53 mL) at
−
78 C was added dropwise freshly distilled
2
2
Hünig’s base (1.40 mL, 8.03 mmol, 1.5 equiv.), and after 5 min triflic anhydride (4.15 mL, 6.96 mmol,
◦
1
.3 equiv.). The dark red solution was stirred at
−
78 C for 1 h, then diluted with CH Cl (30 mL) and
2
2
warmed to room temperature. The reaction was quenched by the addition of water (20 mL) and the
phases were separated. The aqueous phase was extracted with CH Cl (2 20 mL), the organic extracts
were combined, washed with brine (50 mL), dried with Na SO , filtered and concentrated in vacuo.
×
2
2
2
4
The residue was purified by flash column chromatography (PE-Et O, 9:1
→
4:1) to afford the triflate
2
◦
3
(1.82 g, 81% over two steps) as a colourless solid. M.p. 42
−
43 C; R = 0.81 (PE-Et O, 5:5); IR νmax
f
2
−1 1
2
947, 2870, 2176, 1767, 1643, 995, 818 cm ; H-NMR (400 MHz, CDCl )
δ
6.08 (1H, d, J = 1.2 Hz), 5.07
3
(
1H, ddd, J = 4.8, 3.5, 1.2 Hz), 3.09 (1H, dd, J = 17.7, 4.8 Hz), 2.84 (1H, dd, J = 17.7, 3.5 Hz), 1.03 (21H,
13
s); C-NMR (101 MHz, CDCl3)
δ 167.8, 167.2, 118.6 (q, J = 322 Hz), 104.8, 97.3, 87.1, 76.3, 23.1, 18.6,

Molecules 2019, 24, 2654
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1
1.2; LRMS (CI, isobutane): m/z (int) 427 (26), 334 (11), 279 (32), 276 (21), 235 (15), 181 (11), 133 (27), 97
+
(35), 71 (100). HRMS (CI, isobutane) calculated for C H F O SSi [M + H] : 427.1222; found 427.1223.
17 26 3 5
Anal. calculated for C H F O SSi: C, 47.87; H, 5.91. Found: C, 47.85; H, 5.97.
17
25
3
5
4
.3. Synthesis of 4-trimethylstannyl-5-(3-triisopropylsilylprop-2-yn-1-yl)-2,5-dihydrofuran-2-one (4)
In a 50 mL 3-necked flask containing thoroughly flame-dried LiCl (600 mg, 14.2 mmol, 8.0 equiv.)
and Pd(PPh ) (80.1 mg, 0.0693 mmol, 3.9 mol %) was added THF (5 mL). A solution of triflate
3
3
4
(755 mg, 1.77 mmol) in THF (17 mL) was added. After 5 min hexamethylditin (480
µL, 2.31 mmol,
1.3 equiv.) was added and the mixture was heated at reflux for 1.5 h. Further Pd(PPh ) (67.8 mg,
3 4
0
.0586 mmol, 3.3 mol %) was then added and the mixture was stirred for 1.5 h. The mixture was cooled
◦
to 0 C and the reaction was quenched with saturated aqueous NaHCO (15 mL) and diluted with
3
Et O (40 mL). The phases were separated and the aqueous phase was extracted with Et O (2
×
30
2
2
mL). The organic extracts were combined, washed with brine (40 mL), dried with Na SO , filtered and
2
4
concentrated in vacuo. The crude product was purified by flash column chromatography (PE-Et O,
2
◦
1
9:1
→
4:1) to give the corresponding stannane
4
(419 mg, 54%) as a pale yellow solid. M.p. 69
−
72 C;
−1 1
R = 0.21 (PE-Et O, 4:1); IR νmax 2940, 2863, 2176, 1751, 918, 880, 779 cm ; H-NMR (400 MHz, CDCl )
f
2
3
δ
6.22 (1H, d, J = 1.9 Hz), 5.21 (1H, ddd, J = 5.3, 3.6, 1.9 Hz), 3.04 (1H, dd, J = 17.3, 5.3 Hz), 2.65 (1H, dd,
J = 17.3, 3.6 Hz), 1.01 (21H, br s), 0.36 (9H, s); 13C-NMR (101 MHz, CDCl3)
175.4, 172.4, 131.1, 100.4,
9.2; LRMS (CI, isobutane): m/z (int) 443 (76), 441 (57), 337 (11), 279 (48),
δ
8
2
4
5.8, 85.5, 25.1, 18.7, 11.3,
−
120
+
57 (15), 235 (12), 113 (20), 69 (100). HRMS (CI, isobutane) calculated for C H O Si Sn [M + H] :
43.1429; found 443.1424.
19
35
2
4
.4. Synthesis of 1-[4-(tert-butyldimethylsilyloxy)methylfuran-3-yl]butan-1-ol (6)
To a suspension of lithium aluminium hydride (4.74 g, 125 mmol, 2.3 equiv.) in THF (200 mL) at
◦
−
78 C was added a solution of dimethyl 3,4-furandicarboxylate (10.0 g, 54.3 mmol) in THF (200 mL)
◦
over 20 min at
−
78 C. The solution was warmed gently to room temperature over 2 h and stirred
◦
overnight. The reaction was cooled to 0 C and quenched carefully by success addition of water
(4.7 mL), aqueous NaOH (1 m, 4.7 mL) and water (13 mL). After warming to room temperatureand
stirring for 1 h, a cloudy white suspension was formed. MgSO (~15 g) was added and the mixture
4
was filtered through a pad of Celite and washed with ethyl acetate (1 L). After concentration in vacuo,
the pale-yellow oil obtained was used directly for the next step.
To a solution of the crude diol obtained (6.95 g, ~54.2 mmol) in CH Cl (450 mL) was added
2
2
activated manganese(II) oxide (28.3 g, 326 mmol, 6.0 equiv.) at room temperature. The mixture
was stirred vigorously for 2.5 h and further manganese(II) oxide (9.50 g, 108 mmol, 2.0 equiv.) was
added three times at regular intervals. The black suspension was then filtered through a pad of Celite
and washed with CH Cl (1.5 L). After concentration in vacuo, the crude yellow oil was separated
2
2
into two fractions—A (3.46 g) and B (3.72 g)—which were used in the subsequent steps without any
further purification.
To a solution of the crude aldehyde A (3.46 g, ~27.5 mmol) in CH Cl (250 mL), imidazole (2.24 g,
2
2
3
3.0 mmol, 1.2 equiv.), DMAP (336 mg, 2.75 mmol, 0.10 equiv.) and t-butyldimethylsilyl chloride
4.55 g, 30.2 mmol, 1.1 equiv.) were added sequentially. The solution was stirred for 20 min at room
temperature and then water (60 mL) was added. The phases were separated and the aqueous phase
was extracted with CH Cl (2 60 mL). The organic extracts were combined, washed with brine
100 mL), dried over MgSO , filtered and concentrated in vacuo. The resulting pale yellow oil was
(
×
2
2
(
4
used immediately in the next step.
◦
(~27.5 mmol) in THF (250 mL) at 78 C was added
To a solution of the silylated aldehyde
5
−
dropwise n-propylmagnesium chloride (23.3 mL of a 2.0 m solution in THF, 46.6 mmol, 1.7 equiv.).
◦ ◦
The solution was stirred at 78 C for 1.5 h, warmed to 0 C and the reaction was quenched by the
−
addition of a saturated aqueous solution of NH Cl (35 mL). Water (35 mL) and Et O (60 mL) were
4
2
added and the phases separated. The aqueous phase was extracted with Et O (2
×
60 mL) and the
2

Molecules 2019, 24, 2654
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organic extracts washed with brine (120 mL), dried over MgSO , filtered and concentrated in vacuo.
4
The residual material was purified by flash column chromatography (PE-Et O, 9:1) to give the desired
2
alcohol 6 as a colourless oil.
The same procedure was used to convert aldehyde B in the alcohol
6 and the batches were
combined (10.7 g, 69% over 4 steps). R = 0.34 (PE-Et O, 9:1); IR νmax 3349, 2955, 2929, 2858, 1749, 1669,
f
2
−
1 1
9
4
7
60, 877, 815, 777, 760, 742 cm ; H-NMR (400 MHz, CDCl )
δ
7.30 (2H, s), 4.65 (1H, d, J = 12.2 Hz),
.61 (1H, d, J = 12.2 Hz), 4.60 (1H, dt, J = 7.9, 5.6 Hz), 3.58 (1H, d, J = 5.6 Hz), 1.84 (1H, dddd, J = 13.4, 9.8,
.9, 5.5 Hz), 1.73 (1H, dddd, J = 13.4, 9.8, 5.9, 5.6 Hz), 1.57 1.48 (1H, m), 1.43 1.34 (1H, m), 0.96 (3H, t, J
7.4 Hz), 0.91 (9H, s), 0.12 (3H, s), 0.12 (3H, s); 13C-NMR (101 MHz, CDCl )
140.6, 140.1, 128.5, 123.7,
5.2; LRMS (CI, isobutane): m/z (int) 267 (31), 135 (49), 107 (9), 89
3
−
−
=
δ
3
6
(
5.8, 56.8, 38.5, 26.0, 19.5, 18.4, 14.1,
−
+
100), 69 (20). HRMS (CI, isobutane) calculated for C H O Si [M − OH] : 267.1780; found 267.1775.
1
5
27
2
4
.5. Synthesis of 1-[4-(tert-butyldimethylsilyloxy)methylfuran-3-yl]butan-1-one (7)
To a solution of alcohol (522 mg, 1.94 mmol) in CH Cl (20 mL) was added activated manganese(II)
6
2
2
oxide (3.43 g, 39.5 mmol, 20 equiv.). The mixture was stirred at room temperature for 2 h, then heated
at reflux for 2 h, and stirred overnight at room temperature. The suspension was filtered through a pad
of Celite and washed with CH Cl (500 mL). The filtrate was concentrated in vacuo and the residue
2
2
was purified by flash column chromatography (PE-Et O, 19:1), affording the desired ketone
7
(468 mg,
2
9
7
0%) as a colourless oil. R = 0.63 (PE-Et O, 9:1); IR νmax 2957, 2930, 2886, 2859, 2361, 1676, 837, 814,
f
2
−1 1
77 cm ; H-NMR (400 MHz, CDCl ) δ 7.98 (1H, d, J = 1.7 Hz), 7.40 (1H, q, J = 1.7 Hz), 4.87 (2H, d,
3
J = 1.7 Hz), 2.69 (2H, t, J = 7.3 Hz), 1.72 (2H, qt, J = 7.4, 7.3 Hz), 0.97 (3H, t, J = 7.4 Hz), 0.93 (9H, s), 0.10
6H, s); 13C-NMR (101 MHz, CDCl3)
196.3, 148.5, 141.6, 127.1, 125.4, 58.8, 42.3, 26.1, 18.5, 17.9, 14.0,
5.3; LRMS (CI, isobutane): m/z (int) 283 (46), 225 (8), 89 (100), 69 (10). HRMS (CI, isobutane) calculated
(
δ
−
+
for C H O Si [M + H] : 283.1729; found 283.1732.
15
27
3
4
.6. Synthesis of tert-butyldimethyl{[4-(pent-1-en-2-yl)furan-3-yl]methoxy}silane (8)
To a suspension of methyltriphenylphosphonium bromide (2.87 g, 8.03 mmol, 5.0 equiv.) in
◦
THF (7.5 mL) at 0 C was added dropwise a solution of NaHMDS (6.4 mL of a 1.0 m solution in THF,
6
.4 mmol, 4.0 equiv.). The bright yellow suspension was warmed to room temperature and stirred
◦
for 1 h, before being cooled to 0 C. A solution of ketone
7 (453 mg, 1.60 mmol) in THF (7 mL) was
added dropwise and the mixture was stirred for 1 h at room temperature. The reaction was quenched
by the addition of a saturated aqueous solution of NH Cl (10 mL) and the mixture was diluted with
4
Et O (30 mL). The phases were separated and the aqueous phase was extracted with Et O (2 × 20 mL).
2
2
The organic extracts were combined, washed with brine (40 mL), dried over MgSO , filtered and
4
concentrated in vacuo. The residue was purified by flash column chromatography (PE-Et O, 99:1) to
2
give the corresponding 1,1-disubstituted alkene
8 (426 mg, 95%) as a colourless oil. R = 0.91 (PE-Et O,
f 2
−
9:1); IR νmax 2957, 2930, 2857, 1636, 874, 833, 814, 793, 773, 736 cm ; H-NMR (400 MHz, CDCl ) δ
3
1 1
1
7
.36 (1H, s), 7.34 (1H, s), 5.12 (1H, s), 5.00 (1H, d, J = 0.9 Hz), 4.63 (2H, s), 2.29 (2H, t, J = 7.4 Hz), 1.51 (2H,
13
qt, J = 7.4, 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz), 0.91 (9H, s), 0.08 (6H, s); C-NMR (101 MHz, CDCl3)
δ
1
41.4, 140.5, 139.8, 125.7, 124.7, 112.6, 57.6, 38.6, 26.0, 21.5, 18.5, 14.0, 5.1; HRMS (ESI) calculated for
−
+
C H NaO Si [M + Na] : 303.1751; found 303.1744.
16
28
2
4
.7. Synthesis of 2-[4-(tert-butyldimethylsilyloxymethyl)furan-3-yl]pentan-1-ol (9)
To a solution of 1,1-disubstituted alkene (1.07 g, 3.81 mmol) in THF (4 mL), cooled to 0 C,
was added dropwise a solution of 9-BBN (23.0 mL of a 0.5 m solution in THF, 11.5 mmol, 3.0 equiv.).
◦
8
◦
◦
The mixture was warmed to 65 C for 75 min and then cooled to 0 C before careful addition of
EtOH (18 mL) and aqueous 3 m NaOH (11.5 mL). After 15 min, aqueous hydrogen peroxide (30%,
18 mL) was added. The mixture was heated at reflux for 1 h, cooled to room temperature before
the addition of Et O (60 mL) and water (20 mL). The phases were separated and the aqueous phase
2
was extracted with Et O (2
×
50 mL). The organic extracts were combined and washed with brine,
2

Molecules 2019, 24, 2654
9 of 15
dried over MgSO , filtered and concentrated in vacuo. The crude product was purified by flash column
4
chromatography (PE-Et O, 9:1) to give the desired primary alcohol 9 (1.01 g, 89%) as a colourless oil.
2
−1 1
R = 0.18 (PE-Et O, 9:1); IR νmax 3381, 2955, 2930, 2895, 2858, 1602, 1541, 871, 837, 775 cm ; H-NMR
f
2
(
400 MHz, CDCl3) δ 7.33 (1H, d, J = 1.6 Hz), 7.23 (1H, d, J = 1.6 Hz), 4.56 (1H, d, J = 12.5 Hz), 4.53 (1H,
d, J = 12.5 Hz), 3.73 (1H, ddd, J = 10.8, 6.4, 4.9 Hz), 3.61 (1H, ddd, J = 10.8, 7.3, 6.0 Hz), 2.83−2.75 (1H,
m), 2.17 (1H, dd, J = 6.4, 6.0 Hz), 1.67
−
1.57 (1H, m), 1.56
−
1.48 (1H, m), 1.38
−
1.27 (2H, m), 0.91 (9H, s),
0
3
.89 (3H, t, J = 5.9 Hz), 0.10 (6H, s); 13C-NMR (126 MHz, CDCl ) δ 141.1, 140.6, 125.6, 124.9, 66.8, 56.5,
3
+
8.1, 33.8, 26.0, 20.8, 18.5, 14.2,
−
5.2; HRMS (ESI) calculated for C H NaO Si [M + Na] : 321.1856;
16
30
3
found 321.1846.
4
.8. Synthesis tert-butyl{[4-(1-tert-butyldiphenylsilyloxypentan-2-yl)furan-3-yl]methoxy}dimethylsilane (10
)
To a solution of alcohol (1.72 g, 5.76 mmol) in CH Cl (58 mL), DMAP (203 mg, 1.66 mmol,
9
2
2
0
.3 equiv.), t-butyldiphenylsilyl chloride (2.26 mL, 8.81 mmol, 1.5 equiv.) and Et N (1.37 mL, 9.83 mmol,
3
◦
1.7 equiv.) were added successively at 0 C. The solution was stirred overnight at room temperature
and the reaction was quenched with a saturated aqueous solution of NH Cl (20 mL). The phases
4
were separated and the aqueous phase was extracted with CH Cl (2
were combined and then washed with brine (40 mL), dried over MgSO , filtered and concentrated in
×
30 mL). The organic extracts
2
2
4
vacuo. The crude product was purified by flash column chromatography (PE-CH Cl , 9:1) to afford
2
2
furan 10 (2.81 g, 91%) as a colourless oil. R = 0.50 (PE-CH Cl , 8:2); IR νmax 3073, 3050, 2955, 2930,
f
2
2
−1 1
2
857, 1589, 1541, 835, 775, 739, 700 cm ; H-NMR (400 MHz, CDCl )
δ
7.61
−
5.56 (4H, m), 7.44
−
7.33
3
(6H, m), 7.27 (1H, d, J = 0.8 Hz), 7.17 (1H, d, J = 0.8 Hz), 4.45 (2H, s), 3.67 (1H, dd, J = 10.1, 5.8 Hz),
3
6
.63 (1H, dd, J = 10.1, 6.4 Hz), 2.75 (1H, dddd, J = 8.6, 6.4, 6.1, 5.8 Hz), 1.78 (1H, app ddt, J = 13.3, 9.7,
.1 Hz), 1.54 1.44 (1H, m), 1.35 1.20 (2H, m), 1.02 (9H, s), 0.90 0.84 (12H, m), 0.04 (3H, s), 0.03 (3H,
140.4, 139.9, 135.8, 135.7, 133.9, 129.7, 129.7, 127.7, 125.6, 125.5, 67.3,
6.9, 37.5, 34.0, 27.0, 26.0, 20.5, 19.4, 18.4, 14.4, 5.2; LRMS (CI, isobutane): m/z (int) 537 (5), 461 (27),
47 (12), 405 (100), 133 (13). HRMS (CI, isobutane) calculated for C H O Si [M + H] : 537.3220;
−
−
−
13
s); C-NMR (101 MHz, CDCl )
5
4
δ
3
−
+
32
49
3
2
found 537.3221.
4
.9. Synthesis of [4-(1-tert-butyldiphenylsilyloxypentan-2-yl)furan-3-yl]methanol (11)
To a solution of furan 10 (2.81 g, 5.23 mmol) in ethanol (18 mL) was added PPTS (660 mg, 2.63 mmol,
◦
0
.5 equiv.) and the mixture was stirred overnight at 40 C. The reaction was quenched with a saturated
aqueous solution of NaHCO (10 mL) and the ethanol was removed in vacuo. The residue was diluted
3
with Et O (20 mL) and the phases were separated. The aqueous phase was extracted with Et O
2
2
(
2 × 10 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4,
filtered and concentrated in vacuo. Residual material was purified by flash column chromatography
(
PE-Et O, 9:1) to give the desired alcohol 11 (2.09 g, 94%) as a colourless oil. R = 0.20 (PE-Et O, 9:1); IR
2
f
2
−1 1
νmax 3366, 2042, 2893, 2866, 1757, 1600, 1541 cm ; H-NMR (400 MHz, CDCl )
7
dd, J = 9.8, 6.9 Hz), 2.81 (1H, ddt, J = 9.1, 6.9, 5.7 Hz), 1.95 (1H, t, J = 5.4 Hz), 1.69 (1H, dddd, J = 13.1,
9
(
3
(
4
δ
7.62
−
7.53 (4H, m),
3
.45
−
7.34 (7H, m), 7.19 (1H, d, J = 1.5 Hz), 4.42 (2H, d, J = 5.4 Hz), 3.72 (1H, dd, J = 9.8, 5.7 Hz), 3.63 (1H,
1
3
.5, 6.4, 5.7 Hz), 1.54
−
1.42 (1H, m), 1.37
140.5, 140.5, 135.8, 135.7, 133.4, 133.4, 129.8, 127.8, 127.7, 126.1, 125.4, 68.7, 55.5,
7.3, 34.0, 26.9, 20.6, 19.3, 14.3; LRMS (CI, isobutane): m/z (int) 405 (34), 365 (6), 341 (5), 265 (100), 237
−
1.20 (2H, m), 1.02 (9H, s), 0.87 (3H, t, J = 7.3 Hz); C-NMR
101 MHz, CDCl3)
δ
+
12), 217 (75) 135 (9). HRMS (CI, isobutane) calculated for C H O Si [M
05.2252.
−
OH] : 405.2250; found
26
33
2
4
.10. Synthesis of tert-butyl[2-(4-chloromethylfuran-3-yl)pentyloxy]diphenylsilane (12)
To a solution of the alcohol 11 (1.47 g, 3.48 mmol) in CH Cl (12 mL) cooled to 0 C, Et N (870
◦
µL,
2
2
3
6.24 mmol, 1.8 equiv.) and MsCl (405 µL, 5.23 mmol, 1.5 equiv.), both freshly distilled, were added
successively. The mixture was warmed to room temperature, stirred overnight and the reaction was
quenched by the addition of a saturated aqueous solution of NH Cl (10 mL). The phases were separated
4

Molecules 2019, 24, 2654
10 of 15
and the aqueous phase was extracted with CH Cl (2
×
15 mL). The organic extracts were combined
2
2
and dried over MgSO , filtered and concentrated in vacuo. The crude product was purified by flash
4
column chromatography (PE-CH Cl , 9:1) to deliver the chloride 12 (1.38 g, 90%) as a colourless
2
2
−1 1
oil. R = 0.40 (PE-CH Cl , 9:1); IR νmax 3071, 2943, 2910, 2862, 1589, 1543, 864, 702 cm ; H-NMR
f
2
2
(
400 MHz, CDCl3)
δ
7.61
−
7.57 (4H, m), 7.44
−
7.33 (7H, m), 7.20 (1H, d, J = 1.5 Hz), 4.35 (2H, s), 3.67 (2H,
1.46
141.5,
40.9, 135.8, 135.7, 133.8, 133.7, 129.8, 129.7, 127.8, 126.1, 122.5, 67.8, 37.2, 36.4, 34.1, 27.0, 20.6, 19.4, 14.3;
LRMS (CI, isobutane): m/z (int) 441 (60), 405 (98), 363 (72), 241 (61), 227 (77), 185 (100), 149 (45), 91
d, J = 5.8 Hz), 2.82 (1H, dtd, J = 9.0, 5.8, 5.7 Hz), 1.81 (1H, dddd, J = 13.2, 9.3, 6.5, 5.7 Hz), 1.59
(
1
−
1H, m), 1.37
−
1.25 (2H, m), 1.03 (9H, s), 0.90 (3H, t, J = 7.3 Hz); 13C-NMR (101 MHz, CDCl3)
δ
35
+
(
31). HRMS (CI, isobutane) calculated for C H O ClSi [M + H] : 441.2017; found 441.2015. Anal.
26 34 2
calculated for C H O ClSi: C, 70.80; H, 7.54. Found: C, 70.93; H, 7.59.
26
33
2
4
.11. Synthesis of 4-[4-(1-tert-butyldiphenylsilyloxypentan-2-yl)furan-3-yl]methyl-5-[3-triisopropylsilyl-
prop-2-yn-1-yl]-2,5-dihydrofuran-2-one (13)
To a solution of chloride 12 (449 mg, 1.02 mmol) in THF (2 mL) was added Pd (dba) (57 mg,
2
3
0
.062 mmol, 6.6 mol %) and triphenylarsine (106 mg, 0.346 mmol, 0.36 equiv.). The purple to yellow
mixture was stirred for 5 min at room temperature before a solution of the stannane
4 (419 mg,
◦
0.950 mmol) in THF (9 mL) was added. The mixture was heated at 65 C overnight, cooled to room
temperature and then diluted with Et O (30 mL) and H O (10 mL). The phases were separated and the
2
2
aqueous phase was extracted with Et O (2
×
20 mL). The organic extracts were combined, washed with
2
brine (30 mL), dried over MgSO , filtered and concentrated in vacuo. Residual material was purified
4
by flash column chromatography (PE
−
Et O, 95:5
→
92:8) to give the corresponding product 13 (605 mg,
2
9
7
3%) as a pale-yellow oil and an inseparable mixture (1:1) of diastereoisomers. R = 0.69 (PE Et O,
−
1 1
f
2
−
:3); IR νmax 3071, 2932, 2862, 2175, 1759, 1643, 1589, 995, 926, 872, 802, 741, 702, 679 cm ; H-NMR
7.58 7.54 (8H, m), 7.45 7.33 (12H, m), 7.25 (1H, d, J = 1.6 Hz), 7.24 7.23 (2H, m),
.22 (1H, d, J = 1.5 Hz), 5.72 (1H, d, J = 1.3 Hz), 5.67 (1H, d, J = 1.5 Hz), 4.82 (1H, app t, J = 5.0 Hz),
.80 (1H, app t, J = 5.0 Hz), 3.62 3.59 (4H, m), 3.52 (1H, d, J = 17.7 Hz), 3.43 (1H, d, J = 18.4 Hz), 3.24
(400 MHz, CDCl3)
δ
−
−
−
7
4
−
(
1H, dd, J = 17.7, 1.5 Hz), 3.20 (1H, d, J = 18.4 Hz), 2.90 (1H, dd, J = 5.1, 2.0 Hz), 2.86 (1H, dd, J = 5.1, 2.0
Hz), 2.67 (1H, dd, J = 5.1, 4.0 Hz), 2.63 (1H, dd, J = 5.1, 3.9 Hz), 2.54 (1H, dq, J = 9.0, 5.8 Hz), 2.49 (1H,
dq, J = 8.7, 5.8 Hz), 1.79 1.69 (2H, m), 1.51 1.38 (2H, m), 1.30 1.16 (4H, m), 1.05 0.98 (60H, m), 0.86
3H, t, J = 7.3 Hz), 0.87 (3H, t, J = 7.3 Hz); C-NMR (101 MHz, CDCl ) 171.9, 169.7, 169.5, 140.8, 140.7,
40.4, 140.3, 135.7, 135.6, 133.6, 133.5, 129.9, 129.8, 127.8, 126.2, 119.4, 118.4, 99.7, 99.6, 85.4, 80.5, 80.4,
−
−
3
−
−
1
(
δ
3
1
6
7.9, 67.8, 37.5, 34.2, 34.1, 27.0, 23.6, 23.5, 23.1, 23.0, 20.7, 19.4, 18.7, 14.4, 11.3; LRMS (FAB): m/z (int) 705
+
(100), 605 (67), 427 (9), 197 (40), 135 (73), 59 (42). HRMS (FAB) calculated for C H NaO Si [M+Na] :
42
58
4
2
7
05.3771; found 705.3763.
4
.12. Synthesis of 4-[4-(1-hydroxypentan-2-yl)furan-3-yl]methyl-5-(prop-2-yn-1-yl)-2,5-dihydrofuran-2-one (14)
◦
To a solution of 13 (1.23 g, 1.80 mmol) in THF (31 mL) at 0 C was added acetic acid (400
µL,
6
.99 mmol, 3.88 equiv.) and TBAF (7.4 mL of a 1 m solution in THF, 7.4 mmol, 4.1 equiv.). The mixture
was warmed slowly to room temperature, stirred for 24 h and then diluted with water (10 mL) and ethyl
acetate (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2
×
30 mL). The organic extracts were combined, washed with brine (50 mL), dried over MgSO , filtered
4
and concentrated in vacuo. Residual material was purified by flash column chromatography (PE
:1 1:4) to give a diastereomeric mixture of the corresponding unprotected alcohols 14 (461 mg, 89%)
as a pale-yellow oil and a partially separable 1:1 mixture of diastereoisomers. R = 0.44 and 0.42
−
Et O,
2
1
→
f
−
1
(PE-Et O, 1:4); IR νmax 3446, 2954, 2933, 2869, 2360, 1742, 1645, 924, 875, 850, 798 cm ; Less polar
2
1
diastereoisomer H-NMR (400 MHz, CDCl )
δ
7.30 (2H, s), 5.78 (1H, ddd, J = 1.5, 1.5, 1.2 Hz), 5.03 (1H,
3.60 (2H, m), 3.59 (1H, dd, J = 18.3, 1.5 Hz), 3.45 (1H, dd, J = 18.3, 1.5 Hz),
.85 (1H, ddd, J = 17.3, 5.6, 2.6 Hz), 2.73 (1H, ddd, J = 17.3, 4.2, 2.7 Hz), 2.59 (1H, dq, J = 8.6, 5.9 Hz),
.07 (1H, dd, J = 2.7, 2.6 Hz), 1.69 1.59 (1H, m), 1.52 1.41 (1H, m), 1.36 1.23 (2H, m), 0.89 (3H, t, J
3
ddd, J = 5.6, 4.2, 1.2 Hz), 3.68
2
2
−
−
−
−

Molecules 2019, 24, 2654
11 of 15
=
7.3 Hz); Less polar diastereoisomer 13C-NMR (101 MHz, CDCl3)
δ
172.0, 169.9, 141.0, 140.5, 126.0,
1
119.5, 118.5, 80.3, 76.6, 72.6, 66.7, 37.5, 34.5, 23.2, 22.6, 20.7, 14.3; More polar diastereoisomer H-NMR
(
3
6
400 MHz, CDCl3)
δ
7.30 (2H, s), 5.81 (1H, ddd, J = 1.6, 1.6, 1.5 Hz), 5.00 (1H, ddd, J = 6.3, 4.6, 1.5 Hz),
3.59 (2H, m), 3.59 (1H, dd, J = 18.2, 1.6 Hz), 3.44 (1H, dd, J = 18.2, 1.6 Hz), 2.87 (1H, ddd, J = 17.3,
.3, 2.5 Hz), 2.74 (1H, ddd, J = 17.3, 4.6, 2.5 Hz), 2.68 2.55 (1H, m), 2.08 (1H, t, J = 2.5 Hz), 1.69 1.58
1.40 (1H, m), 1.36 1.27 (2H, m), 0.89 (3H, t, J = 7.3 Hz,); More polar diastereoisomer
C-NMR (101 MHz, CDCl ) 172.0, 169.7, 141.1, 140.6, 126.0, 119.4, 118.5, 80.2, 76.5, 72.7, 66.9, 37.5,
4.2, 23.2, 22.6, 20.6, 14.3; LRMS (CI, isobutane): m/z (int) 289 (100), 71 (13). HRMS (CI, isobutane)
.70
−
−
−
(
1H, m), 1.52
−
−
1
3
δ
3
3
+
calculated for C H O [M + H] : 289.1440; found 289.1442.
17
21
4
4
2
.13. Synthesis of (5S*)-4-{4-[(2S*)-1-Hydroxypentan-2-yl]furan-3-yl}methyl-5-(2-iodoprop-2-en-1-yl)-
,5-dihydrofuran-2-one (15a) and (5R*)-4-{4-[(2S*)-1-Hydroxypentan-2-yl]furan-3-yl}methyl-5-
(
2-iodoprop-2-en-1-yl)-2,5-dihydrofuran-2-one (15b)
To a solution of alkynes 14 (419 mg, 1.45 mmol) in THF (6.6 mL) at room temperature was added
Pd(PPh ) (60.1 mg, 0.0520 mmol, 3.6 mol %) followed by tributyltin hydride (425
µL, 1.58 mmol,
3
4
1.1 equiv.). The mixture was stirred for 20 min and the reaction was quenched with saturated aqueous
NaHCO (5 mL). The mixture was diluted with Et O (10 mL) and the phases were then separated.
3
2
The aqueous phase was extracted with Et O (3
×
10 mL) and the organic extracts were combined,
2
washed with brine (20 mL), dried with Na SO , filtered and concentrated in vacuo. The crude
2
4
material was purified by flash column chromatography (PE-Et O, 1:1
regioisomeric mixture (3.2:1 ratio, estimated by H-NMR analysis) in favour of the required vinylic
stannane. Most of the required stannane (572 mg) were isolated and taken straight to the next step for
→
2:3) to give a partially separable
2
1
better characterisation. R = 0.68 and 0.76 (PE-Et O, 1:4).
f
2
◦
To a solution of the vinylic stannane (572 mg, 0.988 mmol) in CH Cl (10 mL) at 0 C was added
2
2
I2 (289 mg, 1.14 mmol, 1.15 equiv.). The mixture was stirred for 20 min and the reaction was then
quenched with a saturated aqueous solution of Na S O (15 mL). The mixture was diluted with CH Cl
2
2
3
2
2
(
(
20 mL) and after 10 min, the phases were separated. The aqueous phase was extracted with CH Cl
2
2
2 × 20 mL) and the organic extracts were combined, washed with brine (30 mL), dried with Na SO ,
2
4
filtered and concentrated in vacuo. The crude product was purified by flash column chromatography
PE-Et O, 55:45) to give the separable diastereomeric vinyl iodides 15a and 15b (378 mg, 62% combined
(
2
over two steps) as colourless oils. 15a (less polar diastereomer) R = 0.36 (PE-Et O, 1:4); IR νmax 3446,
f
2
−1 1
2
δ
5
955, 2929, 2870, 1743, 1637, 1618, 1541, 960, 912, 871, 857, 840, 799 cm ; H-NMR (400 MHz, CDCl )
3
7.30 (2H, s), 6.25 (1H, d, J = 1.7 Hz), 5.91 (1H, d, J = 1.7 Hz), 5.75 (1H, ddd, J = 1.4, 1.1, 1.1 Hz),
.16 (1H, ddd, J = 8.7, 3.6, 1.4 Hz), 3.65 (1H, dd, J = 10.5, 5.6 Hz), 3.59 (1H, dd, J = 10.5, 6.8 Hz), 3.55 (1H,
dd, J = 17.8, 1.1 Hz), 3.46 (1H, dd, J = 17.8, 1.1 Hz), 2.94 (1H, dd, J = 15.0, 3.6 Hz), 2.64 (1H, dd, J = 15.0,
.7 Hz), 2.56 (1H, dddd, J = 8.5, 6.8, 5.9, 5.6 Hz), 1.69 1.58 (2H, m), 1.51 1.40 (1H, m), 1.36 1.23 (2H,
m), 0.89 (3H, t, J = 7.3 Hz); C-NMR (101 MHz, CDCl ) 172.0, 170.2, 141.0, 140.5, 130.5, 126.0, 119.4,
18.3, 102.1, 81.9, 66.8, 48.2, 37.6, 34.4, 23.4, 20.7, 14.3; LRMS (EI+): m/z (int) 416 (100), 385 (10), 289 (56),
71 (20), 215 (33), 161 (35), 119 (21), 91 (45), 77 (20), 55 (10). HRMS (EI+) calculated for C H IO
8
−
−
−
13
δ
3
1
2
1
7
21
4
+
[M] : 416.0485; found 416.0488. 15b (more polar diastereomer) R = 0.31 (PE-Et O, 2:8); IR νmax 3446,
f
−
2
1 1
2
955, 2928, 2869, 1746, 1638, 1618, 1539, 914, 870, 857, 840, 799 cm ; H-NMR (400 MHz, CDCl )
δ
7.30
3
(
(
2H, s), 6.26 (1H, dd, J = 1.7, 0.8 Hz), 5.91 (1H, d, J = 1.7 Hz), 5.78 (1H, ddd, J = 1.5, 1.4, 1.1 Hz), 5.13
1H, ddd, J = 8.6, 3.6, 1.5 Hz), 3.67 (1H, dd, J = 10.5, 5.5 Hz), 3.60 (1H, dd, J = 18.1, 1.1 Hz), 3.59 (1H,
dd, J = 10.5, 6.9 Hz), 3.44 (1H, dd, J = 18.1, 1.4 Hz), 2.95 (1H, dd, J = 15.0, 3.6 Hz), 2.63 (1H, ddd, J =
1
1
5.0, 8.6, 0.8 Hz), 2.57 (1H, dddd, J = 8.6, 6.9, 5.6, 5.5 Hz), 1.63 (1H, dddd, J = 13.1, 9.6, 6.1, 5.6 Hz),
.55 (1H, br s), 1.51 1.41 (1H, m), 1.36
−
−
1.22 (2H, m), 0.89 (3H, t, J = 7.3 Hz); 13C-NMR (101 MHz,
CDCl ) δ 172.0, 170.1, 141.0, 140.6, 130.5, 126.0, 119.4, 118.3, 102.2, 81.8, 67.0, 48.2, 37.6, 34.2, 23.4, 20.7,
3
1
4.3; LRMS (CI, isobutane): m/z (int) 417 (69), 291 (100), 273 (46), 251 (10), 97 (13), 71 (28). HRMS (CI,
+
isobutane) calculated for C H IO [M + H] : 417.0563; found 417.0564.
17
22
4

Molecules 2019, 24, 2654
12 of 15
4
.14. Synthesis of (8S*,9R*,12S*)-9-Hydroxy-10-methylidene-8-propyl-5,13-dioxatricyclo[10.3.0.03,7]
penta-deca-1(15),3,6-trien-14-one (16a) and (8S*,9S*,12S*)-9-Hydroxy-10-methylidene-8-propyl-5,13-dioxa-
tricyclo[10.3.0.03,7]pentadeca-1(15),3,6-trien-14-one (16b)
To a solution of the alcohol 15a (59.2 mg, 0.142 mmol) in CH Cl (2.8 mL) was added Dess-Martin
2
2
periodinane (132 mg, 0.311 mmol, 2.2 equiv.). The mixture was stirred at room temperature for
◦
2
h and then cooled to 0 C. The reaction was quenched by the addition of a saturated aqueous
solution of Na S O (5 mL) and the mixture was diluted with water (5 mL) and CH Cl (5 mL).
2
2
3
2
2
After 10 min, the phases were separated and the aqueous phase was extracted with CH Cl (3
×
5 mL).
2
2
The organic extracts were combined and washed with brine (10 mL), then dried with Na SO , filtered
2
4
and concentrated in vacuo. The crude product was purified quickly by passage through a small plug
of silica (PE-Et O, 4:1) to afford the corresponding aldehyde (50.1 mg, 85%) as a colourless oil.
2
To a solution of CrCl (200 mg, 1.63 mmol, 13.5 equiv.) and NiCl (1.6 mg, 0.012 mmol, 10 mol %)
2
2
in previously degassed (three freeze-thaw cycles) DMSO (6 mL) was added a solution of aldehyde
(
50.1 mg) in degassed (three freeze-thaw cycles) DMSO (6 mL) at room temperature. The dark green
◦
mixture was stirred at room temperature for 24 h and at 50 C for 16 h. The reaction was quenched by
the addition of a saturated aqueous solution of NH Cl (15 mL) and the mixture was diluted with EtOAc
4
(
30 mL). The biphasic mixture was stirred for 30 min, the phases were separated and the aqueous
phase was extracted with EtOAc (3 30 mL). The organic extracts were combined, washed with brine
50 mL), dried over MgSO , filtered and concentrated in vacuo. Residual material was purified by flash
×
(
4
column chromatography (PE-Et O, 9:11) allowing the separation of minor diastereomer 16b (5.5 mg,
2
1
3% over two steps) as a colourless oil and major diastereomer 16a (20.2 mg, 49% over two steps) as
a colourless solid. The crystal structure of the major alcohol product 16a was obtained. 16b (less polar,
◦
minor diastereomer) M.p. 140
1
−
143 C; R = 0.53 (PE-Et O, 1:4); IR νmax 3454, 2955, 2930, 2870, 1743,
f
2
−
1 1
636, 1537, 926, 868, 802, 766, 739 cm ; H-NMR (500 MHz, CDCl )
δ
7.37 (1H, d, J = 1.5 Hz), 7.23 (1H,
3
d, J = 1.5 Hz), 5.89 (1H, ddd, J = 1.6, 1.1, 1.1 Hz), 5.23 (1H, ddd, J = 3.6, 2.7, 1.6 Hz), 4.97 (1H, s), 4.94 (1H,
s), 4.12 (1H, d, J = 1.5 Hz), 3.68 (1H, dd, J = 14.7, 1.1 Hz), 3.01 (1H, dd, J = 14.7, 1.1 Hz), 2.97 (1H, ddd,
J = 8.6, 6.5, 1.5 Hz), 2.91 (1H, dd, J = 16.4, 2.7 Hz), 2.45 (1H, dd, J = 16.4, 3.6 Hz), 1.84
−
1.65 (2H, m,
172.6,
70.3, 143.2, 140.8, 140.5, 122.5, 122.0, 120.0, 113.5, 83.9, 74.8, 38.0, 30.5, 30.2, 21.5, 21.1, 14.1; LRMS (CI,
CH -C7), 1.57 (1H, br s), 1.40
−
1.29 (2H, m), 0.92 (3H, t, J = 7.4 Hz); 13C-NMR (126 MHz, CDCl )
δ
3
2
1
isobutane): m/z (int) 289 (72), 273 (12), 137 (13), 113 (68), 97 (68), 81 (73), 71 (100). HRMS (CI, isobutane)
+
calculated for C H O [M+H] : 289.1440; found 289.1438. 16a (more polar, major diastereomer) M.p.
17
21
4
◦
40 142 C; R = 0.44 (PE-Et O, 2:8); IR νmax 3400, 2957, 2928, 2872, 1736, 1636, 1537, 962, 939, 910, 870,
f 2
1
8
−
−
1 1
02, 777, 739 cm ; H-NMR (500 MHz, CDCl )
δ
7.34 (1H, s), 7.23 (1H, s), 5.93 (1H, s), 5.15 (1H, s),
.92 (1H, s), 4.87 (1H, s), 3.90 (1H, d, J = 4.3 Hz), 3.68 (1H, d, J = 16.0 Hz), 3.27 (1H, br s), 2.81 2.71 (2H,
1.44 (1H, m), 1.39 1.28 (1H, m), 1.27 1.14 (1H, m), 0.89 (3H, t, J
172.8, 170.4, 141.9, 141.5, 141.0, 123.3, 121.1, 119.7, 118.6, 83.2,
3
4
−
m), 2.55 (1H, br s), 1.85 (2H, br s), 1.55
−
−
−
=
7.4 Hz); 13C-NMR (126 MHz, CDCl3)
δ
8
1.5, 39.7, 32.7, 28.9, 22.8, 20.9, 14.2; LRMS (EI+): m/z (int) 288 (100), 270 (43), 259 (36), 219 (64), 173 (51),
+
129 (39), 91 (81), 77 (47), 43 (47). HRMS (EI+) calculated for C H O [M] : 288.1362; found 288.1360.
17
20
4
X-ray crystal data (CCDC 1920025) for C H O (M = 288.34 g/mol): orthorhombic, space group
1
7
20
4
3
P212121, a = 7.2695(5) Å, b = 11.8269(10) Å, c = 17.3278(12) Å, V = 1489.77(19) Å , Z = 4, T = 100 K
,
–1
3
µ(MoKα
) = 0.091 mm , D
= 1.286 g/cm , 37377 measured reflections, 2650 independent reflections
calc.
(
Rint = 0.074). Final R indices R1 = 0.0386 [for 2468 reflections, with I > 2σ(I)], wR2 = 0.0924 (all data).
4
[
8
.15. Synthesis of (8S*,9S*,12R*)-9-Hydroxy-10-methylidene-8-propyl-5,13-dioxatricyclo
10.3.0.03 ]penta-deca-1(15),3,6-trien-14-one and (8S*,9R*,12R*)-9-Hydroxy-10-methylidene-
,7
-propyl-5,13-dioxatricyclo-[10.3.0.03 ]pentadeca-1(15),3,6-trien-14-one (16c, 16d)
,7
To a solution of the alcohol 15b (59.2 mg, 0.142 mmol) in CH Cl (2.5 mL) was added Dess-Martin
2
2
periodinane (80.2 mg, 0.189 mmol, 1.54 equiv.). The mixture was stirred at room temperature for
◦
4
0 min, cooled to 0 C and the reaction was quenched with a saturated aqueous solution of Na S O
2
2
3
(
5 mL). The mixture was diluted with water (5 mL) and CH Cl (5 mL) and after 10 min, the phases
2 2

Molecules 2019, 24, 2654
13 of 15
were separated. The aqueous phase was extracted with CH Cl (3
×
5 mL) and the combined organic
2
2
extracts were washed with brine (10 mL), dried with Na SO , filtered and concentrated in vacuo.
2
4
The crude product was purified quickly by passage through a small plug of silica (PE-Et O, 4:1) to
2
afford the corresponding aldehyde (50.9 mg, 100%) as a colourless oil.
To a solution of CrCl (215 mg, 1.75 mmol, 12.4 equiv.) and NiCl (2.5 mg, 0.019 mmol, 13 mol %)
2
2
in degassed (three freeze-thaw cycles) DMSO (6 mL) was added a solution of aldehyde (50.9 mg) in
degassed (three freeze-thaw cycles) DMSO (6.5 mL) at room temperature. The dark green mixture
◦
was stirred for 48 h at 50 C. The reaction was quenched with saturated aqueous NH Cl (15 mL)
4
and the mixture diluted with EtOAc (30 mL). The biphasic mixture was stirred for 30 min and the
phases were separated. The aqueous phase was extracted with EtOAc (3 × 30 mL) and the combined
organic extracts were washed with brine (50 mL), dried over MgSO , filtered and concentrated in
4
vacuo. The crude product was purified by flash column chromatography (PE-Et O, 9:11) to give an
2
1
inseparable mixture (1:2.4 / 2.4:1 based on H-NMR analysis) of the diastereoisomeric alcohols 16c
and 16d (17.8 mg, 43%). R = 0.25 (PE-Et O, 2:3); IR νmax 3448, 2957, 2928, 2872, 2360, 1748, 1633,
f
2
−
1
1
1
541, 1465 cm ; Minor diastereomer H-NMR (500 MHz, CDCl )
δ
7.34 (1H, d, J = 1.4 Hz), 7.32 (1H, d,
J = 1.4 Hz), 6.02 (1H, br s), 5.14 (1H, s), 5.05 (1H, s), 4.98 (1H, ddd, J = 4.5, 3.6, 1.0 Hz), 4.14 (1H, s), 3.76
1H, dd, J = 18.0, 0.8 Hz), 3.67 (1H, d, J = 18.0 Hz), 2.60 2.48 (2H, m), 2.05 (1H, app ddd, J = 15.2, 3.6,
.3 Hz), 2.11 (1H, br s), 1.92 (1H, br s), 1.56 1.49 (1H, m), 1.37 1.24 (1H, m), 1.23 1.11 (1H, m), 0.87
3H, t, J = 7.4 Hz); 13C-NMR (126 MHz, CDCl )
3
(
1
(
1
−
−
−
−
δ
172.6, 171.4, 146.4, 142.1, 140.4, 123.7, 119.5, 119.4,
3
1
19.2, 82.6, 77.8, 39.6, 35.2, 30.9, 24.2, 20.7, 14.0; Major diastereomer H-NMR (500 MHz, CDCl )
δ
7.28
3
(
1H, s), 7.23 (1H, d, J = 1.5 Hz), 5.90 (1H, ddd, J = 1.5, 1.5, 1.5 Hz), 5.13 (1H, s), 5.05 (1H, s), 4.75 (1H, br
s), 3.98 (1H, d, J = 7.4 Hz), 3.83 3.73 (1H, m), 3.61 (1H, d, J = 17.9 Hz), 2.60 2.48 (2H, m), 2.39 (1H, d,
J = 15.4 Hz), 1.92 (1H, br s), 1.78 1.61 (2H, m), 1.37 1.24 (1H, m), 1.23 1.11 (1H, m), 0.87 (3H, t, J =
.4 Hz); 13C-NMR (126 MHz, CDCl )
172.5, 168.6, 143.4, 141.2, 140.4, 123.7, 119.1, 116.9, 116.4, 86.2,
−
−
−
−
−
7
8
δ
3
1.5, 40.0, 37.1, 31.1, 22.5, 20.8, 14.2; LRMS (CI, isobutane): m/z (int) 289 (100), 271 (24), 137 (10), 71 (13).
+
HRMS (CI, isobutane) calculated for C H O [M + H] : 289.1440; found 289.1436.
17
21
4
4
1
.16. Synthesis of (8S*,12R*)-10-Methylidene-8-propyl-5,13-dioxatricyclo[10.3.0.03,7]pentadeca-
(15),3,6-triene-9,14-dione (17)
To a solution of the diastereoisomeric alcohols 16c and 16d (7.1 mg, 0.025 mmol) in CH Cl (1 mL)
2
2
was added Dess-Martin periodinane (15.6 mg, 0.0368 mmol, 1.49 equiv.). The solution was stirred
◦
at room temperature for 1 h and then cooled to 0 C. The reaction was quenched by the addition of
a saturated aqueous solution of Na S O (5 mL) and the mixture was diluted with water (5 mL) and
2
2
3
CH Cl (5 mL). After 10 min, the phases were separated and the aqueous phase was extracted with
2
2
CH Cl (3
×
5 mL). The organic extracts were combined and washed with brine (10 mL), dried with
2
2
Na SO , filtered and concentrated in vacuo. The crude product was purified by passage through
2
4
a small plug of silica (PE-Et O, 5:5) to give the enone 17 (7.0 mg, 99%) of a colourless oil. R = 0.50
2
f
(
8
PE-Et O, 1:4); IR νmax 3154, 3100, 2959, 2933, 2922, 2872, 1791, 1755, 1688, 1634, 1534, 981, 923, 898, 875,
2
−
59, 804, 765, 746 cm ; H-NMR (500 MHz, CDCl ) δ 7.29 (1H, d, J = 1.2 Hz), 7.28 (1H, s), 5.88 (1H, td,
3
1 1
J = 1.9, 1.3 Hz), 5.74 (1H, d, J = 1.2 Hz), 5.70 (1H, d, J = 1.2 Hz), 4.81 (1H, ddd, J = 8.6, 5.2, 1.3 Hz),
.09 (1H, ddd, J = 10.3, 4.2, 1.2 Hz), 3.62 (2H, d, J = 1.9 Hz), 3.46 (1H, dd, J = 13.9, 5.2 Hz), 2.42 (1H, dd,
J = 13.9, 8.6 Hz), 2.19 2.12 (1H, m), 1.75 (1H, dddd, J = 13.0, 8.5, 7.5, 4.2 Hz), 1.39 (2H, app tq, J = 7.5,
.3 Hz), 0.99 (3H, t, J = 7.3 Hz).
4
−
7
4
3
.17. Luche Reduction of (8S*,12R*)-10-Methylidene-8-propyl-5,13-dioxatricyclo[10.3.0.03,7]pentadeca-1(15),
,6-triene-9,14-dione (17)
To a solution of the enone 17 (5.3 mg, 19
mol, 3.4 equiv.). The reaction was cooled to
.2 equiv.). The mixture was stirred for 1 h and the reaction was quenched by the addition of saturated
µ
mol) in MeOH (1.8 mL) was added CeCl3
·
7H O (24 mg,
2
◦
6
2
4
µ
−
78 C before addition of NaBH (1.6 mg, 42
µmol,
4
aqueous NH Cl (5 mL) and water (5mL). The mixture was warmed to room temperature and EtOAc
4

Molecules 2019, 24, 2654
14 of 15
(
(
10 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc
3 × 10 mL). The organic extracts were combined, washed with brine (20 mL), dried over MgSO ,
4
1
filtered and concentrated in vacuo. Analysis of the residue (5.3 mg, quant.) by H-NMR revealed
a mixture of diastereoisomeric alcohols 16c and 16d with a slightly higher ratio (1:3 / 3:1 determined by
1
H-NMR analysis) in favour of the major isomer produced by the original NHK reaction.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/14/2654/s1,
1
13
H and C-NMR spectra for key compounds 4, 12, 15a, 15b, 16a–d.
Author Contributions: J.S.C. conceived the synthetic route, supervised the project and wrote the paper; J.S.C. and
A.A. designed the experiments; A.A. performed all synthetic work in the laboratory; L.J.F. generated and analysed
X-ray crystallography data for allylic alcohol 16a.
Funding: This research was funded a postgraduate scholarship (A.A.) awarded by the University of Glasgow.
Acknowledgments: The authors would like to express their thanks to Dr. Claire Wilson (University of Glasgow)
for assistance with X-ray crystallography data.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
2
.
.
Haneishi, T.; Nakajima, M.; Koi, K.; Furuya, K.; Iwado, S.; Sato, S. Anhydride Herbicides. U.S. Patent 4897104, 1990.
Haneishi, T.; Nakajima, M.; Koi, K.; Furuya, K.; Iwado, S.; Sata, S. Herbicide, Its Preparation and Use. U.S.
Patent 4990178, 1991.
3
.
Nakajima, M.; Itoi, K.; Takamatsu, Y.; Sato, S.; Furukawa, Y.; Furuya, K.; Honma, T.; Kadotani, J.; Kozasa, M.;
Haneishi, T. Cornexistin: A New Fungal Metabolite with Herbicidal Activity. J. Antibiot. 1991, 44, 1065–1071.
[CrossRef] [PubMed]
4
5
.
.
Fields, S.C.; Gerwick, B.C.; Mireles-Lo, L. Hydroxycornexistin. U.S. Patent 5424278, 1995.
Fields, S.C.; Mireles-Lo, L.; Gerwick, B.C. Hydroxycornexistin: A New Phytotoxin from Paecilomyces Variotii.
J. Nat. Prod. 1996, 59, 698–700. [CrossRef]
6
7
8
9
1
.
.
.
.
Mioso, R.; Toledo Marante, F.J.; Herrera Bravo de Laguna, I. The Chemical Diversity of the Ascomycete
Fungus Paecilomyces Variotii. Appl. Biochem. Biotechnol. 2015, 177, 781–791. [CrossRef] [PubMed]
Chen, X.; Zheng, Y.; Shen, Y. Natural Products with Maleic Anhydride Structure: Nonadrides, Tautomycin,
Chaetomellic Anhydride, and Other Compounds. Chem. Rev. 2007, 107, 1777–1830. [CrossRef] [PubMed]
Amagasa, T.; Paul, R.N.; Heitholt, J.J.; Duke, S.O. Physiological Effects of Cornexistin on Lemna pausicostata.
Pestic. Biochem. Physiol. 1994, 49, 37–52. [CrossRef]
Clark, J.S.; Marlin, F.; Nay, B.; Wilson, C. Synthesis of the Carbocyclic Core of the Cornexistins by Ring-Closing
Metathesis. Org. Lett. 2003, 5, 89–92. [CrossRef] [PubMed]
0. Clark, J.S.; Northall, J.M.; Marlin, F.; Nay, B.; Wilson, C.; Blake, A.J.; Waring, M.J. Synthetic Studies on the
Cornexistins: Synthesis of ( )-5-epi-Hydroxycornexistin. Org. Biomol. Chem. 2008, 6, 4012–4025. [CrossRef]
PubMed]
±
[
1
1
1
1
1. Tung, J.C.; Chen, W.; Noll, B.C.; Taylor, R.E.; Fields, S.C.; Dent, W.H., III; Green, F.R., III. Towards the Synthesis
of the Cornexistins. Synthesis 2007, 2388–2396.
2. Tian, Q.; Zhang, G. Recent Advances in the Asymmetric Nozaki-Hiyama-Kishi Reaction. Synthesis 2016, 48,
4
038–4049.
3. Aimon, A. A NHK Approach Towards the Total Synthesis of the Cornexistins. Ph.D. Thesis, University of
Glasgow, Glasgow, UK, 2013.
4. Fumiyama, H.; Sadayuki, T.; Osada, Y.; Goto, Y.; Nakao, Y.; Hosokawa, S. Synthesis and Antileishmanial
Activity of the Core Structure of Cristaxenicin A. Bioorg. Med. Chem. Lett. 2016, 26, 4355–4357. [CrossRef]
[PubMed]
1
1
5. Momose, T.; Toyooka, N.; Nishi, T.; Takeuchj, Y. 2(3H)- and 2(5H)-Furanones. III. An Efficient Synthesis
and the Eschenmoser-Mannich Reaction of N-Substituted 4-Amino-2(5H)-furanones. Heterocycles 1988, 27,
1
907–1923. [CrossRef]
6. Marshall, J.A.; Jenson, T.M.; DeHoff, B.S. [2,3]-Wittig Ring Contraction. A New Route to Cembranoid Natural
Products. J. Org. Chem. 1986, 51, 4316–4319. [CrossRef]

Molecules 2019, 24, 2654
15 of 15
1
7. Wulff, W.D.; Peterson, G.A.; Bauta, W.E.; Chan, K.-S.; Faron, K.L.; Gilbertson, S.R.; Kaesler, R.W.; Yang, D.C.;
Murray, C.K. A Regioselective Entry to Vinyl Lithiums from Unsymmetrical Ketones via Enol Triflates.
J. Org. Chem. 1986, 51, 277–279. [CrossRef]
1
1
2
8. Cook, M.J.; Forbes, E.J. [4,5-c] Furotropone: A New Heterocyclic System. Tetrahedron 1968, 24, 4501–4508.
[
CrossRef]
9. Tanis, S.P.; Head, D.B. Furans in Synthesis 4. Silyl Furans as Butenolide Equivalents. Tetrahedron Lett. 1984
5, 4451–4454. [CrossRef]
,
2
0. Farina, V.; Krishnan, B. Large Rate Accelerations in the Stille Reaction with Tri-2-furylphosphine and
Triphenylarsine as Palladium Ligands: Mechanistic and Synthetic Implications. J. Am. Chem. Soc. 1991, 113,
9
585–9595. [CrossRef]
1. Smith, N.D.; Mancuso, J.; Lautens, M. Metal-Catalyzed Hydrostannations. Chem. Rev. 2000, 100, 3257–3282.
CrossRef] [PubMed]
2. The X-ray data for the alcohol 16a have been deposited in the Cambridge Crystallographic Database
CCDC 1920025). Available online: http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 31 May
019).
2
2
[
(
2
Sample Availability: Samples of the compounds 1, 2, 5 and 6 are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(