Synthesis of sapphyrins via a '3+1+1' procedure

Article abstract of DOI:10.1016/S0040-4039(01)00198-8

Sapphyrins may be obtained in ca. 30% yield via the condensation of 1 equivalent of a tripyrrane dialdehyde with 2 equivalents of a β-substituted pyrrole, followed by oxidation with DDQ.

Full text of DOI:10.1016/S0040-4039(01)00198-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2447–2450
Synthesis of sapphyrins via a ‘3+1+1’ procedure
Sergiy V. Shevchuk, Julian M. Davis and Jonathan L. Sessler*
Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, The University of Texas at Austin,
Austin, TX 78712-1167, USA
Received 5 January 2001; revised 26 January 2001; accepted 29 January 2001
Abstract—Sapphyrins may be obtained in ca. 30% yield via the condensation of 1 equivalent of a tripyrrane dialdehyde with 2
equivalents of a b-substituted pyrrole, followed by oxidation with DDQ. © 2001 Elsevier Science Ltd. All rights reserved.
Porphyrins, the so-called pigments of life,1 are arguably
among the most widely studied of all macrocyclic com-
pounds. Less well studied are the so-called expanded
porphyrins. The chemistry of these systems, macrocy-
cles that, like porphyrin, are comprised of pyrrolic rings
and meso-carbon bridges had its genesis in the early
1960s when researchers in the Woodward group, while
working on the synthesis of corroles, isolated a brilliant
blue–green solid by-product.2 This system, called sap-
phyrin in light of its startling color, was found to
contain a 22 p-electron aromatic periphery (highlighted
in bold in Scheme 1).3–5 It was also found to be
‘expanded’ relative to porphyrin in that it was seen to
contain one additional pyrrole, ‘inserted’ into its
macrocyclic core. As a consequence, sapphyrins contain
a direct a–a pyrrole link, something not seen in por-
phyrins. They also contain a larger central cavity than
porphyrins and reduced molecular symmetry. Sap-
phyrins thus display properties, such as pyrrole ring
inversion6 and anion binding,7 that differ dramatically
from those of the porphyrins. Needless to say, there-
fore, the synthetic chemistry of sapphyrins has received
considerable attention of late.6–17 Still, improved syn-
theses are needed. In this letter, a novel ‘3+1+1’
approach to sapphyrin is detailed. The strengths and
weakness of this new method are highlighted by com-
parison to two other routes, one
a well-known
approach,5,7–9 and the second a seemingly obvious vari-
ation of a classic synthetic strategy that has apparently
so far escaped mention in the literature.
R
R
R
R
N
H
R'
R'
1. DCM,TFA
2. DDQ
H
N
H
N
+
N
H
N
H
N
H
N
H
O
O
HN
R'
NH
R'
(2 equiv.)
3 R' = Me
4 R' = OMe
5 R' = Et
R'
R'
1 R = CH2OH
2 R = H
6 R = CH2OH R' = Me
7 R = CH2OH R' = OMe
8 R = CH2OH R' = Et
9 R = H
R' = Et
Scheme 1.
Keywords: sapphyrins; macrocycles; 3+1+1 condensation; pyrrole–pyrrole linkage.
* Corresponding author. Fax: (512) 471-7550; e-mail: sessler@mail.utexas.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00198-8

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S. V. She6chuk et al. / Tetrahedron Letters 42 (2001) 2447–2450
HO
OH
OH
HO
N
H
N
1. CH2Cl2,TFA
2. DDQ
N
+
R
R
R
R
N
H
N
H
N
H
N
H
N
H
HN
NH
10 R = CO2H
11 R = CHO
12 R = H
1
R = CHO
8
Scheme 2.
The present route is predicated on the direct formation
of an a–a pyrrole linkage during ring closure (Scheme
1). While it has been known for some time that direct
a–a pyrrole links can be formed during the condensa-
tion/oxidation reaction used to obtain sapphyrins,5 the
power of this approach as a general synthetic strategy
has only recently begun to be appreciated. It has been
used to prepare sapphyrin by ‘4+1’10 and ‘1+1+1+1+1’6
procedures, as well as corrole18,19 and new expanded
porphyrins.20 It has not, however, been applied to
prepare sapphyrins via a ‘3+1+1’ approach involving
the condensation between bisformyl tripyrrane and two
molar equivalents of a bis-a-free pyrrole. We report
here the successful development of such a route.
presumably as the result of 1 or 2 reacting with only
one equivalent of pyrrole prior to ring closure.‡
In order to assess the synthetic value of this new
‘3+1+1’ approach, sapphyrin 8 was also prepared via
two ‘3+2’ methods (Scheme 2). The first, referred to as
Method II, involved reacting bisformyl tripyrrane 1 and
bis-a-free bipyrrole 12. By contrast, the second involved
the condensation of tripyrrane diacid 10 with bisformyl
bipyrrole 11. This latter alternative strategy, referred to
as Method III, is the classic one first developed by the
groups of Woodward4 and Johnson3 and then later
optimized by us.6
Predicative transformations, required to obtain precur-
sors 11 and 12 (as well as 1 from 10), are shown in
Scheme 3. The relative yields of sapphyrin 8 produced
by Methods I, II, and III (as well as 6 and 7 produced
by Method I) are summarized in Table 1. Taken in
concert, Table 1 and Scheme 3 reveal that the macrocy-
clization step of Method I is not as efficient as that of
the ‘3+2’ condensations. On the other hand, since the
need to prepare a bipyrrole precursor is obviated, the
‘3+1+1’ method is three steps shorter and hence more
efficient than the ‘3+2’ approaches in terms of the
overall yield from common precursors, namely 10 and
13. Reversing the nucleophile/electrophile roles in the
traditional ‘3+2’ approach offers a small boost in yield
in the macrocyclization step, although this gain is offset
by the fact that the formylation of tripyrrane 10 is less
efficient than that of bipyrrole 12.
The specific chemistry in question is summarized in
Scheme 1. Briefly, acid-catalyzed condensation between
a diformyl tripyrrane (e.g. 1 or 2) and two molar
equivalents of a bis-a-free, b-substituted pyrrole (e.g. 3,
4, or 5), followed by oxidation with DDQ, is found to
produce the corresponding sapphyrins (6–9) in 28–34%
yield† (Scheme 1). As one might expect, porphyrin was
also isolated from the reaction mixture (510% yield),
† Typical procedure: A 200 ml mixture of 5% TFA in CH2Cl2 was
added to a round bottom flask containing 96 mg (0.2 mmol) of
tripyrrane dialdehyde 1 and 49 mg (0.4 mmol) of diethyl pyrrole 5.
The reaction mixture was stirred overnight at ambient temperature.
The solution was neutralized with TEA, and 45 mg of DDQ (0.2
mmol) was added. The mixture was concentrated to a volume of
100 ml on the rotary evaporator and washed with a saturated
aqueous solution of NaHCO3 (2×100 ml) and H2O (2×100 ml). The
organic layer was dried over MgSO4, filtered, and stripped of
solvents using a rotary evaporator. Purification by column chro-
matography on silica gel, using CH2Cl2:MeOH (96:4) as the eluent,
gave 47 mg (34%) of 8 as dark blue–green crystals. Mp >300°C;
UV–vis (CH2Cl2): umax, nm (log m) 447 (5.45), 612 (4.17), 664 (4.03),
A further advantage of the present ‘3+1+1’ approach is
that it allows ready access to sapphyrins such as 7 for
which the requisite bi- or polypyrrole precursors are not
available. On the other hand, the ‘3+1+1’ approach
does require that the two b-substituents of the pyrrole
(e.g. 3–5) must be identical to avoid the statistical
formation of three different regioisomers. Still, the spe-
cific hydroxypropyl sapphyrins (i.e. 6–9) of this study
can be further derivitized via their hydroxyl groups.
Thus, subject to the symmetry constraints noted, the
1
714; CI–MS: 689 (M+); H NMR (500 MHz, CDCl3): l, ppm −5.02
(1H, NH, s), −4.63 (1H, NH, s), −4.53 (1H, NH, s), 1.80 (6H,
CH2CH3, t), 2.00 (6H, CH2CH3, t), 2.17 (6H, CH2CH3, t), 2.74
(4H, CH2CH2CH2OH, m), 3.95 (4H, CH2CH2CH2OH, t), 4.14 (6H,
CH3, s), 4.47 (4H, CH2CH3, q), 4.53 (4H, CH2CH3, q), 4.62 (4H,
CH2CH3, q), 4.71 (4H, CH2CH2CH2OH, t), 11.53 (4H, meso-H, s);
13C NMR (125 MHz, CDCl3): 12.8, 16.9, 18.3, 18.4, 20.8, 21.7,
23.5, 35.2, 61.7, 91.6, 98.7, 128.9, 130.4, 132.7, 132.9, 135.7, 136.3,
137.6, 138.8, 140.5, 143.1; anal. calcd for C44H57N5O2·2CF3CO2H:
C, 62.94; H, 6.49; N, 7.65; found: C, 62.95; H, 6.47; N, 7.66%.
‡ Unfortunately, the reaction of 1 and b-unsubstituted pyrrole did not
produce useful quantities of the corresponding sapphyrin (yield
<2%).

S. V. She6chuk et al. / Tetrahedron Letters 42 (2001) 2447–2450
OH
2449
HO
R1
R3
N
R
R
N
H
N
H
N
H
R2
5
R1 = R2 = R3 = H
10 R = CO2H
ii
i
13 R1 = R2 = H, R3 = CO2Et
14 R1 = I, R2 = H, R3 = CO2Et
1
R = CHO
iii
iv
v
15 R1 = I, R2 = BOC, R3 = CO2Et
Yield (%)
80
Conditions
i. 1) TFA
2) HC(OCH2CH3)3
3) H2O
R
R
N
H
N
H
4) LiOH in 5% H2O / MeOH
ii. NaOH, HOCH2CH2OH
iii. I2, NaI, NaOAc, H2O
ClCH2CH2Cl
16 R = CO2Et
87
85
vi
12 R = H
vii
98
75
90
87
iv. OC(OtBu)2, DMAP, CH2Cl2
v. Cu, DMF
11 R = CHO
vi. NaOH, HOCH2CH2OH
vii. 1) POCl3, DMF
2) NaOAc in H2O
Scheme 3.
Table 1. Comparison of the three synthetic pathways discussed in this letter
Method
Ring formation yield (%)
Overall yield from 10 and 13 (%)
Number of steps from 10 and 13
I (1+3“6)
I (1+4“7)
I (1+5“8)
I (2+5“9)
II (1+12“8)
III (10+11“8)
28
30
34
33
55
50
–
–
24
–
20
20
–
–
3 (i, ii)a
–
6 (i, iii–vi)a
6 (iii–vii)a
a Refers to steps shown in Scheme 3.
present approach appears to be attractive as one that
offers the possibility of preparing b-substituted sap-
phyrins with controlled regiochemistry and controlled
solubility without requiring the intermediate synthesis
of bipyrrolic precursors.
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Acknowledgements
This work was supported by The National Institutes of
Health (grant no. CA 68682 to J.L.S.) and by Pharma-
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