Total syntheses of gerberinol i and the pterophyllins 2 and 4 using the Casnati-Skatteb?l reaction under different conditions

Article abstract of DOI:10.1039/c7ob01471f

The concise and efficient total syntheses of the naturally-occurring coumarin derivatives gerberinol I, and the pterophyllins 2 and 4, from 5-methyl-4-hydroxycoumarin as a common precursor employing different Casnati-Skatteb?l reaction conditions, are reported. The synthesis of the key intermediate coumarin was achieved by the organocatalytic condensation of acetylacetone and crotonaldehyde followed by a LiCl-assisted cyclization, CuCl₂-promoted aromatization and a final Et₂CO₃-mediated cyclization. A Casnati-Skatteb?l formylation under high-temperature conditions afforded gerberinol I, whereas milder conditions resulted in an unstable 3-formyl-4-hydroxycoumarin derivative, which was subjected to a basic alumina-mediated one pot O-alkylation with chloroacetone and intramolecular aldolization to furnish pterophyllin 4. Wittig methylenation of the latter conveniently afforded pterophyllin 2.

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Takeharu Haino et al.
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Total syntheses of gerberinol I and the pterophyllins 2 and 4
using the Casnati‐Skattebøl reaction under different conditions
Jorgelina L. Pergomet,a Andrea B. J. Braccaa,* and Teodoro S. Kaufmana,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The concise and efficient total syntheses of the naturally‐occurring coumarin derivatives gerberinol I, and the pterophyllins
2 and 4, from 5‐methyl‐4‐hydroxycoumarin as a common precursor employing different Casnati‐Skattebøl reaction
conditions, are reported. The synthesis of the key intermediate coumarin was achieved by the organocatalytic
condensation of acetylacetone and crotonaldehyde followed by a LiCl‐assisted cyclization, CuCl2‐promoted aromatization
and a final Et2CO3‐mediated cyclization. A Casnati‐Skattebøl formylation under high‐temperature conditions afforded
gerberinol I, whereas milder conditions resulted in an unstable 3‐formyl‐4‐hydroxycoumarin derivative, which was
subjected to a basic alumina‐mediated one pot O‐alkylation with chloroacetone and intramolecular aldolization to furnish
pterophyllin 4. Wittig methylenation of the latter conveniently afforded pterophyllin 2.
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evergreen tree known as Rock Ash, which grows on the Natal Group
Sandstone outcrops, in South Africa.5d The isolated amounts were
so minute that some signals could not be observed in the 13C NMR
Introduction
The coumarin framework is a privileged structure with high
biological relevance. This motif is embodied in numerous natural
products and important heterocycles, including pharmaceuticals
and intermediates toward bioactive compounds.1 Coumarins tend
to be associated to anticoagulant activity;2a however, they have
recently emerged as scaffolds for novel antimycobacterial,2b anti‐
oxidant, antiviral,2c anti‐inflammatory,2d and anticancer agents.2e
The furo[3,2‐c]coumarin motif, an angular tricyclic coumarin
structure, is found in many natural products which constitute an
important class of furan derivatives.3a‐c Some furo[3,2‐c] coumarins
exhibit important biological activities, such as antioxidant,
insecticidal, antitumor,3d antimicrobial and antifungal. They are also
NF‐κB inhibitors3e and agents that prevent age‐related
neurodegenerative diseases.3f
spectra of 4a and 4b.
These heterocycles are inherently photosensitive,4a‐e and some
of them possess photo‐chemotherapeutic effects, resulting from
their ability to intercalate with the pyrimidine bases of the DNA of
the target microorganisms.4f Selected examples are neo‐
tanshinlactone (1), isolated from Salvia miltiorrhiza (Figure 1),
which displays potent and selective anti‐breast cancer activity,5a,b
and osthole derivatives 2a‐d which proved to be antifungal
agents.5c
The pterophyllins 1‐5 (3a,b, 4a,b and 5a) are furo[3,2‐
c]coumarin derivatives carrying a 5‐methyl group (numbering of the
isolation paper), which have been isolated from the bark and wood
of Ekebergia pterophylla (C.D.C.) Hofmeyr (Meliaceae), a small
Figure 1. Chemical structures of some naturally‐occurring and synthetic 4H‐
furo[3,2‐c]chromen‐4‐ones (1‐5) and 3,3’‐bis‐coumarin (6,7) derivatives.
a. Instituto de Química Rosario (IQUIR, CONICET‐UNR), and Facultad de Ciencias
Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531,
S2002LRK Rosario, República Argentina.
Electronic Supplementary Information (ESI) available: NMR spectra of the
intermediates and final products and spectral data tables of the natural and
synthetic pterophyllins 2 and 4. See DOI: 10.1039/x0xx00000x
To date, the bioactivity profile of the pterophylins remains
unknown; however, it has been shown that analogues of 4a are
active against phytopathogenic fungi,5c and the related rare plant
metabolite bothrioclinin (5b) proved to be cytotoxic.5e,f In addition,
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the syntheses of pterophyllin 1 (3a),6a pterophyllin 2 (4a)6b and provided by the corresponding retrosynthetic analyses (Scheme 1).
pterophyllin 3 (5a)6a have been achieved, albeit in rather moderate These analyses suggested the use of acetophenone 10 as the first
to low yields, and accompanied by undesired isomers, through key intermediate. This is a valuable product that has been recorded
sequences that employed endangered metal catalysts, hazardous as the result of the light‐promoted Fries rearrangement of an aryl
solvents and/or extreme temperatures.
acetate,14 as well as the Pd‐catalyzed ketone‐directed ortho‐
The interest of Chemists in the 4H‐furo[3,2‐c]chromen‐4‐one hydroxylation of arenes,15a and the Lewis acid‐promoted addition of
skeleton has resulted in the development of various synthetic organolithium or Grignard reagents to a 6‐methylsalicylic ester,15b
approaches to this target. These include the rearrangements of 3‐ among others.15c
formyl‐7a and 3‐halo‐ chromones,7b the oxidative cyclization of 3‐
However, in our hands, the ketone‐directed hydroxylation took
substituted 4‐hydroxycoumarins,7c the cyclization of 4‐hydroxy place on the methyl group and the Fries rearrangement under
coumarins with olefins under Ag(I)‐catalysis,4c and the Cu‐catalyzed various conditions and promoters gave mixtures of ketones, not
intramolecular decarboxylative functionalization of α‐carbonyl unexpectedly containing mainly the undesired isomer.
compounds.8a
Other alternatives, such as Pd‐catalyzed annulation of 3‐alkynyl‐
4‐methoxy coumarins with haloarenes,8b and the cyclization of 3‐
alkynyl chromones,4b,8c as well as cycloaddition,9a tandem9b and
multicomponent4e,9c processes, have also been proposed.
On the other hand, the bis‐coumarins are a comparatively small
group among the coumarin derivatives; naturally, they are mostly
found in plants.10a,b The anticoagulant dicoumarol (6a) and 1‐methyl
gerberinol (6b)11a are two of the few and scattered examples of
natural bis‐coumarins where both heterocyclic units are linked at
the C3‐C3’ level through a one carbon atom unit (methylene/
methine bridge).
Analogues of dicoumarol differ widely in their anticoagulant
activity,10c whereas coumarin dimers containing an aryl substituent
on the central methylene linker were found to inhibit the HIV‐
integrase (6c),10d the severe acute respiratory syndrome (SARS)
coronavirus 3CL protease (7)10e and the c‐Met tyrosine kinase
receptor,10f among other relevant targets.
Gerberinol I (6d) is a unique bis‐coumarin within this group,
which was isolated in minor amounts from different sources,
growing in a wide region between Japan and West Africa, and
including Gerbera laniculata Benth (Compositae),11b Diospyros
canaliculata De Wildeman (Ebenaceae),11c D. crassiflora Hien,11d
and D. kaki var. sylvestris (persimmon, Ebenaceae).11a
Scheme 1. Retrosynthetic analyses of the pterophyllins 2 (4a) and 4 (4b),
and gerberinol I (6d). Coumarin derivative 9 as a common precursor.
The natural product, which has been totally synthetized only
twice,12a,b demonstrated to possess antifungal and strong
antibacterial activity, especially against Shigella dysenteriae and
Salmonella typhi (MIC < 5 µg/mL). Interestingly, a study revealed
that human intestinal bacteria transform the glycoside gerberinside
into gerberinol I.12c,d
Therefore, and as part of our continued effort of substituting
hazardous or less available reagents with simpler and more
environmentally conscious surrogates,13e,16 we opted to devise an
alternative approach to 10, as shown in Scheme 2.
Thus, based on previous findings,17 we performed the L‐proline
organocatalyzed Michael addition between crotonaldehyde (11)
and acetylacetone (12), to afford 58% of the tricarbonylic
intermediate 13, along with 28% of the related diene 13a, resulting
from direct addition‐elimination of 12 to the carbonyl group of 11.
Interestingly, running the reaction under neat (solventless)
conditions proved advantageous, since the use of anhydrous DMF
as solvent furnished diene 13a18 as the exclusive product. On the
other hand, however, it was serendipitously discovered that the use
of approximately 0.1 equiv. of 1‐phenylbutane‐1,4‐diol as
organocatalyst furnished good yields of 13. The best performance
(91% yield) was attained when 0.14 equiv were employed, also
under solventless conditions. Similarly, the best temperature
condition was 0 °C, since running the reaction at room temperature
caused a marked increase in the amounts of 13a and the formation
Further, based on docking results, recent theoretical studies
have forecasted that this natural product may act as antimicrobial
and anticancer agent, and inhibit
neurodegenerative diseases.12e,f
a target associated with
In pursuit of our continuous interest in the development of
concise syntheses of structurally interesting natural products13 and
considering that bis‐coumarins and furo[3,2‐c]coumarins are
synthetically connected,8a,9c herein we report the total syntheses of
pterophyllin 2 (4a), pterophyllin 4 (4b), and gerberinol I (6d) from
coumarin derivative 9 as the common synthetic precursor, through
the use of different Casnati‐Skattebøl reaction conditions.
Results and discussion
The syntheses were carried out according to the guidelines
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of other unidentified products.
paraformaldehyde and Et3N in THF at 80 °C afforded gerberinol I
This was followed by reaction of 13 with LiCl and CuCl2 in DMF (6d) as the main product in 75% yield after 1 h. The NMR spectra of
to effect the sequential intramolecular aldol condensation toward the heterocycle 6d were in full agreement with the literature. This is
14a,b (observed by NMR as a complex mixture of diastereoisomers the first synthesis of gerberinol I under non‐aqueous conditions.
and tautomers), and further oxidative aromatization of the latter to
Although the exact mechanism for the formation of the
give 54% of 10. Presumably, the transformation would proceed coumarin dimer 6d remains unknown, a mechanistic picture
through an α‐carbonyl chlorination process to afford the (Scheme 3) can be drawn based on some literature precedents. In
intermediate 15, which would further undergo a final dehydro‐ this proposal, the Et3N‐MgCl2 base system can pick‐up the acidic
chlorination with concomitant aromatization.19
proton of the starting heterocycle 9, triggering a reaction with
The sequence was continued with the uneventful acquisition MgCl2 to afford the magnesium complex i, with concomitant loss of
of 9 in 79% yield,6a,20 by reaction of 10 with diethyl carbonate in HCl. In turn, this intermediate could interact with formaldehyde
DMF, using KtBuO (3 equiv.) as base. Interestingly, the use of (resulting from the in situ de‐polymerization of the added
metallic sodium (5 equiv.) for this Claisen reaction gave essentially paraformaldehyde), and induce a vicinal hydroxymethylation, to
the same results.
afford the magnesium complex ii.
Under relatively high temperature conditions (80 °C), and due
to the acidity of H‐3, the intermediate ii could decompose through
a retro‐Michael reaction to a mixture of ClMgOH and the strong
Michael acceptor iii, which as soon as it is formed could react with
the 4‐hydroxy coumarin 9, furnishing the methylene‐bridged bis‐
coumarin 6d after a final enolization step.
The proposed path is a known and useful, but little explored
and scarcely exploited side reaction of the Casnati‐Skattebøl
formylation, which seldom proceeds in more than 65% yield.24a‐c
Further, it is mechanistically reminiscent of those reactions put
forward for the formation of analogous bis‐coumarins by the action
of the DMSO/Ac2O reagent system, and under enzymatic
conditions.12c
Scheme 2. Reagents and conditions: a) L‐proline (0.1 equiv.), 0 °C, 20 h (13,
58%; 13a, 28%) or 1‐phenylbutane‐1,4‐diol (0.14 equiv.), 0 °C, 20 h (13,
91%); b) LiCl, CuCl2, DMF, 90 °C, 3 h (54%); c) Et2CO3, KtBuO, r.t., 12 h (79%);
d) POCl3 (3 equiv.), DMF, 0 °C, 12 h (59%); e) MgCl2 (anh.), Et3N, (CH2O)n,
THF, 80 °C, 1 h (75%).
The formylation of 4‐hydroxycoumarins has been recorded to
proceed under Vilsmeier‐Haack conditions (POCl3, DMF, 0 °C),21 and
with the (MeO)3CH/TsOH reagent system.22 Intriguingly, however,
despite the reactions with 4‐hydroxycoumarin as model performed
acceptably, when the same transformations were carried out on
compound 9 they furnished disappointing results.
Employing the (MeO)3CH/TsOH approach afforded a meagre
32% yield of 3‐(methoxymethylene)‐5‐methylchromane‐2,4‐dione,
as stemmed from its diagnostic singlets at δ= 8.57 (=C‐H), 3.91
(OMe) and 2.86 (ArMe) ppm, whereas the Vilsmeier‐Haack
formylation gave rather erratic results and the use of 3 equiv. POCl3
gave at best 59% of 8. Interestingly, the production of 4‐4’‐ether
type dimeric side products during the Vilsmeier‐Haack formylation
of 4‐hydroxycoumarin has been previously reported.21d
Observing that the 4‐hydroxycoumarins are acidic compounds
with pKa values similar to that of AcOH, the Casnati‐Skattebøl
reaction was deemed suitable for C‐3 functionalization of 9.23 To
our delight, heating in a closed vessel a mixture of 9 with MgCl2,
Scheme 3. Proposed mechanism for the synthesis of the bis‐coumarin 6d
under Casnati‐Skattebøl conditions.
Interestingly, a milder treatment of 9 (50 °C, 1 h) with the
same Casnati‐Skattebøl mixture of reagents furnished 8 in 87%
yield.24d Oddly enough, careful 1H NMR analysis of the crude of the
reaction revealed the presence of traces of 6d.
Therefore, we explored the scope of the Casnati‐Skattebøl
reaction, finding that the transformation turns considerably slower
when the reaction temperature is lower than 40 °C, and that at a
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higher temperature (≈ 70 °C) compound 6d became the major OCH2CO) ppm in its 1H NMR spectrum.
product, being formed exclusively at 80 °C.
With scarce literature precedents due to their rather poor
In addition, it was observed that the Casnati‐Skattebøl reaction stability, imines have been previously employed as carbonyl
can also be applied to other 4‐hydroxycoumarins. For example, the protecting groups.28 Therefore, with the aim of reducing the
reaction with 4‐hydroxycoumarin itself at 50 °C gave 91% of the reactivity of the molecule, the formyl moiety of compound 8 was
expected 3‐formyl‐4‐hydroxycoumarin, whereas under the more masked as the corresponding imine (17), which was prepared in
strenuous conditions, the reaction outcome shifted toward the 85% yield by condensation of the aldehyde with 5‐aminopentan‐1‐
dimer (dicoumarol).
ol in toluene at 90 °C.
Mechanistically, in this case the common intermediate ii could
The imine 17, which proved to be remarkably stable and
undergo a formaldehyde‐mediated hydride abstraction as depicted withstood column chromatographic purification, was obtained as
in iv, leading to dehydrogenation of the latter, in a process an inseparable 7:3 (anti‐syn) mixture of geometric isomers, which in
1
reminiscent of the Duff formylation,25 finally affording the formyl turn were observed in their H NMR spectra, as the corresponding
derivative 8. To the best of our knowledge this is the first example ~1:1 mixtures of rotamers. The diagnostic signals of the aldiminic
entailing access to a 3‐formylcoumarin derivative through the hydrogen appeared as singlets at δ = 8.37 and 8.33 ppm for the anti
Casnati‐Skattebøl reaction.
isomer and more deshielded, at δ = 8.50 and 8.45 ppm, for the syn
There are some scattered examples about the O‐alkylation of 4‐ isomer. Luckily, exposure of 17 to the conventional acetonylation
hydroxycoumarins4e,5b,26 and 3‐acetyl‐4‐hydroxy‐ coumarins,27 conditions [ClCH2C(O)Me, K2CO3, DMF, 65 °C, overnight] afforded
generally under very mild conditions; however, the analogous O‐ the expected furo[3,2‐c]coumarin 4b, albeit in low yield (15%),
alkylation of the more unstable and highly reactive 3‐formyl‐4‐ presumably through the intermediacy of 18, which could not be
hydroxycoumarins, bearing a tricarbonylic motif, seems to have no unequivocally identified (TLC reaction monitoring) nor isolated.
direct precedent. Thus, it was not surprising that when the O‐
In view of the instability of the starting material toward the
with chloroacetone was procured under reaction conditions and in search of an improved alternative, the
acetonylation of
8
conventional conditions (K2CO3, EtOH or DMF),13b it met with use of a milder and insoluble base was attempted,29a opting for
failure, leading to complete destruction of the starting MgCO3 which would act “on demand” as an acid scavenger,
heterocycle.7a
because of its insolubility in the reaction medium. However, this
approach gave a complex and inseparable mixture of unidentifiable
products.
Ultimately, however, the paradigm of acid scavenging by means
of an insoluble base proved fruitful, since the reaction of 8 with
chloroacetone in refluxing CH2Cl2, in the presence of a ten‐fold
excess of Brockmann I activated basic alumina (pH of the aqueous
suspension ≥ 9), afforded the desired tricycle 4b in 88% yield.7a,29b,c
Interestingly, the detection of the acetonyl ether intermediate
16 by TLC proved very difficult and all attempts at its isolation were
fruitless. However, an in‐tube NMR experiment employing
anhydrous CDCl3 as solvent revealed that the starting coumarin is
completely consumed within 1 h at room temperature affording a
complex mixture of intermediates.
Finally, the Wittig olefination of 4b was undertaken. After
several attempts with Ph3PMe+I‐ in THF, using KtBuO as base, it was
observed that the reactions did not reach completion, affording
rather low yields of product. This was attributed to a ready
enolization of the ketone moiety. Fortunately, however, the
addition of LiCl afforded the isopropylidene derivative 4a in 78%
yield, based on recovered starting material. This additive proved
relevant for attaining suitable product yields, presumably by
Scheme 4. Reagents and conditions: a) MgCl2 (anh.), Et3N, (CH2O)n, THF, 50 affecting the reaction rate or the enolization equilibrium of the
methyl ketone moiety.30
°C, 1 h (87%); b) ClCH2COCH3, Al2O3, CH2Cl2, 40 °C, 72 h (4b, 88%); c)
1
ClCH2COCH3, K2CO3, DMF, 65 °C, overnight (50%); d) H2N(CH2)4CH2OH, PhMe,
The H NMR spectra of the natural and synthetic pterophyllins
90 °C, 1 h (85%); e) ClCH2COCH3, K2CO3, DMF, 65 °C, overnight (15%); f)
were fully coincident. However, the observed melting points of the
Ph3PMe+I‐, KtBuO, LiCl, THF, rt, 1 h (4a, 58%; 4b, 25%; 4a, 78%, based on
synthetic 4a and 4b were widely different and higher than those
reported for the corresponding natural products, whereas the 13C
recovered starting material).
NMR spectral signatures of these compounds were in good
agreement with those published for the corresponding natural
products, except for some resonances (Table 1).
Oppositely, the O‐alkylation of its precursor 9 was possible
under the same conditions, affording the expected product 9a in
50% yield (Scheme 4), as concluded from examination of the
These discrepancies probably stem from the lack of proper
diagnostic signals at δ = 2.31 (s, 3H, MeCO) and 4.75 (s, 2H,
purity and small sample size of the original isolates, the latter
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precluding a more accurate analysis. Hence, unlike other cases by exposure to 254 nm UV light, and by spraying with ethanolic p‐
where spectral differences resulted from structures other than anisaldehyde/sulfuric acid reagent, followed by careful heating to
those proposed,S4124 in this case, the chemical synthesis helped to improve selectivity. The flash column chromatographies were run
complete and correct the NMR spectral data sets of the natural with silica gel 60 H (particle size 63–200 μm), eluting with hexane‐
products and to obtain their unequivocal assignment.
EtOAc mixtures, under positive pressure and employing gradient of
solvent polarity techniques.
Table 1. Comparison among the 13C NMR chemicals shifts recorded
for natural and synthetic pterophyllins 2 and 4.a
Equipment
The melting points were measured on an Ernst Leitz Wetzlar model
350 hot‐stage microscope and are informed uncorrected. The FT‐IR
spectra were recorded, as solid dispersions in KBr disks or as thin
films held between NaCl cells, on
spectrophotometer.
a Shimadzu Prestige 21
The nuclear magnetic resonance spectra were acquired in CDCl3
unless otherwise noted, on Bruker Avance 300 NMR
Pterophyllin 4
Natural
Pterophyllin 2
Natural
Position
a
Synthetic
157.4
111.8
160.2
111.3
135.3
127.0
131.8
115.3
154.4
21.0
Synthetic
158.4
112.2
157.9
112.0
134.0
126.5
130.0
115.1
153.4
21.0
spectrometer, at 300.13 (1H) and 75.48 (13C) MHz. The chemical
shifts are informed in parts per million in the δ scale. TMS was used
as the internal standard (resonances of CHCl3 in CDCl3: δ 7.26 and
b
b
C‐2
C‐3
―
―
125.9
157.8
112.0
135.1
127.1
131.9
115.2
153.1
21.1
122.1
162.7
108.9
134.0
126.5
130.0
115.1
153.8
22.7
C‐4
1
77.0 for H and 13C NMR, respectively). The coupling constants (J)
C‐4a
C‐5
are given in Hertz. Pairs of signals marked with asterisk (*) or
numeral (#) symbols indicate that their assignments may be
exchanged. Some 2D‐NMR experiments were also performed to aid
unequivocal signal assignment. Structure numbering of the final
products is according to the literature.5d
The high‐resolution mass spectra were obtained from ICYTAC
(Córdoba, Argentina) with a Bruker MicroTOF‐Q II instrument.
Detection of the ions was performed in electrospray ionization,
positive ion mode.
C‐6
C‐7
C‐8
C‐8a
C‐9
C‐1’
C‐2’
C‐3’
C‐4’
C‐5’
114.4
154.2
186.1
―
114.5
153.2
185.9
―
103.7
103.7
157.3
131.7
113.4
19.1
b
―
b
―
113.4
19.1
4‐Acetyl‐3‐methyl‐5‐oxohexanal (13)
26.4
26.4
Method A: Crotonaldehyde (12, 1.05 g, 15 mmol) was added to a
cooled mixture of acetylacetone (1.5 g, 15 mmol) and L‐proline (173
mg, 1.5 mmol), and the reaction was stirred for 20 h at 0 °C. Then,
the reaction was diluted with 1M HCl (100 mL) and the reaction
products were extracted with EtOAc (4 × 50 mL). The combined
organic extracts were washed with brine, dried over anhydrous
MgSO4 and concentrated under reduced pressure. Chromatography
of the residue gave 13a (638 mg, 28%), as a yellow oil.18a,18c 1H NMR
δ: 7.00 (d, J = 10.1, 1H, H‐1’), 6.39 (dd, 1H, J = 5.4 and 10.1, (H‐2’),
6.28‐6.46 (m, 1H, H‐3’), 2.35 (s, 3H, Me‐1),* 2.34 (s, 3H, Me‐5)* and
1.91 (d, 3H, J = 5.4, H‐4’),. 13C NMR δ: 203.2 (C‐2),* 197.3 (C‐4),*
144.8 (C‐1’), 142.8 (C‐3’), 140.3 (C‐3), 127.4 (C‐2’), 31.7 (C‐1),# 26.2
(C‐5)# and 19.2 (C‐4’). Increasing the solvent polarity furnished 13
(1.48 g, 58%) as a yellow oil;17c IR (film, ῡ): 2963, 2732, 1693, 1417,
aAll spectra were taken at 75 MHz, in CDCl3. Pairs of signals exhibiting the
greatest differences are shown in bold.
bThe authors informed that these signals were not observable in their
spectra.
Experimental
General information
The reactions were executed under anhydrous argon atmospheres,
employing oven‐dried glassware and freshly distilled anhydrous
solvents. Anhydrous THF and toluene were obtained by reflux of the
AR solvents over sodium metal (benzophenone as indicator),
followed by distillation. Anhydrous CH2Cl2 was obtained from an M.
Braun solvent purification and dispenser system. Anhydrous Et3N
was prepared by refluxing the solvent over CaH2 for 4 h, followed by
distillation.
1
1360, 1254, 1192, 1024 and 957 cm‐1. H NMR δ: 9.69 (dd, 1H, J =
2.0 and 1.2, H‐1), 3.67 (d, 1H, J = 9.4, H‐4), 2.81‐2.96 (m, 1H, H‐3),
2.47 (dd, 1H, J = 17.2 and 4.0, H‐2), 2.31 (ddd, 1H, J = 17.2, 8.2 and
2.0, H‐2), 2.17 (s, 6H, H‐6, H‐2’) and 0.97 (d, 3H, J = 6.8, Me‐3). 13
C
Anhydrous DMF was prepared by heating and reduced pressure
distillation from dry BaO. All the anhydrous solvents were
transferred via cannula and stored in dry Young ampoules
containing activated molecular sieves. Anhydrous para‐
formaldehyde was obtained from the commercial product, by
drying under vacuum to remove most of the moisture, followed by
sublimation under reduced pressure.
NMR δ: 203.8 (C‐5), 203.5 (C‐1’), 200.8 (C‐1), 73.8 (C‐4), 48.0 (C‐2),
30.2 (2C, C‐6 and C‐2’), 28.1 (C‐3) and 18.0 (Me‐3).
Method B: Crotonaldehyde (12, 0.04 mL, 0.49 mmol) was added to
a cooled mixture of acetylacetone (0.05 mL, 0.49 mmol) and 1‐
phenylbutane‐1,4‐diol (8 mg, 0.05 mmol), and the reaction was
stirred for 20 h at 0 °C. Then, the reaction was diluted with 1M HCl
(10 mL) and the reaction products were extracted with EtOAc (4 ×
10 mL). The combined organic extracts were washed with brine,
The reactions were monitored by TLC run in different hexane‐
EtOAc solvent mixtures. The chromatographic spots were detected
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Organic and Biomolecular Chemistry
dried (MgSO4) and concentrated in vacuo. Chromatography of the 160.8 (C‐2), 157.2 (C‐8a), 141.4 (C‐5), 135.8 (C‐7), 128.1 (C‐6), 115.8
residue gave 13 (76 mg, 91%) as a yellow oil which NMR spectra (C‐8), 113.5 (C‐4a), 101.9 (C‐3) and 23.0 (Me). HRMS m/z calcd for
agreed with those of the aldehyde obtained through Method A.
C11H8O4 204.0373 [M]+; found: 204.0365; m/z calcd for C11H7O4
203.0339 [M ‐ H]+; found: 203.0349.
2’‐Hydroxy‐6’‐methylacetophenone (10)15a
Compound 11 (1.30 g, 7.7 mmol) was added portion‐wise, over a 3,3'‐Methylenebis(4‐hydroxy‐5‐methyl‐2H‐chromen‐2‐one)
period of 30 min., to a stirred mixture of LiCl (325 mg, 7.7 mmol) gerberinol I)
(6d,
and CuCl2 (1.45 g, 10.8 mmol) in DMF (5 mL). The reaction was Anhydrous MgCl2 (300 mg, 3.15 mmol) was added at once to a
further stirred for 2.5 h at 90 °C, when it was allowed to attain room stirred solution of 2H‐chromen‐2‐one 9 (260 mg, 1.48 mmol) and
temperature, diluted with brine (20 mL), and extracted with EtOAc anhydrous Et3N (0.65 mL, 4.67 mmol) in dry THF (5 mL). After
(4 × 30 mL). The combined organic extracts were washed with H2O further stirring for 10 min, anhydrous paraformaldehyde (150 mg,
(3 × 30 mL), dried over anhydrous MgSO4 and concentrated under 5.0 mmol) was added to the resulting suspension, the reaction
reduced pressure. Chromatography of the residue gave 10 (620 mg, vessel was tightly closed and the system was heated at 80 °C for 1
54%), as a yellow oil which crystallized on standing to give a solid, h. The mixture was then cooled to room temperature, diluted with
mp.: 97‐99 °C (Lit.: 93‐98 °C).15c IR (film, ῡ): 3358, 2926, 1620, 1446, 1M HCl (10 mL), and the products were extracted with EtOAc (3 ×
1360, 1286, 1213 and 789 cm‐1. 1H NMR δ: 7.27 (t, 1H, J = 8.0, H‐4’), 30 mL). The combined organic extracts were washed with brine (1 ×
6.84 (d, 1H, J = 8.0, H‐5’), 6.72 (d, 1H, J = 8.0, H‐3’), 2.67 (s, 3H, 10 mL), dried (MgSO4) and concentrated under reduced pressure to
COMe) and 2.60 (s, 3H, Me‐6’). 13C NMR δ: 206.1 (COMe), 162.8 (C‐ afford a brownish solid. Recrystallization from EtOAc gave 6d (210
2’), 139.5 (C‐6’), 134.7 (C‐4’), 123.1 (C‐3’), 121.6 (C‐1’), 116.6 (C‐5’), mg, 75%), as a light brown solid, mp.: 230‐232 °C (dec.); Lit.: 229‐
33.3 (COMe) and 24.5 (Me‐6’).
231 °C.12c IR (KBr, ῡ): 3447, 2930, 1653, 1599, 1464, 1350, 1302,
1
1234, 1119, 1042 and 789 cm‐1. H NMR δ: 11.83 (s, 2H, 2 x OH),
4‐Hydroxy‐5‐methyl‐2H‐chromen‐2‐one (9)
7.41 (t, 2H, J = 8.3, H‐7 and H‐7’), 7.22 (d, 2H, J = 8.3, H‐8 and H‐8’),
A solution of 10 (900 mg, 6 mmol) in THF (15 mL) was added to a 7.11 (d, 2H, J = 8.3, H‐6 and H‐6’), 3.80 (s, 2H, C‐CH2‐C) and 2.81 (s,
stirred suspension of KtBuO (2.02 g, 18 mmol) in THF (30 mL). The 6H, Me‐5 and Me‐5’); 13C NMR δ: 168.5 (2C, C‐2 and C‐2’),* 167.7
mixture was treated drop‐wise with diethyl carbonate (2.2 mL, 18 (2C, C‐4 and C‐4’),* 153.7 (2C, C‐8a and C‐8a’), 138.5 (2C, C‐5 and C‐
mmol) and the reaction was stirred overnight, when the solvent 5’), 131.7 (2C, C‐7 and C‐7’), 128.2 (2C, C‐6 and C‐6’), 115.2 (2C, C‐
was evaporated under reduced pressure and the residue was 4a and C‐4a’), 115.1 (2C, C‐8 and C‐8’), 102.7 (2C, C‐3 and C‐3’), 23.3
treated with 1M HCl (25 mL). The reaction products were extracted (2C, Me‐5 and Me‐5’) and 20.1 (C‐CH2‐C). The spectroscopic data of
with EtOAc (4 × 25 mL) and the combined organic extracts were synthetic 6d were in full agreement with those of the literature for
washed with brine (1 × 10 mL, dried over anhydrous MgSO4 and gerberinol I.11a
concentrated under reduced pressure. Chromatography of the
residue gave 9 (834 mg, 79%) as a yellow solid, mp.: 232‐234 °C 4‐Hydroxy‐3‐{[(5‐hydroxypentyl)imino]methyl}‐5‐methyl‐2H‐
(Lit.: 232‐234 °C).20 IR (KBr, ῡ): 3383, 2974, 1641, 1599, 1558, 1340, chromen‐2‐one (17)
1211, 1043 and 793 cm‐1. 1H NMR (DMSO‐d6) δ: 7.44 (t, 1H, J =7.9, A stirred solution of aldehyde 8 (24 mg, 0.12 mmol) in toluene (1
H‐7), 7.16 (d, 1H, J = 7.9, H‐8), 7.08 (d, 1H, J = 7.9, H‐6), 5.53 (s, 1H, mL) was treated 5‐aminopentan‐1‐ol (12 mg, 0.12 mmol) and the
H‐3), 3.33 (br s, w1/2= 12.8, OH) and 2.65 (s, 3H, Me‐5). 13C NMR mixture was heated at 90 °C for 1 h. The solvent was then
(DMSO‐d6) δ: 169.1 (C‐4), 161.9 (C‐2), 155.4 (C‐8a), 137.6 (C‐5), evaporated, water (5 mL) was added and the organic compounds
132.2 (C‐7), 127.6 (C‐6), 115.2 (C‐8), 114.7 (C‐4a), 91.6 (C‐3) and were extracted with EtOAc (3 × 15 mL). The combined organic
23.1 (Me‐5). HRMS m/z calcd for C10H7O3 175.0375 [M ‐ 1]+; found: extracts were washed with brine (1 × 10 mL), dried over anhydrous
175.0365.
MgSO4 and concentrated under reduced pressure. Silica gel column
chromatography (Hexane:EtOAc, 95:5, containing 0.1% Et3N) of the
residue gave a 7:3 (anti:syn) isomeric mixture of imines 17 (29 mg,
4‐Hydroxy‐5‐methyl‐2‐oxo‐2H‐chromene‐3‐carbaldehyde (8)
Anhydrous MgCl2 (217 mg, 2.27 mmol) was added at once to a 85%), as a brown oil. IR (film, ῡ): 3439, 2926, 2850, 1714, 1643,
stirred solution of 2H‐chromen‐2‐one 9 (200 mg, 200 mmol) and 1593, 1435, 1385, 1042 and 783 cm‐1. Anti‐isomer ‐ 1H NMR δ: 8.37
anhydrous Et3N (0.475 mL) in anhydrous THF (9 mL). After further (s, 0.5H, H‐1’ rotamer‐1), 8.33 (s, 0.5H, H‐1’ rotamer‐2), 7.37 (t, 1H,
stirring for 10 min, anhydrous paraformaldehyde (102 mg, 3.4 J = 7.7, H‐7), 6.98 (d, 1H, J = 7.7, H‐8), 7.00 (d, 1H, J = 7.7, H‐6), 3.67
mmol) was added to the resulting suspension, and the reaction was (t, 2H, J = 6.2, H‐7’), 3.51 (q, 2H, J = 6.6, H‐3’), 2.77 (s, 3H, Me), 1.69‐
heated at 65 °C for 1 h. The mixture was then cooled to room 1.82 (m, 2H, H‐4’), 1.55‐1.67 (m, 2H, H‐6’) and 1.43‐1.55 (m, 2H, H‐
temperature, diluted with 1M HCl (10 mL), and the products were 5’). 13C NMR δ: 183.9 (C‐4), 164.1 (C‐2), 162.0 (C‐1’), 156.1 (C‐8a),
extracted with EtOAc (3 × 25 mL). The combined organic extracts 140.9 (C‐5), 133.0 (C‐7), 127.3 (C‐6), 118.7 (C‐4a), 115.6 (C‐8), 97.4
were washed with brine (1
× 10 mL), dried (MgSO4) and (C‐3), 62.3 (C‐7’), 50.9 (C‐3’), 32.0 (C‐6’), 30.0 (C‐4’), 22.8 (C‐5’)* and
concentrated under reduced pressure to afford a brownish solid. 22.7 (Me‐5)*. Syn‐isomer ‐ 1H NMR δ: 8.50 (s, 0.5H, H‐1’ rotamer‐1),
Recrystallization from EtOAc gave 8 (202 mg, 87%), as a light brown 8.45 (s, 0.5H, H‐1’ rotamer‐2), 7.38 (t, 1H, J =7.7, H‐7), 7.07 (d, 1H, J
solid, mp.: 130‐132 °C (dec.). IR (KBr, ῡ): 3383, 2974, 1641, 1599, = 7.7, H‐8), 7.00 (d, 1H, J = 7.7, H‐6), 3.66 (t, 2H, J = 6.2, H‐7’), 3.55
1558, 1340, 1211, 1043 and 793 cm‐1. 1H NMR δ: 9.96 (s, 1H, COH), (q, 2H, J = 6.5, H‐3’), 2.79 (s, 3H, Me), 1.69‐1.82 (m, 2H, H‐4’), 1.55‐
7.55 (t, 1H, J =7.8, H‐7), 7.17 (d, 1H, J = 7.8, H‐8), 7.11 (d, 1H, J = 7.8, 1.67 (m, 2H, H‐6’) and 1.43‐1.55 (m, 2H, H‐5’). 13C NMR δ: 180.6 (C‐
H‐6) and 2.77 (s, 3H, Me). 13C NMR δ: 194.7 (COH), 179.8 (C‐4), 4), 164.1 (C‐2), 160.8 (C‐1’), 156.1 (C‐8a), 141.6 (C‐5), 133.0 (C‐7),
6 | Org. Biomol. Chem., 2017, 00, 1‐3
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ARTICLE
127.5 (C‐6), 118.9 (C‐4a), 115.6 (C‐8), 97.5 (C‐3), 62.3 (C‐7’), 50.7 (C‐ and straightforward synthetic sequences from crotonaldehyde and
3’), 31.9 (C‐6’), 30.0 (C‐4’), 22.8 (C‐5’)* and 22.7 (Me‐5).* HRMS m/z acetylacetone through the 4‐hydroxy coumarin derivative 9 as their
calcd for C16H19NNaO4 312.1206 [M + Na]+; found: 312.1206.
common synthetic intermediate, and without the use of protecting
groups nor endangered metal‐based catalysts.
2‐Acetyl‐9‐methyl‐4H‐furo[3,2‐c]chromen‐4‐one (4b, pterophyllin
4)
Other key features of the synthesis include the original access
to the heterocycle 9, which was efficiently performed from
Brockmann I activated basic alumina (2000 mg, 19.50 mmol) was inexpensive and readily available starting materials. In addition, the
added to a solution of the aldehyde 8 (200 mg, 0.98 mmol) in Casnati‐Skattebøl reaction was used for the first time to
anhydrous CH2Cl2 (10 mL) and the stirred suspension was treated functionalize the C‐3 position of coumarins. Further, under different
with ClCH2COMe (0.790 mL, 9.80 mmol). The reaction was further temperature conditions and with compound 9 as a suitable
stirred for 24 h at room temperature, when the reaction was common precursor, this transformation granted facile access to
filtered off through Celite to separate the solid promoter, and the either gerberinol I or to the pterophyllins 2 and 4.
Celite was washed with CH2Cl2 (5 mL). The combined filtrates were
In addition, the syntheses of the pterophyllins also entailed the
concentrated under reduced pressure and the residue was first O‐alkylation of the unstable and highly reactive 3‐formyl‐4‐
chromatographed, furnishing 4b (209 mg, 88%) as a yellow solid, hydroxycoumarin tricarbonylic system. Finally, NMR studies
mp.: 161‐163 °C (dec.); Lit.: 60‐62 °C.5e IR (KBr, ῡ): 2922, 2850, 1749, provided the complete sets of 13C NMR signals of the natural
1674, 1539, 1464, 1194 and 781 cm‐1. 1H NMR δ: 7.67 (s, 1H, H‐1’), products and their unequivocal assignments, suggesting that some
7.47 (t, 1H, J = 8.0, H‐7), 7.30 (d, 1H, J = 8.0, H‐8), 7.19 (d, 1H, J = of the original data should be revised.
8.0, H‐6), 2.86 (s, 3H, H‐9) and 2.60 (s, 3H, H‐5’). 13C NMR δ: 185.9
(C‐3’), 160.2 (C‐4), 157.4 (C‐2), 154.4 (C‐8a), 153.2 (C‐2’), 135.3 (C‐
5), 131.8 (C‐7), 127.0 (C‐6), 115.3 (C‐8), 114.5 (C‐1’), 111.8 (C‐3),
Conflicts of interest
111.3 (C‐4a), 26.4 (C‐5’) and 21.0 (C‐9). Except for the signals There are no conflicts of interest to declare.
marked in Table 1, the NMR spectroscopic data of synthetic 4b
were in full agreement with those of the literature for the natural
pterophyllin 4.5e
Acknowledgements
The authors gratefully acknowledge Secretaría de Ciencia
y
9‐Methyl‐2‐(1‐methylethenyl)‐4H‐furo[3,2‐c]chromen‐4‐one (4a, Tecnología de la UNR (SECyT‐UNR, Project BIO457), Consejo
pterophyllin 2) Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP Nº
A suspension of methyl(triphenyl)phosphonium iodide (80 mg, 0.20 2012‐0471), and Agencia Nacional de Promoción Científica y
mmol) in THF (0.4 mL), was treated with KtBuO (21 mg, 0.18 mmol) Tecnológica (ANPCyT, PICT Nº 2014‐0455), for financial support.
and the mixture was stirred for 45 minutes. LiCl (4 mg, 0.09 mmol) J.L.P. also thanks ANPCyT and CONICET for her fellowships.
and a solution of 4b (20 mg, 0.08 mmol) in THF (0.4 mL) were
successively added to the so obtained yellow suspension, and the
Notes and references
reaction was stirred at room temperature for 1 h. The reaction
system was diluted with brine (10 mL), and the products were
extracted with EtOAc (4 × 15 mL). The combined organic extracts
were washed with brine (1 × 5 mL), dried (MgSO4) and concentrated
1
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a
residue which was
chromatographed to furnish 4a (12 mg, 58%) as a colourless solid,
mp.: 142‐144 °C; Lit.: 57‐59 °C.5e In addition, part of the starting
material was recovered (5 mg), increasing the yield to 78%. IR (KBr,
ῡ): 2922, 1741, 1597, 1545, 1325, 1194, 1061 and 791 cm‐1. 1H NMR
δ: 7.37 (dd, 1H, J = 8.3 and 7.4, H‐7), 7.27 (d, 1H, J = 8.3, H‐8), 7.13
(d, 1H, J = 7.4, H‐6), 6.83 (s, 1H, H‐1’), 5.71 (br s, 3H, H‐4a’), 5.23 (t,
3H, J = 1.3, H‐4b’), 2.80 (s, 3H, H‐9) and 2.12 (s, 3H, H‐5’). 13C NMR
δ: 158.4 (C‐2), 157.9 (C‐4), 157.3 (C‐2’), 153.4 (C‐8a), 134.0 (C‐5),
131.7 (C‐3’), 130.0 (C‐7), 126.5 (C‐6), 115.1 (C‐8), 113.4 (C‐4’), 112.2
(C‐3), 112.0 (C‐4a), 103.7 (C‐1’), 21.0 (C‐9) and 19.1 (C‐5’). Except
for the signals marked in Table 1, the NMR spectroscopic data of
synthetic 4a were in full agreement with those informed in the
literature for the natural pterophyllin 2.5e
2
Conclusions
3
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In conclusion, the total syntheses of the natural products gerberinol
I (6d, 4 steps, 29% yield), pterophyllin 4 (4b, 5 steps, 30% yield) and
pterophyllin 2 (4a, 6 steps, 17% yield) have been achieved in short
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Total syntheses of gerberinol I and the pterophyllins 2 and 4
using the Casnati-Skattebøl reaction under different conditions
Jorgelina L. Pergomet, Andrea B. J. Bracca* and Teodoro S.
Kaufman*
The total syntheses of the title compounds were achieved from a
single coumarin precursor, taking advantage of the temperature-
dependent divergent outcomes of the Casnati-Skattebøl reaction.