First enantioselective total synthesis of altersolanol A

Article abstract of DOI:10.1039/c8ob02113a

The first enantioselective total synthesis of altersolanol A, a secondary metabolite from the endophytic fungi Stemphylium globuliferum and Alternaria solani, is described. The key step towards the tetrahydroanthraquinone core was an asymmetric Diels-Alder (D-A) cycloaddition promoted by (R)-3,3′-diphenyl-BINOL/boron Lewis acid with good to excellent yields and excellent diastereo- and enantioselectivity (>95 : 5 dr and 98 : 2 er).

Full text of DOI:10.1039/c8ob02113a

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First enantioselective total synthesis of
altersolanol A†
Bastian Mechsner,a Birgit Henßena,b and Jörg Pietruszka
Cite this: Org. Biomol. Chem., 2018,
16, 7674
a,b
*
The first enantioselective total synthesis of altersolanol A, a secondary metabolite from the endophytic
fungi Stemphylium globuliferum and Alternaria solani, is described. The key step towards the tetrahy-
droanthraquinone core was an asymmetric Diels–Alder (D–A) cycloaddition promoted by (R)-3,3’-diphe-
nyl-BINOL/boron Lewis acid with good to excellent yields and excellent diastereo- and enantioselectivity
(>95 : 5 dr and 98 : 2 er).
Received 28th August 2018,
Accepted 28th September 2018
DOI: 10.1039/c8ob02113a
rsc.li/obc
dated,9,13 and in 2012 the absolute configuration was deter-
mined by Kanamaru et al. using circular dichroism (CD)
Introduction
Many types of cancers have developed multi-resistance mecha- spectroscopy.14
nisms for a suite of different drugs making it important to
It was shown that enantioselective D–A reactions represent
develop new alternatives.1 Altersolanol A is a highly sought a powerful transformation in organic chemistry with formation
after member of the tetrahydroanthraquinone class of sub- of two new σ-bonds and up to four adjacent stereogenic
strates. These species are known to be widely distributed as centers.15–19 To the best of our knowledge, two reports on
secondary metabolites in natural sources.2,3 Representative racemic total synthesis of altersolanols have been reported to
analogues include the polyketide family of altersolanols (alter- date. Altersolanol B was prepared by Kelly and Montury in
solanol A–C, 1–3)4–6 and alterporriols (alterporriol D, 4)5,7 197820 and altersolanol A was prepared by Krohn and co-
(Fig. 1). These natural compounds were isolated from multiple workers in 1988.21 Kelly used a boron-mediated D–A reaction
endophytic fungi including Stemphylium globuliferum,8 of dienophile 5a with an excess of diene 6a to obtain 7 in 80%
Alternaria solani9 and Alternaria porri.10 Altersolanol A is yield (Scheme 1, entry a). Alternatively, Krohn presented the
known to inhibit plant respiration11 and exhibits cytotoxic D–A reaction of acetate dienophile 5d and OTMS-protected
activity against 34 human cancer cell lines.12 In 1967 Stoessl diene 6b to form 7 in 66% yield (Scheme 1, entry b). The start-
et al. isolated altersolanol A for the first time from Alternaria
solani. Two years later the relative configuration was eluci-
Fig. 1 Structure of altersolanol A–C (1–3) and alterporriol: D (4).
aInstitut für Bioorganische Chemie (IBOC), Heinrich-Heine-Universität Düsseldorf im
Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany.
E-mail: j.pietruszka@fz-juelich.de
bIBG-1: Biotechnologie, Forschungszentrum Jülich, 52425 Jülich, Germany
†Electronic supplementary information (ESI) available: Experimental details and
spectra of all products. See DOI: 10.1039/c8ob02113a
Scheme 1 Key reaction of racemic total synthesis of altersolanol A and
B via a regioselective Diels–Alder reaction [by Kelly and Montury20 (a) as
well as the Krohn group21 (b), and an investigation of Böse et al.22 (c).
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ing point for the total synthesis of enantiomerically pure alter-
solanol A (1) consists of an enantioselective D–A reaction
between juglone-based dienophiles 5c and 1-oxygenated
dienes 6c. Product 9 was successfully accessed using a
BINOL-Ti-derived catalyst first prepared by our group members
Böse et al.22 (Scheme 1, entry c). Herein we would like to
present our enantioselective synthetic route towards altersola-
nol A (1) via a chiral Lewis acid promoted D–A reaction.
Fig. 2 HMBC-correlations showing the relative regioselectivity of D–A
product 10 to aromatic protons and diastereotopic protons (red).
experiment and significant correlations of the carbonyl group
(C-10) with the aromatic proton and the diastereotopic protons
allowed an unambiguous assignment; D–A product 10 had full
endo-selectivity, and no exo-product was detected.
Results and discussion
Our total synthesis was initiated by preparing the chloro-sub-
stituted dienophile 5d following procedures reported by
Brassard et al.23 and the Dallavalle group24 (for detailed con-
ditions see the ESI†). In contrast to the dienophiles 5a–c, the
halogen substituent showed a significant effect on the regio-
selectivity. In previous studies it was shown that the phenolic
proton of the dienophiles functioned as a weak Lewis acid, but
the additional electron-withdrawing effect of the halogen led
to an enhanced regioselectivity of >95 : 5 dr.25 However, pre-
vious literature focused only on the regioselectivity and sub-
sequent aromatization steps where the chiral information is
lost.26,27 Another benefit of the herein presented dienophile
5d is the basic workup that was sufficient to establish the
benzoquinone core in quantitative yield, instead of oxidation
procedures.21 It was shown that peri-hydroxynaphthoquinones
are attractive candidates for Lewis acid promotion because of
the complex formation of the hydroxy group and the coordi-
nation of the carbonyl with highly diminishing conformational
mobility. By using achiral or chiral Lewis acids regiocontrol
could be influenced in a predictable manner.20 Most impor-
tantly asymmetric induction should take place for this system
as a result of the steric hindrance at one site of the quinone
moiety.28–30
Inspired by the asymmetric D–A reaction of juglone-based
moieties,28–30 our results of BINOL/boron Lewis acid promoted
cycloaddition are presented in Table 1. At this point it is worth
mentioning that water-free conditions were essential for the
success of the reaction. The dark red colour of the complex
from the chiral Lewis acid and dienophile confirmed that the
reaction conditions were sufficiently dry. Another important
observation is that complex formation between the dienophile
and BINOL–boron reagent was complete within 10 min.
However, no D–A product was formed over the course of an
hour.30 Using (S)-BINOL (S)-L1 as a chiral ligand the cyclo-
addition in THF resulted in 80% yield, but in a moderate enan-
tiomeric ratio of 33 : 67 of products (1R,4aR,9aR)-10 and
Table 1 Screening of the chiral ligand for the asymmetric D–A reaction
The study was initialized by investigating the cycloaddition
between chloro-substituted naphthoquinone 5d and 2.0 equiv.
of OTBS-protected diene 6d22 (for detailed synthetic con-
ditions see the ESI†) yielding racemic D–A product 10
(Scheme 2). As a first objective, we wanted to find a convenient
purification protocol for the isolation of product 10, because
standard procedures (chromatography on silica gel) led to aro-
matisation, which is well documented.31 However, upon treat-
ment with n-pentane the excess of diene was extracted, while
at the same time analytically pure D–A product 10 was formed
as a precipitate. A 2D-NMR study verified that 10 was syn-
thesised as a single constitutional isomer (Fig. 2). HMBC
Entry
Ligand
Equiv. (ligand)
T [°C]
Yielda [%]
erb
1
(S)-L1
(S)-L1
(S)-L1
(S)-L1
(S)-L2
(R)-L2
(R)-L2
(R)-L2
2.0
2.0
2.0
2.0
2.0
2.0
1.2
2.0
22
22
22
4
4
4
80
94
41
85
90
77
72
86
33 : 67
36 : 64
28 : 72
34 : 66
3 : 97
98 : 2
72 : 28
98 : 2
2c
3d
4
5e
6e
7e
8f,g
4
4
a Conditions: Chiral ligand, BH3·THF, AcOH, dienophile 5d (1.00
equiv., 0.10 mmol), diene 6d (2.00 equiv.), isolated yield. b er =
(1R,4aR,9aR)-10:(1S,4aS,9aS)-10, determined by chiral HPLC [Lux-
Amylose (250 mm 46 mm, Fa. Phenomenex)]. c Reaction in toluene.
d Reaction in CH2Cl2. e 5d (0.05 mmol). f With the recycled ligand, one
cycle, 98% recovery (R)-L2. g 5d (0.63 mmol).
Scheme 2 Racemic D–A reaction of dienophile 5d with diene 6d to D–
A product 10.
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(1S,4aS,9aS)-10 (Table 1, entry 1). We next changed the solvent
to toluene and increased the yield, but a comparable enantio-
meric ratio was obtained (Table 1, entry 2). Using dichloro-
methane as a solvent, the yield dropped significantly to 41%. A
slightly better enantiomeric ratio of 28 : 72 was observed
(Table 1, entry 3). For the next optimisation, we used THF as a
solvent, because of reaction handling. The temperature was
lowered to 4 °C, but no improvement with ligand (S)-L1 was
observed (Table 1, entry 4).
Employing the bulkier ligand (S)-L2 afforded excellent
selectivity of product (1S,4aS,9aS)-10 with an enantiomeric
ratio of 3 : 97 and a yield of 90% (Table 1, entry 5). According
to Kelly and co-workers (S)-diphenyl-BINOL (S)-L2 favours the
formation of the (S)-configuration at C-1, which was deter-
mined during the synthesis of (−)-bostrycin.28,32 With the
potential catalyst and the optimised reaction conditions we
had to use the (R)-L2 ligand to selectively prepare the (R)-con-
figured D–A product 10 (at C-1).14 Herein we expected that
complex 11 was formed under water-free conditions with the
upper side being blocked by the phenyl residue. As a result,
for the D–A reaction with endo-selectivity the diene 6d had to
approach the complexed dienophile 11 from the lower face
(Fig. 3). Ligand (R)-L2 was synthesised on a 10 g scale accord-
ing to a previously reported procedure33,34 (for detailed con-
ditions see the ESI†). The asymmetric D–A product
(1R,4aR,9aR)-10 was prepared in 77% yield and with an excel-
lent enantiomeric ratio of 98 : 2 (Table 1, entry 6). When the
amount of chiral BINOL–boron reagent was reduced to 1.2
equiv., the enantiomeric ratio decreased dramatically (Table 1,
entry 7).30 Finally, it should be noted that recycled ligand (R)-
L2 yielded in a subsequent reaction 86% of (1R,4aR,9aR)-10 in
an enantiomeric ratio of 98 : 2 (Table 1, entry 8).
Scheme 3 Reaction scheme for the synthesis of OTBS-protected diol
(1S,2S)-14.
The epoxide was then opened with the sterically hindered base
diisopropylethylamine (DIPEA). This produced the allyl
alcohol (1S,2S)-14 in 33–62% yield over three steps with excel-
lent enantiomeric ratios of 94 : 6 to 96 : 4 and >95 : 5 dr. Mono-
OTBS-protected cis-diol was not observed, likely due to its aro-
matisation under basic conditions.
In the next step towards the total synthesis of altersolanol A
(1), the allyl alcohol double bond of (1S,2S)-14 was epoxidized
(Scheme 4). Treatment of 14 with mCPBA led to separable dia-
stereoisomers (1aR,2R,3S,9bS)-15 and(1aS,2R,3S,9bR)-16 in
The next step was the epoxidation of (1R,4aR,9aR)-10 and
the conversion to TBS-protected diol (1S,2S)-14 (Scheme 3).
Due to the instability of compound 10 upon common workup
methods, the epoxidation was attempted first without further
purification of the intermediate. However, no conversion
towards epoxide 12 was observed. As a result, it was necessary
to purify product 10 utilizing a water-cooled flash-chromato-
graphy system. Subsequently, epoxide 12 was obtained in a dia-
stereomeric ratio of 5.5 : 1 after 4 d, and basic aqueous NaOH
washes led to the elimination product 13 in quantitative yield.
Fig. 3 Demonstration of the intermediacy of the Lewis acid complex
with dienophile 5d and diene 6d in the endo-transition state.
Scheme 4 Epoxidation and epoxide opening to (1S,2R,3R,4S)-17 and
altersolanol A (1).
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yields from 32 to 71% with a diastereomeric ratio of 1 : 1.5 25 g phosphomolybdic acid, 60 mL conc. H2SO4, 940 mL H2O].
(15 : 16) (for further epoxidation experiments see the ESI†). Preparative TLC was performed on precoated TLC plates SIL
First epoxide 15 was opened under aqueous acidic conditions. G-100 UV254 (20 cm × 20 cm) (Macherey-Nagel). NMR spectra
Herein we found that the epoxide was opened with high regio- were recorded on a Bruker Advance DRX/600 spectrometer.
selectivity at the allylic position through a trans-diaxial addition 1H-NMR analysis was performed at 600 MHz and 13C-NMR
of water. The all-trans product 17 was obtained in 60% yield and spectra were proton decoupled at 151 MHz. Chemical shifts are
97 : 3 er. We could identify a diagnostic long-range coupling con- reported in ppm relative to residual solvent signals (CDCl3:
1
stant of 1.3 Hz for 1- and 3-H (W-coupling), which shows the cis- 7.26 ppm for H-NMR and 77.16 ppm for 13C-NMR, DMSO-d6:
1
relationship of these protons. The spectral data were identical to 2.50 ppm for H-NMR and 39.52 ppm for 13C-NMR, MeOD-d4:
those published by Krohn et al.21 Finally, altersolanol A (1) was 3.31 ppm for 1H-NMR and 49.0 ppm for13C-NMR). The multi-
obtained in 61% yield with an enantiomeric ratio of 98 : 2 after plicity in NMR spectra is given in the following abbreviations: s,
the hydrolytic ring opening of epoxide 16. The correct classifi- singlet; d, doublet; t, triplet; q, quartet; m, multiplet. The enan-
cation of epoxide opening for 1 was confirmed unambiguously tiomeric excess of the products was determined by HPLC
with an authentic sample of the natural product35 and the ana- (DIONEX GmbH, Chiralcel ODH, Chiralpak IA, Chiralpak IB,
lytics were in agreement with literature values.14,36
Chiralpak IC columns, flow 0.5 mL min−1, 25 °C). High resolu-
tion mass spectra were recorded by FT-IR-MS using electrospray
ionization (ESI+) (Applied Biosystems/MDS SCIEXQ Model Trap
4000). Infrared data were recorded on
a
PerkinElmer
Conclusions
SpectrumOne instrument and PerkinElmer SpectrumTwo instru-
ment as neat samples. Melting points were measured on a
Büchi Melting Point B-540 instrument. Optical rotations were
recorded on an A. Krüss Optronic P8000 polarimeter.
In summary, we have successfully presented a new synthetic
strategy for altersolanol A and its first enantioselective total
synthesis. The key element of the synthesis was the asym-
metric D–A cycloaddition promoted by the BINOL/boron Lewis
acid complex in high yield with >95 : 5 dr and 98 : 2 er. Next
the consecutive synthetic route was used towards trans-diol 14
in 62% yield over four steps. The additional epoxidation led to
two diastereomers in a total yield of 71%, in which we could
determine the absolute configuration. In the last step,
aqueous acidic conditions led to epoxide opening and alterso-
lanol A (1) and its all-trans derivative 17 were obtained with
high enantiomeric ratios of 98 : 2 and 97 : 3, respectively.
Indirectly, we thus also proved the assumed stereochemical
outcome of the D–A reaction. The determination of the physio-
logical data from the synthesised products is in progress.
Activation of molecular sieves
The success of the asymmetric Diels–Alder reaction of dieno-
phile 5d and diene 6d promoted by (R)-L2, borane-THF
complex and glacial acetic acid is dependent on the activation
of 3 Å molecular sieves and the use of fresh, nitrogen flushed
glacial acetic acid.
The 3 Å molecular sieves were used directly at room temp-
erature without pre-drying in an oven. We used about 20 g of
3 Å molecular sieves (Carl Roth, molecular sieves 3 Å, 0.3 nm,
type 564, pearls, ø1.6–2.5 mm) for 250 mL of THF, and 3.5 g of
3 Å molecular sieves for 10 mL of glacial acetic acid. First the
3 Å molecular sieves were placed in a 250 mL flask, which was
heated to 450 °C with a heat gun for 15 min under high
vacuum (10−3 mbar). Further activation at 250 °C overnight
under high vacuum (10−3 mbar) was performed. After heating
for 18 h dry and degassed THF was obtained from the solvent
purification system [MB SPS-800 (M Braun)] and fresh glacial
acetic acid was transferred into the flasks with activated 3 Å
molecular sieves under an atmosphere of dry argon. To our
Experimental
Experimental procedures and characterization data for com-
pounds 5d, 6d and (R)-L2 are provided in the ESI.†
General information
Unless specified, the reactions were carried out by the standard knowledge, storage of both solvents over sieves for 48 h pro-
Schlenk-technique under dry Ar/N2 and magnetic stirring. All duced the optimal solvent dryness, which resulted in the best
reagents were used as purchased from commercial suppliers enantiomeric control for the asymmetric Diels–Alder reaction.
without further purification. Glassware was oven-dried at 120 °C One major problem was the use of glacial acetic acid, because
overnight. Solvents were dried and purified by conventional of its high hygroscopicity. A new bottle of glacial acetic acid
methods prior to use. THF and dichloromethane were used was used two to three times after opening (no more than two
directly from an MB SPS-800 (M Braun). Solvents for chromato- weeks after opening), otherwise the enantiomeric excess of the
graphy (petroleum ether, ethyl acetate, dichloromethane and Diels–Alder product dropped dramatically to 40 to 60% ee.
methanol) were distilled prior to use. Column chromatography
(1R,4aR,9aR)-1-((tert.Butyldimethylsilyl)oxy)-9a-chloro-8-
hydroxy-6-methoxy-3-methyl-1,4,4a,9a-tetrahydroanthracene-
9,10-dione (10)
was performed on silica gel 60, 0.040–0.063 nm
(230–400 mesh). Thin layer chromatography (TLC) was per-
formed on silica gel POLY-GRAM® SIL G/U254 plates
(Macherey-Nagel) and was visualized with UV light (254/366 nm Following the “activation of molecular sieves” THF and glacial
UV-lamp) and cerium-molybdate-solution [10 g Ce(SO4)2·4 H2O, acetic acid were prepared. In a 100 mL Schlenk-tube (R)-L2
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