Synthesis and Bergman cyclization of a β-extended porphyrenediyne

Article abstract of DOI:10.1039/b312001e

Condensation of a porphyrin-2,3-dione with a 1,2-diaminoarenediyne affords a β-extended porphyrinic-enediyne: upon thermal Bergman cyclization the quinoxaline spacer positioned between the macrocycle and the enediyne prevents tandem radical cyclization to

Full text of DOI:10.1039/b312001e

Synthesis and Bergman cyclization of a b-extended porphyrenediyne†
John D. Spence,* Eric D. Cline, Domingo M. LLagostera and Patrick S. O’Toole
Trinity University, Department of Chemistry, One Trinity Place, San Antonio, TX, 78212, USA.
E-mail: john.spence@trinity.edu; Fax: +1-210-999-7569; Tel: +1-210-999-7660
Received (in Corvallis, OR, USA) 30th September 2003, Accepted 12th November 2003
First published as an Advance Article on the web 9th December 2003
Condensation of a porphyrin-2,3-dione with a 1,2-diaminoar-
enediyne affords a b-extended porphyrinic-enediyne: upon
thermal Bergman cyclization the quinoxaline spacer positioned
between the macrocycle and the enediyne prevents tandem
radical cyclization to a picenoporphyrin.
To prevent participation of the meso-phenyl substituents in the
reaction pathway we have prepared a porphyrenediyne that
contains a conjugated spacer between the enediyne core and the
porphyrin macrocycle. The presence of this spacer displaces the
enediyne away from the porphyrin and removes the enediyne
alkene from the aromatic pathway of the macrocycle. As a result the
enediyne can react as a typical arenediyne and avoid alternative
reaction pathways, such as tandem radical cyclization and macro-
cycle reduction, previously observed for porphyrinic-enediynes.
We have employed the well established condensation of
porphyrin-2,3-diones with aromatic diamines as a rapid entry to
The Bergman cyclization1 of cis-1,5-diyne-3-enes to produce
1,4-phenyl diradicals is an attractive mode of action for the
destruction of biological targets. Enediyne antitumor antibiotics
utilize their complex molecular architecture to control the delivery
and activation of cyclic enediynes to bind and ultimately cleave
2
12
DNA leading to their potent cytotoxicity. Use of these natural
porphyrins containing b-fused enediyne units. This strategy
products, however, is limited by a lack of tumor cell selectivity and
their long term toxicity. Conjugation of a porphyrin macrocycle to
an enediyne pro-drug can provide an improved delivery system
with enhanced pharmacokinetic properties. In particular, the
development of cationic porphyrins as sensitizers for photo-
simultaneously incorporates a quinoxaline spacer between the
porphyrin and the enediyne core preventing tandem radical
cyclization to a picenoporphyrin.
The synthesis of a 1,2-diaminoarenediyne and resulting con-
densation with a porphyrin-2,3-dione to produce the porphyr-
enediyne is outlined in Scheme 2. Di-iodination of 1,2-dini-
3
dynamic therapy has led to the design of macrocycles that display
4
13
modest tumor selectivity and bind to DNA and proteins like bovine
trobenzene readily affords 1,2-diiodo-4,5-dinitrobenzene 3.
serum albumin5 making them ideal delivery vehicles for ene-
diynes.
Subsequent coupling with two equivalents of trimethylsilylacety-
lene followed by reduction with Zn in 5% acetic acid–ethanol gives
diamine 4 in 62% yield. Condensation of 4 with free-base
The first example of a porphyrin-annulated enediyne was
reported by Smith et al. who prepared Ni(II) 2,3-dialkynyl-
porphyrin-2,3-dione 514 in CH
2
Cl
90% yield. To facilitate Bergman cyclization the trimethylsilyl
groups are removed by stirring with K CO in THF–MeOH to
afford a 90% yield of porphyrenediyne 7.‡
2
then gives porphyrenediyne 6 in
6
5
,10,15,20-tetraphenylporphyrin. Upon thermal cyclization the
1
,4-didehydrobenzene intermediate undergoes a tandem radical
2
3
7
cyclization with the neighboring meso-phenyl substituents fol-
lowed by dehydrogenation to afford highly conjugated macrocycles
referred to as picenoporphyrins (Scheme 1). Further studies by
Zaleski et al. revealed that this cascade event can occur at room
temperature in the presence of DDQ indicating that the dehydroge-
1
The structure of 7 is evident from its H NMR spectrum which
displays C2v symmetry similar to dione 5 with the presence of a new
aromatic 2H singlet at d 8.05 and a 2H singlet at d 3.52 due to
8
nation step is rate limiting. In the absence of DDQ the reaction
temperature, as measured by DSC, is influenced by both steric and
8
electronic factors.9 The accelerated reactivity of these acyclic
enediynes may be similar to the enhanced rate of cyclization of
ortho-substituted arenediynes operating by steric assistance.10
Extension of this methodology to octaalkynylporphyrins results in
significant exotherms indicative of Bergman cyclization in DSC
studies, however, thermal and photochemical solution cyclizations
1
1
lead to reduction of the porphyrin macrocycle.
Scheme 1 Tandem radical cyclization of 2,3-dialkynylporphyrins.
†
Electronic Supplementary Information (ESI) available: experimental
1
13
details for the synthesis of compounds 7 and 8; H and C NMR spectra of
7
and 8. See http://www.rsc.org/suppdata/cc/b3/b312001e
Scheme 2 Synthesis of b-extended porphyrenediyne 7.
1
80
C h e m . C o m m u n . , 2 0 0 4 , 1 8 0 – 1 8 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

acetylenic hydrogens in CDCl
3
. The 13C NMR spectrum further
that utilize the macrocycle to facilitate delivery and activation of
the enediyne. Kinetic studies along with alkyne functionalization,
including phenylethynyl and cyclic derivatives for improved
photochemical activation, are currently under investigation.
This work was supported by the Research Corporation
(CC5242), the Robert Welch Foundation and the Merck/AAAS
Undergraduate Science Research Program.
confirms the molecular symmetry with 23 signals and the UV-Vis
spectrum of 7 is characteristic of porphyrins containing an
exocyclic ring with a strong Soret band at 421 nm along with Q
bands at 531, 602 and 652 nm that are slightly red-shifted compared
to tetraphenylporphyrin.
In contrast to the room temperature cyclization of 2,3-dialky-
3
nylporphyrins stirring a solution of 7 in CHCl –MeOH in the
presence of DDQ does not promote cyclization. Similarly, heating
a solution of 7 up to 110 °C for several hours shows no evidence of
a cyclized product. In each case unreacted starting material is
obtained as the only isolated porphyrinoid product.
The cyclization of porphyrenediyne 7 can be effected at higher
temperatures in the presence of 1,4-cyclohexadiene (1,4-CHD) to
afford adduct 8 in 92% yield (Scheme 3). The high reaction
temperatures for the cyclization of 7, requiring heating at 180 °C for
Notes and references
‡
(
Selected data. 7: d
10H, m), 7.90 (2H, t, J 7.4), 8.05 (2H, s), 8.12 (4H, d, J 7.3), 8.21 (4H, d,
J 7.3), 8.72 (2H, s), 8.93 (2H, d, J 4.9), 8.96 (2H, d, J 4.9). d (CDCl ) 81.6,
2.7, 117.3, 121.8, 124.5, 126.8, 126.9, 127.8, 127.9, 128.1, 128.3, 133.8,
34.3, 134.5, 135.3, 138.1, 139.5, 140.0, 141.5, 141.7, 144.9, 153.2, 155.1.
max(CH Cl ) (log e)/nm 421 (5.27), 531 (4.23), 602 (4.05), 652 (3.31).
max(TFA–CH Cl ) (log e)/nm 466 (5.20), 483 (5.22), 605 (3.93), 699
), 765.2767. Found
) 22.43 (2H, br s), 7.56 (2H, dd, J 6.7, 3.0),
7.74–7.85 (10H, m), 7.95 (2H, t, J 7.6), 8.15 (2H, dd, J 6.4, 3.4), 8.18–8.23
8H, m), 8.47 (2H, s), 8.69 (2H, s), 8.91 (2H, d, J 4.4), 8.94 (2H, d, J 5.0).
H 3
(CDCl ) 22.59 (2H, br s), 3.52 (2H, s), 7.73–7.79
C
3
8
1
l
2
2
l
2
2
24 hours, is likely due to annulation to the aromatic quinox-
(4.56). HRMS (FAB): calcd for C54H33N6 (MH
765.2770. 8: d (CDCl
+
alinoporphyrin resulting in the reversibility of the Bergman
cyclization. Supporting this, the reaction time was found to be
dependent upon the concentration of 1,4-CHD indicating that
hydrogen atom abstraction is rate limiting as previously observed
H
3
(
d
1
1
C
(CDCl
28.5, 128.8, 133.7, 133.9, 134.0, 134.4, 137.7, 137.8, 139.8, 141.8, 141.9,
46.1, 153.3, 154.8. lmax(CH Cl ) (log e)/nm 426 (5.34), 533 (4.58), 608
Cl ) (log e)/nm 422 (4.99), 459 (5.17),
03 (4.95), 626 (4.40), 711 (4.63). HRMS (FAB): calcd for C54
3
) 116.4, 121.9, 126.2, 126.8, 127.0, 127.7, 127.8, 127.9, 128.0,
15
for arenediynes.
2
2
The structure of compound 8 was confirmed by 1H NMR
spectroscopy by the disappearance of the terminal alkyne protons
present in 7 along with the appearance of two new aromatic
(4.36), 660 (3.98). lmax(TFA–CH
2
2
5
35 6
H N
+
(MH ), 767.2923. Found 767.2921.
1
3
multiplets centered at d 7.56 and 8.15. The C NMR spectrum
further confirmed the structure of 8 displaying the anticipated 23
aromatic carbon resonances while the UV-Vis spectrum contains a
strong Soret band at 427 nm along with Q bands at 533, 607 and 660
nm that are red shifted compared to 6 and 7 as a result of increased
conjugation.
1 R. G. Bergman, Acc. Chem. Res., 1973, 6, 25.
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1
387.
3
4
E. D. Sternberg, D. Dolphin and C. Bruckner, Tetrahedron, 1998, 54,
4
151; R. W. Boyle and D. Dolphin, Photochem. Photobiol., 1996, 64,
Photochemical activation of porphyrenediyne 7 under a variety
of conditions, however, results in recovery of unreacted starting
material using isopropanol or 1,4-CHD as the hydrogen atom
donor. This result is not surprising as there are no literature
examples describing photocyclization of terminal enediynes such
as 7.
4
69.
H. Ogoshi, T. Mizutani, T. Hayashi and Y. Kuroda, in The Porphyrin
Handbook, ed. K. M. Kadish, K. M. Smith and R. Guilard, Academic
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6
H. Aihara, L. Jaquinod, D. J. Nurco and K. M. Smith, Angew. Chem.,
Int. Ed., 2001, 40, 3439.
The design of a porphyrenediyne that undergoes a traditional
Bergman cyclization has potential for the development of pro-drugs
7
8
J. W. Grissom and T. L. Calkins, J. Org. Chem., 1993, 58, 5422.
M. Nath, J. C. Huffman and J. M. Zaleski, Chem. Commun., 2003,
8
58.
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1484.
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003, 42, 5158.
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9.
9
1
1
1
1
4
2
3
1
1
3 J. Arotsky, R. Butler and A. C. Darby, J. Chem. Soc. C, 1970, 1480.
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1
7
Scheme 3 Bergman cyclization of porphyrenediyne 7.
C h e m . C o m m u n . , 2 0 0 4 , 1 8 0 – 1 8 1
181