Carbophilic 3-component cascades: Access to complex bioactive cyclopropyl diindolylmethanes

Article abstract of DOI:10.1002/chem.201202647

Naturally occurring indole-3-carbinol and 3,3-diindolylmethane show bioactivity in a number of disparate disease areas, including cancer, prompting substantial synthetic analogue activity. We describe a new approach to highly functionalised derivatives that starts from allene gas and proceeds via the combination of a three-component Pd⁰-catalysed cascade with a one-pot, three-component carbophilic Pt^II cascade linked to a stereoselective acid-catalysed Mannich-Michael reaction that generates complex cyclopropyl diindolylmethanes which show selective activity against prostate cancer cell lines. Copyright

Full text of DOI:10.1002/chem.201202647

DOI: 10.1002/chem.201202647
Carbophilic 3-Component Cascades: Access to Complex Bioactive
Cyclopropyl Diindolylmethanes
Nigel M. Groome,[a] Elghareeb E. Elboray,[a] Martyn W. Inman,[a] H. Ali Dondas,[a]
Roger M. Phillips,[b] Colin Kilner,[a] and Ronald Grigg*[a]
Abstract: Naturally occurring indole-3-carbinol and 3,3-diindolylmethane show
bioACHTUNGTRENNUNGactivity in a number of disparate disease areas, including cancer, prompting
substantial synthetic analogue activity. We describe a new approach to highly func-
tionalised derivatives that starts from allene gas and proceeds via the combination
of a three-component Pd0-catalysed cascade with a one-pot, three-component car-
bophilic PtII cascade linked to a stereoselective acid-catalysed Mannich–Michael
reaction that generates complex cyclopropyl diindolylmethanes which show selec-
tive activity against prostate cancer cell lines.
Keywords: 3-azabicyclo-
AHCTUNGTRENN[GUN 4.1.0]heptene · diindolylmethanes ·
enynes · palladium · platinum ·
prostate cancer
Introduction
creased production of the cyclin-dependent kinase (CDK)
inhibitor p27,[6] and by inhibition of Akt (serine/threonine-
specific protein kinase).[7] These and other observations
have resulted in uncovering the pleiotropic nature of 1a, 1b
and analogues. Thus, Kamal et al.[8] report the synthesis of
four 3,3’-diindolyl oxindoles with IC50 values of 1.2–3.6 mm
against the DU145 prostate cancer cell line, possibly by
CDK inhibition, although the precise mechanism of action
and molecular target is unclear.
The indole moiety is a key component of many bioactive
natural products.[1] Two simple interconnected examples at-
tracting substantial current interest are indole-3-carbinol
(I3C, 1a) and its metabolite 3,3’-diindolylmethane (DIM,
1b; Figure 1).
Classical methods for the synthesis of diindolylmethanes,
of which there are many, usually involve the reaction of ali-
phatic or aromatic aldehydes with indoles by employing acid
catalysis in solution,[9] in the solid state[10] or under ultra-
sound radiation.[11] Molecular iodine[12] or ammonium chlor-
ide[13] catalysts have also been used. A photochemical syn-
thesis has been reported.[14] The methylene linkage between
the two indole moieties may be provided by hexamethylene
tetramine (HMTA) by using either InCl3 catalysis[15] or the
ionic liquid (Bmim)BF4.[16] In the main, these syntheses of
DIMs produce relatively simple molecules with limited
scope for the introduction of structural diversity.
Figure 1. Indoles that are present in fruits and cruciferous vegetables.
These occur naturally in some fruits and cruciferous vege-
tables such as cabbage, cauliflower, broccoli and Brussels
sprouts and have shown efficacy against a number of human
cancers,[2,3] including by promoting apoptosis in vitro.[4] B-
DIM (Bioresponse-DIM, Indolplex), a dietary ingredient
that is microencapsulated in a water-soluble matrix gives en-
hanced human blood-levels over the crystalline form[5] and
causes G1–S cell-cycle arrest in prostate cancer cell lines by
down-regulation of the androgen receptor (AR) by the in-
Results and Discussion
We have developed a three-stage synthesis which combines
a three-component Pd0-catalysed cascade synthesis of 1,6-
enynes with a subsequent carbophilic[17a–e] PtII-catalysed re-
arrangement followed by a proton-driven Mannich–Michael
addition of one or two indoles to generate complex 3,3’-diin-
dolylmethanes (DIMs) with multiple points of diversity. Our
initial target was a cascade to generate a variety of 3-
[a] N. M. Groome, E. E. Elboray, Dr. M. W. Inman, Prof. H. A. Dondas,
C. Kilner, Prof. R. Grigg
School of Chemistry, University of Leeds
Leeds, LS2 9 JT (UK)
Fax : (+44)0113-343-6501
E-mail: r.grigg@leeds.ac.uk
[b] Dr. R. M. Phillips
azabicycloACHTUNTRGNEUNG[4.1.0]hept-4-enes (see below).
Institute of Cancer Therapeutics, University of Bradford, Bradford,
BD7 1DP (UK)
The synthesis proceeded from N-tosylpropargylamine (2),
which was prepared in 83% yield from propargylamine and
para-toluenesulfonyl chloride (see the Supporting Informa-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202647.
2180
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FULL PAPER
Scheme 1. Sonogashira coupling of 2.
tion). Sonogashira coupling was then used to prepare a
small series of alkynylarylated N-tosylpropargylamines 3a–c
from 2 (Scheme 1, see also the Supporting Information).
With 2 and 3a–c in hand, a Pd-catalysed, three-compo-
nent allene cascade that was developed within the Grigg
group[18] was adapted to access the nitrogen-tethered 1,6-
enynes 4a–i and 5a–j (Scheme 2, Table 1).
Scheme 3. PtII-catalysed cycloisomerisation.
Table 2. PtCl2-Catalysed cycloisomerisation of 1,6-enynes to 3-
azabicyclo
[4.1.0]hept-4-enes.[a]
AHCTUNGTRENNUNG
Entry
4/5
R
Ar
Product
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4a
4b
4c
4d
4e
4 f
4g
4h
5a
5b
5c
5d
5e
5 f
5g
5h
5i
–
–
–
–
–
–
–
–
H
H
H
H
H
H
H
Phenyl
6a
6b
6c
6d
6e
6 f
6g
45
58
60
60
44
52
42
3,4-Dichlorophenyl
4-Methoxyphenyl
4-Acetylphenyl
4-Nitrophenyl
Indol-5-yl
4-(Pyrrol-1-yl)-phenyl
3-Pyridyl
4-Tolyl
4-Chlorophenyl
4-Methoxyphenyl
4-Acetoxyphenyl
4-Trifluoromethyl
Indol-5-yl
[c]
[c]
–
–
7a
7b
7c
7d
7e
7 f
7g
7h
7i
79
92
72
63
85
42
44
74
80
Scheme 2. Pd0-catalysed three-component cascades.
Table 1. Cascade synthesis of mono- and bis-aryl 1,6-enynes.[a]
2-Thienyl
Phenyl
Phenyl
3-Pyridyl
Entry
2/3
R
Ar
Product
Yield
[%][b]
OMe
COOMe
H
[c]
[c]
5j
–
–
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2
2
2
2
2
2
2
2
–
–
–
–
–
–
–
–
–
H
H
H
H
H
H
H
Phenyl
4a
4b
4c
4d
4e
4 f
4g
4h
4i
5a
5b
5c
5d
5e
5 f
5g
5h
5i
83
76
65
64
30
46
38
55
34
81
61
77
55
82
61
72
69
72
65
3,4-Dichlorophenyl
4-Methoxyphenyl
4-Acetylphenyl
4-Nitrophenyl
Indol-5-yl
4-(Pyrrol-1-yl)-phenyl
3-Pyridyl
2-Thienyl
[a] Reaction conditions: PtCl2 (5.0 mol%), toluene, 808C, 3.5 h. [b] Yield
of isolated product. [c] No reaction.
sise a platinum(II) complex of 4h under the reaction condi-
tions employed in the cyclisation was unsuccessful.
The proposed mechanism (Scheme 4) for the PtII-cata-
lysed cycloisomerisation of the 1,6-enyne to 3-azabicyclo-
2
3a
3a
3a
3a
3a
3a
3a
3b
3c
3a
4-Tolyl
4-Chlorophenyl
4-Methoxyphenyl
4-Acetoxyphenyl
4-Trifluoromethyl
Indol-5-yl
2-Thienyl
Phenyl
Phenyl
3-Pyridyl
AHCTUNGTREG[NNUN 4.1.0]hept-4-enes commences with an endo-dig nucleophilic
attack of the alkene component on the Pt-complexed alkyne
component. Cationic intermediate 8 then converts to a cy-
clopropyl metallocarbenoid[17,20] species 9, which rearranges
to form 10. Decomplexation of the catalyst affords the 3-
OMe
COOMe
H
azabicycloACTHNUGRTNEUNG[4.1.0]heptenes 6a–g and 7a–i. Recent related
5j
[a] Reaction conditions: Pd2ACTHNUTRGNNEG(U dba)3 (0.25 mol%), triACHTUNGTNER(NUGN 2-furyl)phosphine
(TFP; 10 mol%), K2CO3 (2 equiv), allene gas, MeCN, 808C, 24 h.
[b] Yield of isolated product.
A PtII-catalysed cascade (Scheme 3) was then employed
to cycloisomerise 4a–g and 5a–i to their respective 1-aryl-3-
azabicyclo[4.1.0]hept-4-enes
6a–g
and
1,6-diaryl-3-
azabicyclo[4.1.0]hept-4-enes 7a–i (Table 2). No conversion
ACHTUNGTRENNUNG
of 4h or 5j was observed and it is hypothesised that chela-
tion of the PtII catalyst by the pyridyl nitrogen atoms was re-
sponsible. However, although trans-dichlorobis
ACHTUNGTRENUN(NG pyridine)–
Scheme 4. Proposed mechanism for the cycloisomerism of 1,6-enynes to
3-azabicyclo[4.1.0.]hept-4-enes.
platinum(II) complexes are known,[19] an attempt to synthe-
AHCTUNGTRENNUNG
Chem. Eur. J. 2013, 19, 2180 – 2184
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2181

R. Grigg et al.
work illustrates the influence of the Lewis acidity of AuI,
MnI and other metal complexes on N- and O-tethered 1,6-
enyne cyclisation.[17h,i]
Next, our efforts were directed to merging the Pt-cata-
lysed generation of the 3-azabicycloACTHNUTRGNEUNG[4.1.0]hept-4-enes with
the installation of the DIM moiety. The bis-aryl 1,6-enynes
5a and 5h were each subjected to the PtII-catalysed cycloiso-
merisation cascade reaction with three equivalents of indole
added at the start of each reaction. A mixture of a major
product and a minor product was obtained in each case and
separated chromatographically. The major products proved
to be the desired DIM compounds 11a,b (Scheme 5,
Table 3). The structure of 11a was confirmed by X-ray crys-
tallography (see the Supporting Information).
structure of 13a was confirmed by X-ray crystallography
(see the Supporting Information). Note that the NTs and
DIM moieties are cis in both diaryl and monoaryl cases;
that is, the cyclopropane moiety remains intact. Traces of
analogues of 12a,b were indicated spectroscopically in the
reaction mixture, but the amounts were too low to be isolat-
ed.
Echavarren et al. have reported an AuI-catalysed addition
of indoles to 1,6-enynes that proceeds through a bifunctional
cyclopropyl-carbene intermediate, giving rise to two distinct
types of non-DIM mono-indole products,[21] both of which
are very different from our products.
In our case (Scheme 6), the highly nucleophilic indole at-
tacks the sulfonyliminium ion, generating the monoindolyl
species; this then fragments to a Michael acceptor, allowing
the addition of the second indole.[22]
Scheme 5. Isolation of both diindolylmethane and its intermediate.
Table 3. PtCl2-catalysed cycloisomerisation of 1,6-enynes in the presence
of indole.[a]
Entry
4/5
R1
R2
R3
Product
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5a
5h
4a
4b
4c
4d
4g
4a
4b
4c
4d
4a
4b
4c
4d
H
H
H
H
H
H
H
F
F
F
F
OMe
OMe
OMe
OMe
Ph
4-OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Me
4-H
4-H
3,4-Cl
4-OMe
4-COMe
4-(N-Pyrrole)
4-H
11a/12a
11b/12b
13a
13b
13c
13d
13e
13 f
13g
13h
13i
13j
13k
13l
13m
45/10
57/26
62
76
63
63
24
67
71
63
60
39
62
40
50
3,4-Cl
Scheme 6. Acid-catalysed Mannich–Michael mechanism for the double
addition of indole to the 3-azabicycloACTHNUGRTNEUNG[4.1.0]hept-4-ene intermediate.
4-OMe
4-COMe
4-H
3,4-Cl
4-OMe
4-COMe
Evidence that the conversion of the azabicycloACHTNUTRGNE[NUG 4.1.0]hept-
4-enes to the diindolylmethanes is a proton-catalysed Man-
nich–Michael process rests on the observation that when the
azabicycloheptene 7a (Table 2, entry 9) was reacted with
three equivalents of indole in the presence of 0.1 equivalents
of dry HCl (1m in Et2O) in toluene (see the Supporting In-
formation) and in the absence of PtCl2 (using a fresh reac-
tion flask and stirrer bar), the reaction mixture was essen-
tially identical by 1H NMR spectroscopy to that of the
PtCl2-catalysed reaction proceeding from the 1,6-enyne 5a.
A sample of 7a was submitted to Davy Technology Ltd.,
Stockton-on-Tees, for the determination of parts per million
of platinum content by atomic absorption spectroscopy. No
detectable levels of platinum were found. Further definitive
evidence for the mechanism shown in Scheme 6 was provid-
[a Reaction conditions: PtCl2 (5.0 mol%), indole (3 equiv), toluene,
808C, 3.5 h. [b] Yield of isolated product.
Spectroscopy of the minor products indicated that they
were monoindolyl adducts 12a,b (Scheme 5), with the azabi-
cycloheptene ring having been preserved intact. The struc-
ture of 12a was confirmed by X-ray crystallography (see the
Supporting Information).
A number of the monoaryl 1,6-enyne substrates were re-
acted with three equivalents of indole in a similar way, and
also with 5-fluoroindole and 5-methoxyindole, resulting in
the generation of diindolylmethanes 13a–m (Table 3). The
2182
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Chem. Eur. J. 2013, 19, 2180 – 2184

Complex Bioactive Cyclopropyl Diindolylmethanes
FULL PAPER
a solution of iodobenzene (1 equiv), triethylamine (2.00 mol equiv), cop-
per(I) iodide (10 mol%), palladium acetate (5 mol%) and triphenylphos-
phine (10 mol%) in DMF (1.25 mL per mmol). The mixture was stirred
at room temperature for 4–14 h, poured into water (10 mL per mmol)
and extracted with ethyl acetate (3ꢁ5 mL per mmol). The aqueous layer
was extracted with ethyl acetate (3ꢁ5 mL per mmol). The organic ex-
tracts were combined, dried (MgSO4), filtered and the filtrate was evapo-
rated under reduced pressure. The residue was purified by flash chroma-
tography on silica gel.
ed by stirring freshly prepared 12a and two equivalents of
indole in toluene containing 0.1 equivalents of dry HCl (1m
in Et2O) at ambient temperature for 2 h. This gave 11a with
only a trace amount of 12a (see the Supporting Informa-
tion), indicating that the loss of HCl was occurring at higher
temperatures and accounting for the incomplete conversion
to 11a at 808C.
A number of the diindolylmethane compounds were
tested against prostate cancer cell lines DU145, PC3 and
LNCaP. Compounds 13d, 13m and 13l showed <10 mm ac-
tivity against LNCaP cell line with some selectivity (Table 4,
General procedure for Pd0-catalysed three-component cascade reactions:
Aryl iodide (1.05–2.10 mmol), nucleophile (1.00–2.00 mmol), Pd
2ACHTUNGTRENNUNG(dba)3
(0.023–0.046 g, 0.025–0.05 mmol), tri(2-furyl)phosphine (0.023–0.046 g,
AHCTUNGTRENNUNG
0.10–0.20 mmol), potassium carbonate (0.15–0.55 g, 1.00–4.00 mmol) and
acetonitrile (10–30 mL) were placed in a Schlenk tube. The tube was
sealed and its contents were frozen by immersion of the tube in liquid ni-
trogen followed by evacuation to 10À4 bar. The contents were allowed to
thaw. This freeze–pump–thaw cycle was repeated once, then the tube and
its contents were re-frozen and the tube re-evacuated. Allene gas
(0.5 bar) was then introduced to the tube, which was re-sealed, and the
contents were thawed. The mixture was stirred and heated at 80–1008C
in an oil bath, behind a blast shield, for 15–24 h, then allowed to cool to
room temperature. Excess allene was vented. The mixture was diluted
with EtOAc (30 mL) and filtered. Silica gel (0.5–1.0 g) was added to the
filtrate and the mixture evaporated to a powder under reduced pressure,
then purified by flash column chromatography on silica gel (60–120 g)
unless otherwise stated. Elution with an appropriate solvent followed by
evaporation under reduced pressure gave the product.
Table 4. In vitro screening of diindolyl compounds against prostate
cancer cell lines.
Entry
Compound
DU145 IC50
LNCaP IC50
PC3 IC50
[mM]
[mM]
[mM]
1
2
3
4
5
13d
13l
13m
14a
14b
>100
>100
>100
41.4
4.84
8.17
3.01
0.45
1.02
26.86
19.63
40.44
2.10
36.2
1.21
General procedure for PtII-catalysed unimolecular cascade reactions: A
stirred mixture of the 1,6-enyne (0.500 mmol) and platinum(II) chloride
(0.007 g, 0.025 mmol) in toluene (5 mL) was heated at 808C for 2.0–3.5 h.
The mixture was allowed to cool to room temperature, diluted with
EtOAc (30 mL) and filtered. The filtrate was concentrated by evapora-
tion under reduced pressure and purified by flash column chromatogra-
phy on silica gel.
entries 1–3). The compounds proved to be poorly soluble in
the culture medium, so this level of activity is likely to be an
underestimate. Derivatisation of 13d and 13m to their
oximes 14a,b (85–86%, Figure 2) greatly improved their
General procedure for PtII-catalysed three-component cascade reactions:
1,6-Enyne (0.5–1.00 mmol), indole or substituted indole (1.5–3.00 mmol)
and platinum (II) chloride (5 mol%) were dissolved in toluene (5–
20 mL) and the mixture was stirred at 808C for 3.0–3.5 h. The reaction
mixture was allowed to cool to room temperature, diluted with EtOAc
(30 mL) and filtered. The filtrate was concentrated by evaporation under
reduced pressure and the residue was purified by flash column chroma-
tography on silica gel.
General procedure for the synthesis of cyclopropyl diindole oximes: Hy-
droxylamine hydrochloride (0.035 g, 0.50 mmol) was added to a stirred
solution of compound 13d or 13m (0.25 mmol) in pyridine (1 mL) and
stirred at RT for 1.5 h. Pyridine was removed under reduced pressure
and the residue was dissolved in EtOAc (10 mL), washed with water
(10 mL) and the combined aqueous layers were extracted with EtOAc
(3ꢁ10 mL). The organic layers were combined and evaporated under re-
duced pressure to give the product, which was purified by trituratation
with hexanes.
Figure 2. Oximes that are selective for prostate cancer cell lines.
aqueous solubility and activity against the LNCaP and PC3
cell lines (Table 4, entries 4 and 5).
Conclusion
Acknowledgements
An atom-economical route to new cyclopropyl dindolylme-
thanes that offers many potential points of structural diversi-
ty has been developed. Two derivatives of 14a,b show en-
couraging levels of activity and selectivity against prostate
cancer cell lines.
We thank the EPSRC, St. James Hospital, Egyptian Government (South
Valley University) and Leeds University.
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