Phorbol Rearrangements

Article abstract of DOI:10.1021/acs.jnatprod.8b00607

An alternative procedure for isolation of 4β-phorbol from seeds of Croton tiglium has been developed, and an artifact containing a furan ring formed by rearrangement of 12,13,20-O-triacylated phorbol derivatives into (6bS,7R,8R,8aS)-2-(hydroxymethyl)-5,7,9,9-tetramethyl-3,7,8,9,9a,9b-hexahydrocyclopropa[3′,4′]benzo[1′,2′:3,4]cyclohepta[1,2-b]furan-6b,8,8a-triol (8a) has been characterized. A mechanism involving an oxidative rearrangement and a decarboxylation for formation of the artifact is proposed.

Full text of DOI:10.1021/acs.jnatprod.8b00607

Note
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Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Phorbol Rearrangements
Tomas Zimmermann,† Henrik Franzyk, and Søren Brøgger Christensen*
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen Ø, Denmark
S
* Supporting Information
ABSTRACT: An alternative procedure for isolation of 4β-phorbol from seeds of Croton tiglium has been developed, and an
artifact containing a furan ring formed by rearrangement of 12,13,20-O-triacylated phorbol derivatives into (6bS,7R,8R,8aS)-2-
(hydroxymethyl)-5,7,9,9-tetramethyl-3,7,8,9,9a,9b-hexahydrocyclopropa[3′,4′]benzo[1′,2′:3,4]cyclohepta[1,2-b]furan-6b,8,8a-
triol (8a) has been characterized. A mechanism involving an oxidative rearrangement and a decarboxylation for formation of the
artifact is proposed.
he oil from the seeds of Croton tiglium L. (Euphorbia-
Tceae) was imported from India to Europe around 1812 as
a new purgative drug.1 However, application of the oil on the
skin causes severe skin irritation and redness.2 Except for
periorbital facial rejuvenation3 the use of croton oil has been
abandoned because of its proinflammatory and tumor-
promoting effects.4 Due to compound lability, the correct
structures of the active phorbol esters were not elucidated until
1967 by X-ray crystallographic analysis,5 although preliminary
structural studies were reported.6,7 The 12,13-O-diacyl
derivatives of phorbol (Scheme 1, 1a) are potent agonists
acting on members of the protein kinase C (PKC) enzyme
family.2,8
12,13-O-phorbol diesters only differing in the acyl groups
(Scheme 1) are present in croton oil together with some
12,13,20-O-triesters.2,8b The most used tool in bioassays for
investigating the effects of PKC has become 12-O-tetradeca-
noylphorbol 13-acetate (TPA, 1b), also named phorbol 12-
myristate 13-acetate (PMA). In order to avoid a tedious and
difficult separation of the ester derivatives, most protocols for
gram-scale isolation suggest that the crude oil be saponified by
using barium hydroxide as the base, thus providing the
pentavalent alcohol, 4β-phorbol (2) (Scheme 1), which can be
readily purified. Subsequently, the acyl groups may be
reintroduced.9
The use of harsh alkaline conditions on a multifunctional
unsaturated molecule containing several rings might be
expected to cause side reactions such as degradation and
rearrangement. Two such reactions have already been
described, namely, oxidative opening of the pentenone
ring.10 A putative mechanism for the oxidative rearrangement
has been proposed (Scheme S1, Supporting Information).10
The second described rearrangement is an epimerization at C-
4 (Scheme S2, Supporting Information).2 This reaction was
described to occur when treating 2 with sodium methoxide.2,11
Compounds 6 and 7, epimerized at C-10 and C-2, respectively,
were observed as minor side products. The mechanism
outlined in Scheme S2 may explain how this product mixture
may arise.
The intriguing bioactivities of the phorbols have promoted
an interest in development of protocols enabling isolation of
the compounds in gram scale from croton oil.2,9 A number of
Scheme 1. Saponification of Esters of 4β-Phorbol (1a)
Received: July 25, 2018
© XXXX American Chemical Society and
American Society of Pharmacognosy
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DOI: 10.1021/acs.jnatprod.8b00607
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
Epimerization at C-4 has as a consequence that the
corresponding 12,13-O-diesters lose affinity for PKC.12 Instead
they possess a high affinity for the vanilloid transient receptor
potential (TRP) cation channel subfamily V member 4 (i.e.,
TRPV4).13 Esterification at O-20 in phorbol 12,13-O-diesters
with homovanillic acid also confers an affinity for TRPV4 to
the resulting triesters.14 However, masking of O-20 causes a
loss of affinity for PKC.15 The PKC activation by some 20-
acylated phorbols may be explained by nonspecific inter-
actions.16
Besides 2 and a small amount of epimer 5, an additional spot
was observed by thin-layer chromatography (TLC) of the
reaction mixture. Visualization by heating the TLC plate when
sprayed with 10% sulfuric acid in MeOH revealed a magenta
spot, a color very different from the brown color of the spots of
the phorbols. The NMR spectra of the purified byproduct were
similar to those of the phorbols except for the signals
originating from the cyclopentenone moiety, which either
had disappeared or were shifted to very different resonance
values. A signature signal appeared in the HSQC spectrum at
δH 6.1,δC 108, which is characteristic for H-3,C-3 in a furan
ring. Two isomers appeared to be possible considering that the
product was derived from a phorbol drivative. Strong
correlations in the HMBC spectrum were present between
the two protons attached to C-5 and the two carbon atoms
attached to the oxygen in the furan ring (i.e., C-2 and C-4). In
contrast, no correlations were observed between H-5 and the
remaining two carbon atoms of the furan ring (i.e., C-1 and C-
10). The signature signal at δH 6.1,δC 108 could then be
assigned to H-1 and C-1. These observations are in agreement
with the proposed structure 8a.
The presence of 8a in the solvolysis mixture of the seeds of
C. tiglium extract can be explained by one of two options: (i)
compound 8a or esters of compound 8a are natural products,
which previously have been disregarded in the studies of
extracts of croton seeds, or (ii) compound 8a is an artifact
formed by an oxidative rearrangement followed by a
decarboxylation of natural products present in the seeds. An
HSQC correlation of the crude phorbol ester fraction prior to
saponification revealed no signal at δH 6.1,δC 108, indicating
that compound 8a is an artifact. Since only some furans exhibit
signals at this location of HSQC correlation, no interfering
weak signals from other molecules would seem to contradict
the interpretation that the compound is an artifact.
To elucidate how 8a may originate from phorbol derivatives
found in the seeds of C. tiglium, several attempts at
rearrangement of 4β-phorbol, 4α-phorbol, and 12,13-O-
phorbol diesters were performed, but no furan derivatives
were formed. In contrast, if 4β-phorbol 12,13,20-O-tridodeca-
noate (1c)18 was treated with barium hydroxide in MeOH
under similar conditions to those used for base-catalyzed
solvolysis of the methanol extract of C. tiglium seeds,
compound 8a was indeed formed. The oxidative opening of
the cyclopentenone ring depicted in Scheme S1 also only
occurs for phorbol esters masked at O-20.10 Thus, the presence
of 4β-phorbol 12,13,20-O-triesters in C. tiglium8b infers that
these derivatives are likely substrates that may be transformed
into furan derivatives during the saponification procedure. No
attempts were made to identify compounds possessing the
skeleton of artifact 4 in the solvolysed mixture, since these are
formed from 3 only after a prolonged exposure to sodium
methoxide and oxygen (Scheme S1).10
In order to enable the synthesis of peptide-based enzyme-
activated prodrugs of 2 similar to those reported for the natural
product thapsigargin,17 gram-scale isolation of phorbol esters
1a was undertaken by using procedures similar to those
previously published.2,9 However, instead of using croton oil,
seeds of C. tiglium were selected as the starting material. We
had to try to extract C. tiglium seeds instead of croton oil,
because we were not able to isolate phorbol esters from the
purchased croton oil. Our hypothesis is that phorbol esters had
been purposely removed, probably due to toxicity issues.
Repeated extraction of finely ground seeds with ethyl acetate
under sonication at 40 °C yielded upon evaporation a dark
yellow tar. As noticed previously,9 direct solvolysis of the
extract with methanolic base was problematic, as 4β-phorbol
(2) and 4α-phorbol (5) proved difficult to separate from the
glycerol produced during solvolysis of the triacylglycerols
present in the extract. In order to avoid this obstacle, a
defatting step was included in the protocol. Thus, the
concentrated crude extract was dissolved in MeOH, affording
two separable phases, in which undesired lipophilic com-
pounds were retained in the upper phase. A potential loss of a
fraction of phorbol triesters during this defatting procedure
was accepted since the procedure was fast and afforded the
desired 4β-phorbol 2 in good yield. The lower methanolic
phase, mainly containing phorbol diesters and triesters, was
diluted with MeOH and treated with barium hydroxide. Strong
basicity of the solution is very important for efficient
quantitative solvolysis. However, if the solvolysis was
performed at room temperature, extensive epimerization to 5
occurred. A difficult separation of 2 and 5 causing substantial
loss in the yield of 2 rendered these conditions undesirable.
Attempts to get a good separation of the two epimers by
column chromatography using silica gel or reversed-phase C18
silica gel failed if 2 and 5 were present in similar amounts. In
this case a substantial number of the fractions contained both
compounds. Fortunately, almost no epimerization occurred if
the solvolysis was performed at a lower temperature, although
a prolonged reaction time was required, as this expectedly
made the conversion more sluggish. Indeed, when the
solvolysis was performed at 0 °C for 18 h, only a trace
amount of epimer 5 was generated.
Inspired by the suggested mechanism for the oxidative
opening of the cyclopentenone ring converting 3 into 4
(Scheme S1, Supporting Information),10 an oxidative decar-
boxylative mechanism may be proposed for the formation of
8a (Scheme 2). Triplet oxygen reacts with a triacylphorbol (I)
to give allylic hydroperperoxide II, which by attack from a
hydroxide ion on the C-3 carbonyl and concomitant loss of a
hydroxide ion from the hydroperoxide functionality is
converted into the vinylogic β-keto carboxylate III. After
decarboxylation, dienol IV is formed, which can cyclize and
eliminate water to give furan VI, which is solvolysed to give
Figure 1. Two possible structures for the rearranged phorbol product
containing a fused furan ring.
B
DOI: 10.1021/acs.jnatprod.8b00607
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Journal of Natural Products
Note
Scheme 2. Oxidative Decarboxylation of O-20-Masked Phorbol
Solvolysis and Isolation of 4β-Phorbol (2) and Compound
8a. A solution of crude phorbol esters (3.52 g) in MeOH (80 mL)
was cooled on ice, and then Ba(OH)2·8H2O (3.8 g; 12 mmol) was
added. The mixture was stirred at 0 °C for 18 h and then neutralized
by dropwise addition of 2 M H2SO4 until a weakly acidic solution was
obtained. After filtration, the filtrate was concentrated and the residue
chromatographed over silica gel (500 g) starting with CH2Cl2−
MeOH (50:1; 5 L) and gradually increasing the concentration of
MeOH to CH2Cl2−MeOH (12:1). 4β-Phorbol (2, 1.06 g) was eluted
with CH2Cl2−MeOH (11:1), while compound 8a (174 mg) was
eluted with CH2Cl2−MeOH (12:1). Both compounds were obtained
compound 8a. In both this rearrangement and the rearrange-
ment described in Scheme S1, a nucleophilic attack on the
carbonyl group opens the cyclopentenone ring. The
assumption that a free C-20 hydroxy group prohibits this
attack would explain why this group has to be masked. Before
workup, the reaction mixture was neutralized with sulfuric acid.
The last steps in the migration path might occur after the
reaction mixture has been made slightly acidic.
EXPERIMENTAL SECTION
1
as a colorless, amorphous powder. The H NMR and 13C NMR data
■
for 4β-phorbol (2) were identical to those reported.19 The data for 8a
were identical to those acquired for the sample obtained from
solvolysis of 12,13,20-tridodecanoate 4β-phorbol.
General Experimental Procedures. Optical rotations were
measured on a Rudolph Research Analytical Autopol VI automatic
polarimeter. The NMR spectra were recorded on Bruker Advance 400
and 600 MHz spectrometers. ACD NMR manager was used to
process NMR spectra. Samples were dissolved in methanol-d4 or
CDCl3 and analyzed at 300 K. The residual solvent peaks were used
as internal standards (i.e., methanol-d4: δC 49.00; δH 3.31; CDCl3: δC
77.00; δH 7.26). HRMS were recorded on a Bruker micrOTOF-Q
instrument using electrospray ionization in the positive mode.
Column chromatography was performed over silica gel 40−63 μm.
HPLC was performed on a Water Alliance 2695 apparatus using an
Agilent Zorbax XDB C18 analytical column (particle size: 3.5 μm, 4.6
× 75 mm), using an aqueous MeOH gradient with 0.1%
trifluoroacetic acid (TFA) added (eluent A: H2O + 0.1% TFA,
eluent B: MeOH + 0.1% TFA).
12,13,20-Tridodecanoate 4β-phorbol (1c). To a solution of
4β-phorbol (52 mg; 0.142 mmol) in tetrahydrofuran (THF)−CH2Cl2
(1:1; 4 mL) were added N-ethyl-N′-(3-(dimethylamino)propyl)-
carbodiimide (108 mg; 0.565 mmol), dodecanoic acid (340 mg; 1.7
mmol), and 4-dimethylaminopyridine (35 mg; 0.287 mmol), and then
the mixture was stirred under argon at room temperature for 22 h. On
concentration, the residue was dissolved in EtOAc, and upon addition
of NaHCO3, the solution was washed twice with water, dried with
Na2SO4, and concentrated to give a tar. The tar was chromatographed
over silica gel (80 g) using hexane−EtOAc (4:1; 500 mL) to obtain
1
4β-phorbol 12,13,20-tridodecanoate (1c, 111 mg; 84.7%): H NMR
(400 MHz, CDCl3) δH 7.59 (1H, s, H-1) 5.71 (1H, d, J = 4.3 Hz, H-
7), 5.40 (1H, d, J = 10.1 Hz, H-12), 4.47 (1H, d, J = 12.3 Hz, H-20a)
4.43 (1H, d, J = 12.3 Hz, H-20b), 3.24 (1H, d, J = 2.3 Hz, H-8), 3.23
(1H, m, H-10) 2.51 (1H, d, J = 18.4 Hz, 1H, H-5a), 2.41 (1H, d, J =
18.4 Hz, H-5b), 2.34−2.24 (6 H, m, 3 × DodecanoylH-2 (DoH-2)),
2.13 (1H, dq, J = 6.3, 5.30 Hz, H-11), 1.76 (3 H, d, J = 1.5 Hz, H-19),
1.67−1.53 (6 H, m, 3 × DoH-3), 1.32−1.23 (17H, m, 3 × DoH-4−
11, H-17), 1.20 (3 H, s, H-16), 1.03 (1H, d, J = 5.1 Hz, H-14), 0.86
(12 H, t, J = 6.5 Hz, 3 × DoH-12, H-18); 13C NMR (400 MHz,
CDCl3) δC 208.8 (C-3), 176.3 (DoC-1), 173.4−173.6 (2 × DoC-1)
160.9 (C-1), 135.7 (C-6), 132.8 (C-2), 132.7 (C-7), 78.1 (C-12),
76.5 (C-9), 73.5 (C-4), 69.1 (C-20), 65.3 (C-13), 56.1 (C-10), 43.0
(C-11), 39.3 (C-8), 38.9 (C-5), 36.2 (C-14), 34.5 (DoC-2), 34.3
(DoC-2′), 34.2 (DoC-2″), 31.9 (3 × DoC-10), 29.7−28.9 (3 × DoC-
4-C-9) 25.7 (C-15), 25.2 (DoC-3) 24.9 (DoC-3′), 24.5 (DoC-3″),
23.8 (3 × DoC-11), 22.7 (C-17), 16.8 (C-16), 14.4 (C-18), 14.1 (3 ×
DoC-12), 10.1 (C-19).
Plant Material. Croton tiglium seeds were purchased from
Herbalveda UK, East Harrow Middlesex, UK. A sample is deposited
at the Pharmacognostic Collection at the Department of Drug Design
and Pharmacology under the code PC2018-001.
Extraction and Isolation. Seeds of C. tiglium (1493 g) were
ground in EtOAc (600 mL) and then sonicated at 40 °C for 1 h. The
mixture was filtered, and the ground seeds were sonicated in EtOAc
(600 mL) two additional times (for 4 and 1 h). The combined
extracts were concentrated. The residue was dissolved in MeOH (500
mL) and shaken in a separation funnel, and then two phases were
formed. The lower MeOH layer was isolated, while the upper, mainly
triacylglycerol, layer was extracted twice with MeOH (600 mL). The
combined MeOH phases were concentrated and chromatographed
over silica gel (600 g) starting with heptane−EtOAc (5:1) as an
eluent (4 L) and gradually increasing the concentration of EtOAc to
heptane−EtOAc (1:1). After concentration, the residue was
chromatographed over silica gel (500 g) using gradient elution
starting with CH2Cl2−MeOH (100:1; 3 L) and gradually increasing
the concentration of MeOH to CH2Cl2−MeOH (50:1). After
concentration of the combined phorbol-containing fractions, the
residue (12 g) mainly consisted of phorbol esters.
(6bS,7R,8R,8aS)-2-(Hydroxymethyl)-5,7,9,9-tetramethyl-
3,7,8,9,9a,9b-hexahydrocyclopropa[3′,4′]benzo[1′,2′:3,4]-
cyclohepta[1,2-b]furan-6b,8,8a-triol (8a). To a solution of
12,13,20-tridodecanoate-4β-phorbol (58 mg; 0.064 mmol) in
MeOH (6 mL) was added Ba(OH)2·8H2O (110 mg; 0.349 mmol)
C
DOI: 10.1021/acs.jnatprod.8b00607
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Journal of Natural Products
Note
at 0 °C, and then the mixture was stirred at 0 °C for 18 h. The
reaction mixture was neutralized with 1 M H2SO4 and concentrated,
and the formed precipitate of BaSO4 removed by filtration. The
filtrate was concentrated, and the residue chromatographed over silica
gel (60 g) using CH2Cl2−MeOH (20:1; 400 mL) gradually increasing
the gradient toward CH2Cl2−MeOH (12:1) to give compounds 8a
(10 mg, 45%) and 2 (5 mg; 21%), which were obtained as a colorless,
amorphous powder. 8a [(6bS,7R,8R,8aS)-2-(hydroxymethyl)-5,7,9,9-
tetramethyl-3,7,8,9,9a,9b-hexahydrocyclopropa[3′,4′]benzo-
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[1′,2′:3,4]cyclohepta[1,2-b]furan-6b,8,8a-triol] (10 mg; 45%): [α]21
D
64.0 (c 1; MeOH); 1H NMR (400 MHz, CD3OD) δH 5.85 (1H, d, J
= 1.0 Hz, H-1), 5.31 (1H, br d, J = 5.1 Hz, H-7), 3.91 (1H, d, J = 10.5
Hz, H-12), 3.85 (1H, d, J = 13.0 Hz, H-20b), 3.80 (1H, br d, J = 13.0
Hz, H-20a), 3.17 (1H, br d, J = 16.9 Hz, H-5b), 2.93 (1H, d, J = 16.9
Hz, H-5a), 2.27 (1H, t, J = 5.0 Hz, H-8), 1.97 (3H, br s, H-19), 1.24
(1H, dq, J = 10.4, 6.5 Hz, H-11), 1.08 (3H, s, H-16) 1.04 (3H, d, J =
6.4 Hz, H-18), 0.98 (3H, s, H-17), 0.61 (1H, d, J = 4.4 Hz, H-14);
13C NMR (400 MHz, CD3OD) δC 148.5 (C-1), 146.8 (C-4), 143.1
(C-6), 130.0 (C-7), 123.1 (C-10), 108.8 (C-1), 79.0 (C-12), 74.6 (C-
9), 65.3 (C-20), 61.6 (C-13), 47.8 (C-11, overlapped by signal from
CD3OD), 41.4 (C-8), 36.9 (C-14), 27.4 (C-5), 25.1 (C-15), 23.1 (C-
18), 15.9 (C-17), 13.8 C-16), 11.8 (C-19); HRMS m/z 357.1676 [M
+
+ Na]+ (calcd for C19H26NaO5 357.1672). The homogenity was
checked by analytical HPLC at a flow of 0.7 mL/min with a gradient
method: 10% → 50% B over 25 min. The product 8a was eluted at
22.7 min with a purity of more than 98%.
ASSOCIATED CONTENT
* Supporting Information
■
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b00607.
1
Copies of the H, 13C, HCOSY, HSQC, NOESY, and
HMBC NMR spectra and HRMS spectrum of
1
compound 8a and H and 13C NMR spectra of 4β-
phorbol 12,13,20-tridodecanoate (1c); schemes depict-
ing the suggested mechanisms for the oxidative opening
of the cyclopentenone ring and epimerization at C-4
(PDF)
(19) Li, Z.-Q.; Liu, Y.; Liu, B.-Y.; Wang, H.; Ye, H.-C.; Li, G.-F. J.
Integr. Plant Biol. 2006, 48, 1486−1492.
AUTHOR INFORMATION
Corresponding Author
*Tel: +45 3533 6253. E-mail: soren.christensen@sund.ku.dk
(S. B. Christensen).
■
ORCID
Tomas Zimmermann: 0000-0003-0529-723X
Henrik Franzyk: 0000-0002-2822-1927
Søren Brøgger Christensen: 0000-0002-5773-6874
Present Address
†Technicka 5, Prague 6, 166 28, UCT Prague, Czech Republic.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a grant from The Czech Republic
Technical University to T.Z.
■
REFERENCES
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D
DOI: 10.1021/acs.jnatprod.8b00607
J. Nat. Prod. XXXX, XXX, XXX−XXX