Biosynthesis of porphyrins and related macrocycles. Part 49. Exploration of synthetic routes to analogues of the spiro-intermediate for porphyrin biosynthesis

Article abstract of DOI:10.1039/a708134k

The proposed intermediacy of the spiro-pyrrolenine 1 for the biosynthesis of uroporphyrinogen III has focussed attention on its synthesis. Several different approaches to close analogues of this compound are explored, including (a) the synthesis of a dila

Full text of DOI:10.1039/a708134k

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Biosynthesis of porphyrins and related macrocycles. Part 49.1
Exploration of synthetic routes to analogues of the
spiro-intermediate for porphyrin biosynthesis
Craig J. Hawker, Paul M. Petersen, Finian J. Leeper and Alan R. Battersby*
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
The proposed intermediacy of the spiro-pyrrolenine 1 for the biosynthesis of uroporphyrinogen III has
focussed attention on its synthesis. Several different approaches to close analogues of this compound are
explored, including (a) the synthesis of a dilactone bridged dipyrrolic pyrrolenine, (b) deactivation of two
of the pyrrole rings of the macrocycle by attaching 3-methoxycarbonyl groups and (c) approaches to
spiro-macrocyclic compounds via dipyrroketones. The chemistry of the different types of synthetic
intermediates is described.
The proposed involvement of the spiro-system 1 in the reaction
sequence by which the enzyme cosynthetase (uroporphyrinogen
III synthase) converts hydroxymethylbilane into uroporphyrino-
as the best diol to use by molecular modelling using Macro-
model version 5.5.3 The macrocycle built from this meta-isomer
was favoured by ca. 10 kJ molϪ1 over that based on the ortho-
isomer and by ca. 15 kJ molϪ1 over the one built from the para-
diol. It was also encouraging to find that the ring strain energy
of the preferred macrocycle was calculated to be only ca. 10 kJ
molϪ1, which is less than the ring strain of other macrocycles
which have been successfully synthesised by macrolactonisation
procedures.4
P
A
A
A
P
A
B
HN
HN
NH
Preliminary experiments showed that the dilactone should be
built in a stepwise fashion so the benzyl group was cleaved from
lactam diester 25 by hydrogenolysis and the resultant acid was
directly coupled with benzene-1,3-dimethanol to yield the ester
3, 71%, Scheme 1. Cleavage of the trimethylsilylethyl group
C
A
D
P
N
P
1
A = CH2CO2H, P = CH2CH2CO2H
gen III was described more fully with leading references in the
introduction to the first paper in this set of four.2 That paper
described a way of making 2H-pyrrole (pyrrolenine) rings from
the corresponding thiolactams, which promised well for our
eventual goal of synthesising spiro-pyrrolenine 1. However a
number of difficulties became apparent which prevented us
from achieving that goal. One was that 2-(pyrrolylmethyl)-
pyrrolenines, especially 2,2-bis(pyrrolylmethyl)pyrrolenines,
seem to be strongly resistant to the addition of nucleophiles to
the imine carbon, C-5, possibly because of steric hindrance
from the pyrrolic ring(s). The second difficulty was the lability
under acidic conditions of both pyrrolylmethylpyrrolenines
and their thiolactam precursors when the pyrrole ring(s) lacked
deactivating electron-withdrawing groups.
MeP
O
MeP
CO2CH2CH2SiMe3
MeA
O
MeA
NH
O
NH
CO2R
AMe
PMe
O
HN
MeA
MeP
HN
MeA
MeP
AMe
NH
PMe
NH
O
ii
O
2 R = Bn
3 R = CH2C6H4-m-CH2OH
4
i
MeP
S
S
S
R
CO2CH2CH2SiMe3
NH
MeA
The present paper describes studies into the synthesis of
analogues of spiro-system 1 in which the aim was to circum-
vent one or other of these difficulties by modification of the
synthetic approach.
P
P
S
R
CO2Bn
HN
MeA
MeP
AMe
5 R = C6H4-p-OMe
6 R = SMe
7 R = SC6H4-p-Me
8 R = SC6H4-p-OPh
PMe
N
MeO
9
Results and discussion
Building a dilactonic bridge
AMe = CH2CO2Me, PMe = CH2CH2CO2Me
The steric hindrance at C-5 of 2,2-disubstituted pyrrolenines
was clear from all the experiments described in the previous
paper,2 especially so for those molecules carrying two pyrrolyl-
methyl groups. We therefore envisaged tying back the pyrrolyl-
methyl groups of a compound such as lactam 2 by replacing
the two separate α-pyrrolic ester groups by a single diester
bridge. For this we planned to use one of the three benzene-
dimethanols. These were chosen so as to allow subsequent
removal of the bridge by hydrogenolysis after the lactam ring
had been appropriately modified. The meta-isomer was selected
Scheme 1 Reagents: i, Pd/C, H2 then 1,3-C6H4(CH2OH)2, DCC,
DMAP; ii, TBAF then 2-chloro-1-methylpyridinium iodide, Et3N
from 3 using fluoride ion afforded the acid ready for macro-
cyclisation. In this case, the best yield of bis-lactone 4, 46%,
came from using the Mukaiyama conditions6 (2-chloro-1-
methylpyridinium iodide and triethylamine). Disappointingly,
none of the thionating reagents 5–82,7 converted 4 into the
corresponding thiolactam; starting material was recovered
J. Chem. Soc., Perkin Trans. 1, 1998
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under mild conditions and more forcing ones caused total
decomposition. It appeared that forming the bis-lactone, whilst
possibly helping with steric hindrance, had now decreased the
stability of the whole system and was not, therefore, helpful.
Before leaving this section, the methoxypyrrolenine 9 was
prepared from lactam 2 during the foregoing work and is
reported in the Experimental. However, in common with earlier
work,2 attempts at reduction of this imino ether were unsuc-
cessful and so this approach was not pursued.
was that the acetoxy compound 15 would not couple with the
pyrrole 12 whereas the chloromethyl analogue 14 did so.9 The
usual conditions2,10 were used to combine iododipyrromethane
18 with acetoxymethylpyrrole 1910 to give the lactam 20.
With that success, the next step was to plan for methoxycar-
bonyl groups on both pyrrole rings flanking the lactam residue.
Accordingly, the pyrrole 22 was synthesised by reacting tosyl-
methyl isocyanide11 with dimethyl hex-2-enedioate 21, Scheme
3. The coupling reaction of acetoxymethylpyrrole 19 with this
PMe
MeA PMe
CO2Me
i
MeO2C
Approaches to deactivated analogues of the spiro-intermediate
The experience gained from the foregoing work and from the
research in the preceding papers1,2 pointed to the need for
a reassessment of our general strategies so as to deal with
the facile fragmentation reactions that we had frequently
encountered. One possible way forward was to aim for a relative
of the spiro-intermediate 1 in which the correctly substituted
pyrrolenine ring would be in place but the pyrrole rings A and C
of 1 would now be deactivated by electron-withdrawing groups.
The sequence lactam→thiolactam→pyrrolenine described in
the first paper2 worked well for both mono- and di-pyrrolic
systems provided the pyrrole ring(s) carried an electron-
withdrawing group at C-5. To have such a group at C-3 should
have a similar effect, so our synthetic target for the first foray
was the spiro-macrocycle 10 having directly bonded methoxy-
CO2Bn
N
H
N
H
AcO
MeO2C
21
22
19
ii
PMe
MeA PMe
MeO2C
R
CO2Bn
N
N
H
H
23 R = H
AMe
iii
MeP
24 R = CHO
25 R = CH2OH
26 R = CH2OAc
iv
v
PMe
MeO2C
NH HN
NH HN
CO2Bn
CO2Bn
vi
MeP
PMe
MeA
MeO2C
PMe
MeP
CO2Bn
I
N
H
N
O
MeA
CO2Me
MeP
AMe
PMe
AMe
H
MeP
18
27
MeO2C
MeA
PMe
O
HN
HN
HN
HN
NH
NH
Scheme 3 Reagents: i, TsCH2NC, NaH; ii, TsOH; iii, DMF, POCl3;
iv, NaBH4; v, MsCl, Et3N then NaOAc, AcOH; vi, SnCl4
MeA
MeP
MeA
MeP
pyrrole 22 occurred at the expected site to afford the dipyrro-
methane 23, whose structure was confirmed by NOE experi-
ments. This was then formylated under Vilsmeier conditions
and the steps forward from the resultant aldehyde 24 were
standard ones, via 25 through to 26. When the acetoxymethyl
compound 26 and the iododipyrromethane 18 were treated with
stannic chloride as usual,2 the only product, 60%, was the
bilane 27, the result of bond formation between the iodine-
bearing carbon of 18 and the acetoxymethyl carbon of 26 with
loss of the iodine. There was no detectable amount of the
desired halopyrrolenine arising from attack at the arrowed site
of 18. Evidently the delicate balance of reactivity that gave
success earlier with this coupling process2,10 had been too far
disturbed in this case.
AMe
AMe
PMe
N
N
CO2Me
10
11
carbonyl groups on rings A and C. An alternative approach was
to deactivate rings A and C by means of interpyrrolic ketone
groups which leads to 11 as the second target.
The chemistry for the former ‘nuclear ester’ approach was
first explored by aiming for the lactam 20. The required
iododipyrromethane 18 was prepared by standard steps 13→14
(ϩ 12)8→16→17→18, Scheme 2. The only change from normal
CO2Me
Attention therefore turned to the second plan based on
dipyrroketones and having 11 as the target. This had the further
attraction that dipyrroketones can be reduced under mild con-
ditions to give dipyrromethanes12 thus offering the possibility
of a final reductive step to reach the spiro-intermediate 1 as its
octamethyl ester.
AMe
PMe
CO2Bn
MeP
ButO2C
MeO2C
X
MeO2C
Me
i
O
+
CO2Bn
N
N
H
H
HON
O
12
13 X = H
ii
The best synthesis of dipyrroketones is that of Kenner and
co-workers12 which uses Vilsmeier chemistry. Accordingly, the
amide 29 was prepared by standard steps12 from the pyrrole 288
and its conversion by phosphorus oxychloride into the reactive
species 30 was demonstrated spectroscopically, Scheme 4. How-
ever, on mixing 30 with the α-free pyrrolic lactam 312 under a
variety of conditions, the new chromophore 32 was not gener-
ated; work-up gave starting amide 29, 50%, and none of the
desired dipyrroketone. Use of the more stable benzyl ester 38
(Scheme 5) gave the same result. It was possible that the reagent
30 was reacting preferentially with the lactam functionality of
31 to form an O-phosphorylated species, e.g. 33. Therefore,
methoxypyrrolenine 36 was prepared, either from the lactam
34 using Meerwein’s reagent to give methoxypyrrolenine 35
followed by removal of the tribromoethyl ester functionality or
by direct methylation of lactam 31. However, compound 36
also failed to react with the reagent 30.
14 X = Cl
15 X = OAc
iii
MeP
MeA
iv
CO2Bn
NH
MeP
MeA
PMe
MeO2C
CO2Bn
HN
MeA
MeP
PMe
CO2Bn
R
N
N
H
H
CO2Me
NH
16 R = CO2But
17 R = CO2H
18 R = I
v
vii
20
O
vi
MeA PMe
CO2Bn
19
N
H
AcO
Scheme 2 Reagents: i, Zn, AcOH; ii, SO2Cl2; iii, NaOAc, AcOH; iv,
PhMe, reflux; v, SnCl4; vi, KI3, NaHCO3; vii, SnCl4 then AgOAc, H3Oϩ
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MeA
R
PMe
CO2But
MeA
MeP
N
H
N
28 R = Me
29 R = CONMe2
30 R = C(OPOCl2)=N+Me2
i
Cl2OPO
33
ii
NMe2
MeP
MeP
AMe
PMe
CO2But
CO2Bn
AMe
MeA
MeA
NH
NH HN
+
X
CO2Bn
HN
MeA
MeP
HN
MeA
MeP
AMe
NH
NH
PMe
PMe
31
32
O
O
iii
iii
MeP
MeP
CO2CH2CBr3
R
MeA
MeA
Fig. 1 Change in the UV–VIS spectrum as the nickel() complex of
pyrrolenine 52 is treated with ethylene diamine to give uncomplexed 52
NH
NH
CO2Bn
HN
CO2Bn
ling of 3713 and 38 gave the ketone 39 in 93% yield and this was
converted into the acetoxy derivative 40 by standard chlorin-
ation followed by displacement with acetate ion. Synthesis of
the iododipyrromethane 44 from 128 and 4110 ran smoothly
through the steps 42→43→44. The usual conditions2,10 for the
reaction of an acetoxypyrrole with an iodopyrrole had to be
modified for the coupling of 40 and 44; then the complete
dipyrroketone 45 was obtained in 29% yield. Deprotection of
ring C of 45 was by the familiar steps 45→46→47→48 and
hydrogenolysis then removed the benzyl group to afford the
acid 49 ready for experiments on closing the macrocycle.
In parallel with the foregoing work, we were also exploring
other facets of the required chemistry. It was especially import-
ant to learn whether a pyrrolenine attached to a dipyrroketone
would be sufficiently stable to handle. The simpler system 51
was therefore built by alkylating iodopyrrole 5010 with
acetoxymethylpyrrole 40 as above and the product was treated
with hydrogen sulfide in the presence of silver acetate to afford
the thiolactam 53, Scheme 6. Desulfurisation using nickel
MeA
MeP
MeA
MeP
HN
AMe
AMe
NH
N
PMe
PMe
34
O
MeO
iv
35 R = CO2CH2CBr3
36 R = H
Scheme 4 Reagents: i, ButOCl then Me2NH then H2O; ii, POCl3;
iii, Me3OBF4, proton sponge; iv, Zn, AcOH then KI3, NaHCO3 then
PtO2, H2
MeA PMe
PMe
MeA
Me2NOC
+
Me
CO2Bn
38
N
N
H
H
37
MeP AMe
MeP AMe
i
+
ButO2C
12
CO2CH2CBr3
41
N
N
H
H
AcO
iii
MeA PMe
MeA PMe
MeP AMe
CO2Bn
MeP AMe
MeP AMe
CO2CH2CBr3
N
H
N
O
AMe
MeP
H
R
O
I
Me
PMe
MeA
N
H
R
N
H
i
39 R = H
N
ii
50
NH HN
Me
H
40 R = OAc
CO2Bn
42 R = CO2But
43 R = CO2H
44 R = I
40
iv
v
MeA
MeP
MeA
MeP
vi
O
Me
N
NH
NH
Me
O
X
AMe
MeP
AMe
X
MeP
MeP
ii
51 X = Cl (I)
52 X = H
53 X = S
PMe
MeA
PMe
CO2Bn
R
AMe
MeA
iii
HN
NH
HN
HN
55
NH
54 X = H,H
v
iv
CO2R
viii
Scheme 6 Reagents: i, SnCl4; ii, H2S, AgOAc; iii, nickel boride then
MeA
MeP
MeA
MeP
HN
H2NCH2CH2NH2; iv, NaBH4; v, TsOH
AMe
AMe
boride2 led to the desired pyrrolenine 52 but as a nickel com-
plex, indicated to be a 1:1 complex by mass spectrometry. The
pyrrolenine 52 was smoothly decomplexed by treatment with
ethylenediamine as shown by the striking changes in the UV–
VIS spectrum, Fig. 1; the pyrrolenine 52 was satisfyingly stable.
Reduction of the nickel complex with borohydride also released
the organic component but as the dihydropyrrolenine 54, iden-
tical to material prepared by borohydride reduction of the pyr-
rolenine 52 itself. Treatment of the uncomplexed pyrrolenine
52 or its nickel complex with toluene-p-sulfonic acid caused
fragmentation–rearrangement to afford the tripyrroketone 55
in 76 and 30% yield, respectively, together with 50% recovered
starting material in the latter case.
NH
NH
PMe
PMe
O
O
45 R = CO2CH2CBr3
46 R = CO2H
47 R = I
48 R = Bn
49 R = H
vii
v
ix
Scheme 5 Reagents: i, POCl3; ii, ButOCl then NaOAc, AcOH;
iii, TsOH; iv, SnCl4; v, KI3, NaHCO3; vi, SnCl4 then AgOAc, H3Oϩ;
vii, Zn, AcOH; viii, PtO2, H2; ix, Pd/C, H2
These results led to a change in the order of the coupling
steps illustrated in Scheme 5; now the aim was to construct the
tripyrrolic lactam 46 in one step from the acetoxymethyl dipyr-
roketone 40 and the iododipyrromethane 44. Vilsmeier coup-
J. Chem. Soc., Perkin Trans. 1, 1998
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The stability of the foregoing pyrrolenine 52 encouraged
efforts to run the sequence lactam→thiolactam→pyrrolenine
and for these experiments a still closer model dipyrroketone was
used. The system 57 was constructed by alkylating the iodide
561 with 40 as usual (Scheme 7), and this product with Davy’s
39
i
MeA PMe MeA PMe
MeA PMe MeA PMe MeP AMe
COX
Me
Me
Me
N
N
N
N
H
N
H
H
H
H
O
O
O
X
67
37
64 X = OH
65 X = NMe2
66 X = SePh
AMe
MeP
MeP AMe MeA PMe
CO2Bn
ii,
iii
ii, iv
40
v
MeA
PMe
i
I
NH HN
HN
N
N
CO2Bn
CO2Bn
Scheme 8 Reagents: i, Pd/C, H2; ii, (imidazolyl)2C᎐O; iii, PhSeNa;
H
H
᎐
56
iv, Me2NH; v, CuOTf–PhH, CaCO3
MeA
MeP
O
MeP
PMe
have been used as acylating agents15 in reactions catalysed by
the copper() complex [Cu(OSO2CF3)]C6H6 and this approach
was shown to be very effective in the pyrrole series.16 The seleno
ester 66 was prepared from 64 and in the presence of the CuI
catalyst, did react with 37 to give the tripyrrodiketone 67 but in
a very low yield (ca. 5%) that we were unable to improve. From
these results, the lack of examples of such tripyrrodiketones in
the literature is understandable.
MeA
NH
AMe
NH
Y
57 X = Y = O
58 X = S, Y = O
59 X = Y = S
MeA
MeP
ii
N
iii, iv
60 X = SMe
61 X = H
X
X
Despite these difficulties, the approach via 49 to 11 does offer
some promise for the future though not as much, we believe, as
that to be described in the next paper.5
MeA PMe MeA PMe
Me CO2Bn
MeA PMe MeA PMe
Me CO2Bn
N
N
N
N
H
H
H
X
SMe
Experimental
General directions are as in the preceding paper.2
iv
iii
39 X = O
62 X = S
ii
63
Scheme 7 Reagents: i, SnCl4 then AgOAc, H3Oϩ; ii, Davy’s reagent 6;
Molecular modelling
iii, TFA, TMOF; iv, H3Oϩ
Molecular modelling was performed using the program Macro-
Model ver. 5.5.3 To simplify the energy minimisation process all
acetate and propionate side-chains were replaced by methyl
groups. The search for the global minimum used the Monte
Carlo method. In each case, the torsion angles of eight of the
C᎐C bonds of the macrocycle were varied and one was used as
the ring-closure bond. The ester C᎐O bond was set in the s-trans
conformation and was not varied. 1000 Starting conformations
were minimised using the MM2* force-field. The global min-
imum energies were as follows: diester 4 with benzene-1,3-
dimethanol, E = 461.12 kJ molϪ1 (found 23 times); diester with
benzene-1,2-dimethanol, E = 472.72 kJ molϪ1 (found 5 times);
diester with benzene-1,4-dimethanol, E = 476.45 kJ molϪ1
(found 30 times).
The strain energy of the macrocycle was calculated by com-
paring the energy change between the diester (Ediester) and the
corresponding diacid plus diol (Ediacid ϩ Ediol) with twice the
energy change between a simple non-macrocyclic monoester
(benzyl 3,4,4-trimethylpyrrole-2-carboxylate; Emonoester) and the
corresponding monoacid plus alcohol (Emonoacid ϩ EBnOH).
Thus:
reagent 6 yielded a mixture of the dipyrrothioketone lactam 58,
50%, and the dipyrrothioketone thiolactam 59, 30%. Increasing
the amount of 6 used led to 52% of the thiolactam 59 being
isolated. Attempted hydrolysis of the thioketone group of 59
with alkaline hydrogen peroxide14 destroyed the material, so
other conditions were sought.
Trials were carried out on the dipyrrothioketone 62, prepared
in 69% yield by reacting the ketone 39 with Davy’s reagent.
Trimethyl orthoformate and TFA converted 62 into the S-
methyl derivative 63, which was hydrolysed back to the starting
ketone 39, 82%, by aqueous toluene-p-sulfonic acid. When this
procedure was applied to the thiolactam 59, both sulfur atoms
were methylated and just one S-methyl moiety was hydrolysed
by the aqueous acid. Judging by the hydrolysis of 63 to 39
under these conditions, the product was expected to be methyl-
thiopyrrolenine 60 and this was confirmed by the similarity of
its UV spectrum to the spectra of dipyrroketones 39 and 57;
that of 62 was substantially different. Difficulties had been pre-
viously experienced in reducing such a methylthiopyrrolenine
with nickel boride but in that case Raney nickel was successful.2
Disappointingly, neither of these nickel reagents yielded any of
the desired pyrrolenine 61 from 60. Other ways for selective
hydrolysis of the thioketone can be envisaged but have not so
far been studied.
Another key step for the synthesis of the macrocyclic system
11 is the generation of a tripyrrodiketone unit; there is no
precedent in the literature for this synthesis. Clearly the best tri-
pyrrodiketone to build is the macrocycle 11 and many attempts
were made to cyclise the acid 49. These ranged from a variety of
acidic and Lewis acidic conditions and use of dehydrating
agents through to many standard reagents for activation of
carboxy groups. All of these led to one or a combination of
three results: recovery of starting material, decomposition or
decarboxylation of the pyrrolic carboxy group.
Strain Energy =
(Ediester Ϫ Ediacid Ϫ Ediol) Ϫ 2(Emonoester Ϫ Emonoacid Ϫ EBnOH).
Various different conformations of the diacid were min-
imised to find the global minimum but a full conformational
search was not considered necessary for this or the simpler mol-
ecules. The strain energies so calculated were: diester 4 with
benzene-1,3-dimethanol, 9.52 kJ molϪ1; diester with benzene-
1,2-dimethanol, 15.61 kJ molϪ1; diester with benzene-1,4-
dimethanol, 23.62 kJ molϪ1
.
4-[5-(3-Hydroxymethylbenzyloxycarbonyl)-3-(2-methoxy-
carbonylethyl)-4-(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-
2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonyl-
methyl)-9-(2-trimethylsilylethoxycarbonyl)-4,5-dihydro-
dipyrrin-1(10H)-one 3
Further studies were made with simpler molecules. The
dimethylamide 65 was prepared from 39 via 64 by standard
steps but the Vilsmeier reagent prepared from it did not react
with the α-free pyrrole 37, Scheme 8. However, seleno esters
A solution of benzyl ester 25 (110 mg, 0.11 mmol) in methanol
(8 cm3) was stirred with sodium carbonate (70 mg) and 10%
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J. Chem. Soc., Perkin Trans. 1, 1998

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palladium-on-charcoal (30 mg) under an atmosphere of hydro-
gen for 30 min, then filtered through Celite, diluted with water
(50 cm3), acidified with glacial acetic acid and extracted with
dichloromethane (3 × 50 cm3). The combined extracts were
dried (Na2SO4) and evaporated under reduced pressure. A solu-
tion of the resultant crude carboxylic acid and benzene-1,3-
dimethanol (170 mg, 1.1 mmol) in dry tetrahydrofuran (10 cm3)
under argon was treated with a solution of N,NЈ-dicyclo-
hexylcarbodiimide (25 mg, 0.12 mmol) and 4-dimethyl-
aminopyridine (1.3 mg, 11 µmol) in tetrahydrofuran (1 cm3)
and heated at reflux for 1 h, then filtered through Celite, diluted
with dichloromethane (100 cm3), washed with dilute hydro-
chloric acid (2 mol dmϪ3; 2 × 20 cm3) then water (20 cm3), dried
(Na2SO4) and evaporated under reduced pressure. Purification
by PLC, eluting with ethyl acetate–light petroleum (4:1),
gave the 3-hydroxymethylbenzyl ester 3 (80 mg, 71%) as an
oil (Found: MH2ϩ, 1025.4232. C50H65N3O18Si requires MH2,
1025.4189); δH(CDCl3) 0.02 (9 H, s, SiMe3), 1.04 (2 H, t, J 9,
CH2Si), 2.32–2.49 (8 H, m), 2.69 (2 H, t, J 8) and 2.90 (2 H, t,
J 8, 3 × CH2CH2), 2.75 and 2.99 (each 1 H, d, J 15, 4-CH2), 2.81
and 3.06 (each 1 H, d, J 15, 4-CH2), 3.13 and 3.33 (each 1 H, d,
J 17, CH2CO2), 3.44 and 3.63 (each 1 H, d, J 15, CH2CO2), 3.50,
3.50, 3.55, 3.58, 3.59, 3.81 (each 3 H, s, OMe), 3.74 and 3.89
(each 1 H, d, J 17, CH2CO2), 4.18–4.28 (2 H, m, CH2CH2Si),
4.62 (2 H, s, ArCH2OH), 5.16 and 5.21 (each 1 H, d, J 12.6,
CO2CH2Ar), 7.17–7.32 (4 H, m, Ar), 7.55, 7.74, 9.32 and 10.14
(each 1 H, br s, 3 × NH and OH); δC(CDCl3) Ϫ1.75 (SiMe3),
17.32 (CH2Si), 19.10, 19.43, 20.29, 29.10, 29.48, 30.31, 30.68,
31.95, 33.61, 34.61 and 34.66 (11 × CH2), 51.26, 51.41, 51.57,
51.77, 52.14 and 52.95 (OMe), 62.11, 64.19, 65.36 and 66.28
(3 × CH2O and C-4), 115.22, 118.57, 118.88, 121.84, 122.70,
127.66, 127.90, 128.94, 135.98, 137.53, 141.15, 142.00 and
172.33, 173.24, 173.40 and 173.76 (C᎐C); m/z (FD) 905 (Mϩ,
᎐
100%).
Heating a solution of the hydroxy acid (10 mg, 11 µmol),
N,NЈ-dicyclohexylcarbodiimide (2.5 mg, 12 µmol) and 4-
dimethylaminopyridine (0.1 mg, 1 µmol) in toluene (3 cm3) at
reflux under argon for 22 h gave the same macrocyclic diester 4
(3.6 mg, 37%).
4-[5-Benzyloxycarbonyl-3-(2-methoxycarbonylethyl)-4-
(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-1-methoxy-2,8-
bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonylmethyl)-9-
(2-trimethylsilylethoxycarbonyl)-4,5-dihydrodipyrrin 9
A mixture of lactam 25 (15 mg, 15 µmol), trimethyloxonium
tetrafluoroborate (4.5 mg, 30 µmol) and 1,8-bis(dimethyl-
amino)naphthalene (3.6 mg, 17 µmol) was stirred in dry dichlo-
romethane (2 cm3) at room temperature under argon for 3 h and
then evaporated under reduced pressure. Purification by PLC,
eluting with ethyl acetate–light petroleum (2:1), gave the
methoxypyrrolenine 9 (11.8 mg, 78%) as an oil (Found: Mϩ,
1007.4087. C50H65N3O17Si requires M, 1007.4083); δH(CDCl3)
0.04 (9 H, s, SiMe3), 1.04 (2 H, t, J 9, CH2Si), 2.27–2.41 and
2.90–2.95 (11 H, m), 2.45 (1 H, d, J 15), 2.50 (2 H, t, J 8) and
2.64 (2 H, t, J 7.6, 3 × CH2CH2 and CH2CCH2), 2.98 and 3.05
(each 1 H, d, J 15, CH2CO2), 3.30 and 3.39 (each 1 H, d, J 16,
CH2CO2), 3.46, 3.58, 3.59, 3.59, 3.59, 3.64, 3.76 (each 3 H, s,
OMe), 3.74 and 3.86 (each 1 H, d, J 17, CH2CO2), 4.20–4.32 (2
H, m, CH2CH2Si), 5.18 and 5.25 (each 1 H, d, J 12, CH2Ph),
7.30–7.40 (5 H, m, Ph) and 9.98 and 10.31 (each 1 H, br s, NH);
δC(CDCl3) Ϫ1.57 (SiMe3), 17.57 (CH2Si), 19.24, 19.55, 20.46,
29.46, 30.47, 30.47, 31.12, 31.37, 34.84 and 35.00 (CH2), 51.35,
51.52, 51.59, 51.75, 51.81, 52.84 and 55.11 (OMe), 61.98
(CH2CH2Si), 65.75 (CH2Ph), 77.19 (C-4), 115.26, 117.45,
117.71, 121.82, 122.53, 129.05, 129.60, 129.78, 134.25 and
149.46 (C᎐C), 125.28, 126.10, 126.44 and 128.10 (C᎐CH) and
᎐
᎐
159.88, 160.83, 171.42, 171.89, 172.08, 173.26, 173.40, 173.47
136.22 (C᎐C), 128.14, 128.44 and 128.59 (C᎐CH), 155.99
᎐ ᎐
and 173.69 (C᎐O); m/z (FD) 1023 (Mϩ, 100%).
(N᎐C᎐C᎐C) and 160.27, 160.89, 171.15, 171.37, 172.01, 172.23,
᎐ ᎐
᎐
172.98, 173.34 and 173.77 (C᎐O and C᎐N); m/z (FD) 1007 (Mϩ,
᎐
᎐
Macrocyclic diester 4
100%).
A solution of lactam trimethylsilylethyl ester 3 (163 mg, 159
µmol) and tetrabutylammonium fluoride (125 mg, 478 µmol) in
tetrahydrofuran (10 cm3) was stirred at room temperature under
argon for 24 h, then diluted with dichloromethane (20 cm3),
washed with dilute sulfuric acid (2 × 10 cm3) then water (10
cm3), dried (Na2SO4) and evaporated under reduced pressure.
Purification by PLC, eluting with dichloromethane–methanol
(9:1), gave the hydroxy acid (93 mg, 63%) as an oil; m/z (FD)
923 (Mϩ, 100%).
2-Benzyloxycarbonyl-4-methoxycarbonyl-3-(2-methoxy-
carbonylethyl)-5-methylpyrrole 13
A solution of sodium nitrite (1.3 g) in water (2.5 cm3) was
added dropwise to a mixture of acetic acid (10 cm3) and benzyl
5-methoxycarbonyl-3-oxopentanoate (5 g, 18 mmol) at such a
rate that the temperature did not exceed 25 ЊC. The solution
was stirred at room temperature overnight and then added
dropwise to a mixture of methyl acetoacetate (2.5 g, 2.3 cm3, 20
mmol), acetic acid (8 cm3), zinc dust (3.5 g) and ammonium
acetate (3.5 g) at such a rate that the temperature was main-
tained at between 50 and 70 ЊC. The mixture was vigorously
stirred at room temperature for 30 min, then diluted with ice–
water (50 cm3), stirred for a further 30 min and then filtered.
The filtrate was extracted with dichloromethane (4 × 50 cm3)
and the combined extracts were washed with aqueous sodium
carbonate, dried and evaporated under reduced pressure.
Recrystallisation from diethyl ether gave the pyrrole 13, mp
120–121 ЊC (Found: C, 63.8; H, 6.1; N, 3.65. C19H21NO6
requires C, 63.5; H, 5.9; N, 3.9%); νmax(CH2Cl2)/cmϪ1 3350,
3020, 1710, 1430, 1260 and 910; δH(CDCl3, 400 MHz) 2.48 (3
H, s, 5-Me), 2.53 and 3.37 (each 2 H, t, J 7, CH2CH2), 3.61 and
3.80 (each 3 H, s, OMe), 5.29 (2 H, s, OCH2), 7.30–7.41 (5 H, m,
Ph) and 9.15 (1 H, br s, NH); δC(CDCl3, 100 MHz) 14.29 (5-
Me), 21.28 (CH2CH2CO2), 34.93 (CH2CH2CO2), 50.89 and
51.44 (OMe), 66.31 (OCH2), 112.94, 117.64, 128.34, 128.60,
A solution of 2-chloro-1-methylpyridinium iodide (66 mg,
260 µmol) in toluene (35 cm3) was heated at reflux under argon
and a solution of the hydroxy acid (60 mg, 65 µmol) and tri-
ethylamine in toluene (25 cm3) and acetonitrile (1 cm3) was
added continuously over 1 h. The solution was heated at reflux
for a further 1 h, then diluted with ethyl acetate (50 cm3),
washed with dilute hydrochloric acid (2 × 5 cm3) then water
(5 cm3), dried (Na2SO4) and evaporated under reduced pressure.
Purification by PLC, eluting with dichloromethane–methanol
(9:1), gave the dilactone 4 (27 mg, 46%) as an oil (Found: Mϩ,
1
905.3187. C45H51N3O17 requires M, 905.3217); the H NMR
spectrum at room temperature showed a number of broad or
poorly resolved peaks; δH(C7D8, 70 ЊC) 2.06–2.08, 2.36–2.45
and 2.49–2.69 (each 4 H, m, 3 × CH2CH2), 3.14 (1 H, d, J 15.5),
3.19 (1 H, d, J 13.4), 3.21 (1 H, d, J 14.6) and 3.34–3.54 (7 H,
obscured, 3 × CH2CO2 and CH2CCH2), 3.34, 3.35, 3.36, 3.39,
3.43, 3.48 (each 3 H, s, OMe), 4.74, 5.04, 5.18 and 5.40 (each 1
H, br d, J 11, 2 × CO2CH2Ar), 6.69–7.27 (4 H, m, Ar) and 8.63,
9.86 and 9.91 (each 1 H, br s, NH); δC(CDCl3, 25 ЊC) 19.30,
19.34, 20.76, 29.50, 29.67, 30.94, 31.27, 31.49, 34.50 and 34.59
(CH2), 51.47, 51.54, 51.86, 52.46 and 52.63 (OMe), 64.40
(br, 2 × OCH2), 77.20 (C-4), 116.07, 117.09, 119.54, 122.56,
123.50, 125.08, 125.21, 127.70, 128.08, 128.81, 130.39, 133.77,
133.59, 135.67 and 139.40 (C᎐C) and 160.78, 165.30 and 173.49
᎐
(C᎐O); m/z (FD) 359 (Mϩ, 100%).
᎐
5-Acetoxymethyl-2-benzyloxycarbonyl-4-methoxycarbonyl-3-
(2-methoxycarbonylethyl)pyrrole 15
A solution of pyrrole 13 (1.5 g, 4.2 mmol) in dry dichlorometh-
137.61, 137.75 and 153.64 (C᎐C) and 160.50, 160.82, 169.56,
ane (20 cm3) at 0 ЊC was stirred with freshly distilled sulfuryl
᎐
J. Chem. Soc., Perkin Trans. 1, 1998
1523

View Article Online
chloride (0.35 cm3, 4.4 mmol) under argon for 1 h and then
evaporated under reduced pressure. A mixture of the residue,
glacial acetic acid (20 cm3) and sodium acetate (1.00 g) was
heated at 70 ЊC for 1 h, then cooled, poured into water (500
cm3) and extracted with dichloromethane (4 × 50 cm3). The
combined extracts were washed with water (100 cm3), dried
and evaporated under reduced pressure. Recrystallization from
dichloromethane–diethyl ether–hexane gave acetoxymethyl-
pyrrole 15 (1.58 g, 91%) as fine needles, mp 90–91 ЊC (Found:
C, 60.2; H, 5.55; N, 3.4. C21H23NO8 requires C, 60.4; H, 5.55;
N, 3.35%); νmax(CH2Cl2)/cmϪ1 3450, 1730, 1230 and 1100;
δH(CDCl3, 400 MHz) 2.10 (3 H, s, Ac), 2.52 and 3.37 (each 2
H, t, J 7, CH2CH2), 3.60 and 3.81 (each 3 H, s, OMe), 5.30 (2 H,
s, CH2Ph), 5.37 (2 H, s, CH2OAc), 7.31–7.40 (5 H, m, Ph) and
9.64 (1 H, br s, NH); δC(CDCl3, 100 MHz) 20.74 and 20.96
(MeCO and CH2CH2CO2), 34.76 (CH2CH2CO2), 51.19 and
51.37 (OMe), 58.40 (CH2OAc), 66.45 (CH2Ph), 113.51, 119.40,
3.50, 3.63, 3.66 and 3.90 (each 3 H, s, OMe), 4.10 (2 H, s, 5-H2),
5.27 (2 H, s, CH2Ph), 7.30–7.35 and 7.40–7.42 (5 H, m, Ph) and
9.26 and 10.41 (each 1 H, br s, NH); δC(CDCl3, 100 MHz)
21.29, 22.02, 23.84, 30.47, 34.73 and 35.03 (CH2), 51.47, 51.56,
51.59 and 52.38 (OMe), 66.10 (CH2Ph), 111.58, 112.90, 118.49,
125.53, 128.16, 128.39, 128.46, 131.43, 132.31, 135.80 and
140.23 (C᎐C) and 160.18, 166.93, 173.35, 173.47 and 174.06
᎐
(C᎐O); m/z (FD) 708 (Mϩ, 100%).
᎐
9-Benzyloxycarbonyl-4-[5-benzyloxycarbonyl-3-methoxy-
carbonyl-4-(2-methoxycarbonylethyl)pyrrol-2-ylmethyl]-2,8-
bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonylmethyl)-
4,5-dihydrodipyrrin-1(10H)-one 20
Acetoxymethylpyrrole 1910 and iododipyrromethane 18 were
coupled using stannic chloride and the resulting halopyr-
rolenine was hydrolysed under the standard conditions (see for
example the synthesis of lactam 30 in the preceding paper1).
The product was purified by flash chromatography, eluting with
diethyl ether then 5% methanol in diethyl ether, to give the
lactam 20 (29%) as a gum (Found: Mϩ, 969.3518. C50H55N3O17
requires M, 969.3531); νmax(CH2Cl2)/cmϪ1 3300, 2950, 1740,
1685, 1450 and 1065; δH(CDCl3, 400 MHz) 2.27–2.33 (8 H, m),
2.48 (2 H, t, J 7), 2.92 (2 H, t, J 7), 3.02 (1 H, d, J 15) and 3.20–
3.30 (5 H, m, 3 × CH2CH2, CH2CCH2 and CH2CO2), 3.42 and
3.50 (each 1 H, d, J 17, CH2CO2), 3.52, 3.58, 3.60, 3.61, 3.70
and 3.79 (each 3 H, s, OMe), 5.17 and 5.28 (each 1 H, d, J 12,
CH2Ph), 5.21 and 5.28 (each 1 H, d, J 12, CH2Ph), 7.27–7.39
(11 H, m, Ph and lactam-NH) and 9.89 and 10.09 (each 1 H, br
s, pyrrole-NH); δC(CDCl3, 100 MHz) 19.52, 20.38, 21.35, 29.42,
30.20, 30.80, 31.46, 33.08, 34.65 and 35.03 (CH2), 51.32, 51.42,
51.44, 51.53, 52.30 and 53.14 (OMe), 65.74 and 66.24 (CH2Ph),
114.24, 115.36, 118.23, 119.21, 128.04, 128.26, 128.30, 128.41,
128.29, 128.53, 132.86 and 135.47 (C᎐C) and 160.47, 164.38,
᎐
170.94 and 173.21 (C᎐O); m/z (FD) 417 (Mϩ, 100%).
᎐
1-Benzyloxycarbonyl-9-tert-butoxycarbonyl-3-methoxy-
carbonyl-2,8-bis(2-methoxycarbonylethyl)-7-methoxycarbonyl-
methyldipyrromethane 16
A solution of pyrrole 13 (100 mg, 0.28 mmol) in dry dichloro-
methane (2 cm3) was stirred at room temperature under argon
with freshly distilled sulfuryl chloride (24 µl, 0.28 mmol) for 30
min and then evaporated under reduced pressure. A solution of
the residue and α-free pyrrole 128 (91 mg, 0.28 mmol) in dry
toluene (5 cm3) was heated under reflux for 16 h, then cooled
and evaporated under reduced pressure. Purification by PLC,
eluting with 15% hexane in diethyl ether, gave dipyrromethane
16 as a gum (Found: Mϩ, 682.2731. C35H42N2O12 requires
M, 682.2738); νmax(CH2Cl2)/cmϪ1 3350, 1725, 1700, 1170
and 1070; δH(CDCl3, 400 MHz) 1.51 (9 H, s, But), 2.49–2.54
(4 H, m, 2 × CH2CH2CO2), 2.96 and 3.33 (each 2 H, t, J 7,
CH2CH2CO2), 3.51 (2 H, s, CH2CO2), 3.50, 3.63, 3.63 and 3.90
(each 3 H, s, OMe), 4.15 (2 H, s, 5-H2), 5.26 (2 H, s, CH2Ph),
7.29–7.41 (5 H, m, Ph) and 9.93 and 10.39 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 20.33, 21.28, 23.66, 29.73 and 34.97
(CH2), 28.31 (CMe3), 51.42, 51.45, 51.50 and 52.40 (OMe),
66.10 (CH2Ph), 80.68 (CMe3), 113.11, 118.57, 119.59, 128.17,
128.54, 129.91, 132.14, 135.68, 136.11, 138.35, 149.09 (C᎐C)
᎐
and 160.08, 165.98, 172.15, 172.25, 173.13, 173.34 and 173.67
(C᎐O); m/z (FD) 969 (Mϩ, 100%).
᎐
3-Methoxycarbonyl-4-(2-methoxycarbonylethyl)pyrrole 22
A solution of dimethyl hex-2-enedioate 21 (700 mg, 4.07 mmol)
and tosylmethyl isocyanide (794 mg, 4.07 mmol) in dry diethyl
ether (13 cm3) and dry dimethyl sulfoxide (6 cm3) was added
dropwise under argon to a stirred mixture of sodium hydride
(60% dispersion in oil; 200 mg, 5.0 mmol) in dry diethyl ether
(7 cm3). The mixture was stirred for 25 min and then water
(20 cm3) was added followed by glacial acetic acid (1.5 cm3).
The organic layer was separated and the aqueous layer was
extracted with dichloromethane (3 × 10 cm3). The combined
organic layers were dried and evaporated under reduced pres-
sure. Purification by flash chromatography, eluting with hexane–
diethyl ether (2:3), gave the pyrrole 22 (395 mg, 44%) as a gum
(Found: Mϩ, 211.0832. C10H13NO4 requires M, 211.0845);
νmax(CH2Cl2)/cmϪ1 3500, 1725, 1160 and 1090; δH(CDCl3, 400
MHz) 2.64 and 3.04 (each 2 H, t, J 7, CH2CH2), 3.64 and 3.78
(each 3 H, s, OMe), 6.56 (1 H, br s, CH), 7.33 (1 H, t, J 3, CH)
and 9.13 (1 H, br s, NH); δC(CDCl3, 100 MHz) 21.57
(CH2CH2CO2), 34.84 (CH2CH2CO2), 50.66 and 51.36 (OMe),
128.38, 128.45, 130.58, 135.77 and 139.37 (C᎐C) and 160.16,
᎐
166.52, 173.48, 173.66 and 174.11 (C᎐O); m/z (FD) 682 (Mϩ,
᎐
100%).
1-Benzyloxycarbonyl-9-iodo-3-methoxycarbonyl-2,8-bis-
(2-methoxycarbonylethyl)-7-methoxycarbonylmethyldipyrro-
methane 18
A solution of tert-butyl ester 16 (500 mg, 0.73 mmol) in dry
dichloromethane (20 cm3) was stirred at 0 ЊC under argon while
stannic chloride (96 µl, 0.80 mmol) was added dropwise. After
75 min aqueous sodium acetate (10%; 18 cm3) was added and,
after a further 5 min, the organic layer was separated and the
aqueous layer was extracted with dichloromethane (5 × 10
cm3). The combined organic layers were dried and evaporated
under reduced pressure. A solution of the residue in dichloro-
methane (10 cm3) was stirred vigorously with sodium hydrogen
carbonate (500 mg) and water (10 cm3) while an aqueous
solution (8 cm3) of iodine (0.1 mol dmϪ3) and potassium iodide
(0.2 mol dmϪ3) was added dropwise over 3 min. After a further
20 min excess iodine was destroyed by the addition of sodium
metabisulfite. The organic layer was separated and the aqueous
layer was then extracted with dichloromethane (3 × 10 cm3).
The combined organic phases were dried and evaporated under
reduced pressure. Purification by flash chromatography, eluting
with hexane–diethyl ether (1:4), gave iododipyrromethane 18
(341 mg, 66%) as a gum (Found: Mϩ, 708.1150. C30H33IN2O10
requires M, 708.1139); νmax(CH2Cl2)/cmϪ1 3350, 2970, 1740,
1710, 1440 and 1070; δH(CDCl3, 400 MHz) 2.41, 2.53, 2.65 and
3.33 (each 2 H, t, J 7, 2 × CH2CH2), 3.50 (2 H, s, CH2CO2),
113.60, 117.21, 123.74 and 124.84 (C᎐C) and 165.78 and 174.18
᎐
(C᎐O); m/z (FD) 211 (Mϩ, 100%).
᎐
1-Benzyloxycarbonyl-8-methoxycarbonyl-2,7-bis(2-methoxy-
carbonylethyl)-3-methoxycarbonylmethyldipyrromethane 23
A solution of pyrrole 22 (150 mg, 0.71 mmol) and toluene-p-
sulfonic acid (14 mg, 0.07 mmol) in dry dichloromethane
(3 cm3) under argon at room temperature was treated dropwise
over 30 min with a solution of acetoxymethylpyrrole 19 (306
mg, 0.71 mmol) in dichloromethane (10 cm3), stirred for 90 min
and then added to water (100 cm3). The organic layer was sep-
arated and the aqueous layer extracted with dichloromethane
(2 × 25 cm3). The combined organic layers were dried and
evaporated under reduced pressure. Purification by column
chromatography, eluting with hexane–diethyl ether (1:2), gave
1524
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
dipyrromethane 23 (292 mg, 71%) as an oil (Found: Mϩ,
582.2221. C30H34N2O10 requires M, 582.2214); νmax(CH2Cl2)/
cmϪ1 3350, 1720, 1150 and 1050; δH(CDCl3, 400 MHz) 2.47
(2 H, t, J 7), 2.81 (2 H, t, J 7) and 2.94–3.00 (4 H, m,
2 × CH2CH2), 3.46, 3.60, 3.74 and 3.76 (each 3 H, s, OMe), 3.59
(2 H, s, CH2CO2), 3.90 (2 H, s, 5-H2), 5.22 (2 H, s, CH2Ph),
7.26–7.34 (6 H, m, Ph and 9-H) and 10.12 and 10.14 (each 1 H,
br s, NH); δC(CDCl3, 100 MHz) 19.39, 20.53, 21.60, 29.27,
34.05 and 34.72 (CH2), 50.53, 51.39, 51.58 and 52.64 (OMe),
65.61 (CH2Ph), 112.72, 113.98, 117.97, 118.47, 124.44, 127.81,
34.11 and 34.77 (6 × CH2 and COMe), 50.69, 51.42, 51.69 and
52.63 (OMe), 59.44 (CH2OAc), 65.69 (CH2Ph), 109.97, 114.15,
118.08, 119.77, 126.88, 128.10, 128.21, 128.47, 129.79, 132.42,
132.78 and 136.11 (C᎐C) and 160.54, 165.41, 170.67, 173.58,
᎐
᎐
175.05 and 175.75 (C᎐O); m/z (FD) 654 (Mϩ, 100%).
1,19-Bis(benzyloxycarbonyl)-3,12-bis(methoxycarbonyl)-
2,8,13,18-tetrakis(2-methoxycarbonylethyl)-7,17-
bis(methoxycarbonylmethyl)bilane 27
The coupling of acetoxymethyldipyrromethane 26 and
iododipyrromethane 18 was carried out using the standard
stannic chloride-catalysed conditions (see for example the
synthesis of 30 in the preceding paper1). Purification by PLC,
eluting with diethyl ether, gave the bilane 27 (60%) as a gum
(Found: Mϩ, 1176.4374. C61H68N4O20 requires M, 1176.4426);
νmax(CH2Cl2)/cmϪ1 3350, 1740, 1720, 1160 and 1080; δH(CDCl3,
400 MHz) 2.26, 2.45, 2.51, 2.72, 2.76, 2.95, 2.97 and 3.34 (each
2 H, t, J 8, 4 × CH2CH2), 3.38 and 3.47 (each 2 H, s, CH2CO2),
3.50, 3.59, 3.61, 3.61, 3.63, 3.73, 3.77 and 3.84 (each 3 H, s,
OMe), 3.83, 3.92 and 4.08 (each 2 H, s, 5-, 10 and 15-H2), 5.22
and 5.25 (each 2 H, s, CH2Ph), 7.26–7.40 (10 H, m, 2 × Ph) and
9.24, 10.10, 10.21 and 10.26 (each 1 H, br s, NH); δC(CDCl3,
100 MHz) 19.16, 19.98, 20.62, 21.26, 21.54, 23.89, 24.17, 29.48,
30.14, 34.39, 34.73, 34.91 and 35.76 (CH2), 50.60, 51.14, 51.72,
52.24 and 52.51 (OMe), 65.69 and 66.04 (CH2Ph), 109.01,
109.95, 112.31, 114.08, 116.06, 117.98, 118.40, 118.80, 124.41,
125.43, 128.13, 128.22, 128.38, 128.48, 129.88, 129.98, 132.85,
128.04, 128.13, 128.42, 133.03 and 136.06 (C᎐C) and 160.30,
᎐
165.52, 173.56, 175.15 and 175.76 (C᎐O); m/z (FD) 582 (Mϩ,
᎐
100%).
1-Benzyloxycarbonyl-9-formyl-8-methoxycarbonyl-2,7-bis-
(2-methoxycarbonylethyl)-3-methoxycarbonylmethyldipyrro-
methane 24
A solution of α-free dipyrromethane 23 (210 mg, 0.36 mmol)
in dry dimethylformamide (1 cm3) was added dropwise under
argon to a stirred solution of phosphorus oxychloride (50 µl,
0.45 mmol) in dry dimethylformamide (250 µl). The solution
was heated at 60 ЊC for 10 min, stirred at room temperature for
1 h and then poured into methanol–water (2:1; 25 cm3). The
mixture was stirred for 10 min at 40 ЊC, then added to saturated
aqueous sodium carbonate (50 cm3) and extracted with dichloro-
methane (4 × 15 cm3). The combined organic extracts were
washed with water (2 × 15 cm3), dried and evaporated under
reduced pressure. Purification by PLC, eluting with diethyl
ether–hexane (1:3), gave formyldipyrromethane 24 (156 mg,
71%), which was recrystallised from diethyl ether–hexane, mp
143–144 ЊC (Found: C, 60.5; H, 5.7; N, 4.45. C31H34N2O11
requires C, 60.9; H, 5.7; N, 4.6%); νmax(CH2Cl2)/cmϪ1 3350,
2930, 1700, 1650 and 1070; δH(CDCl3, 400 MHz) 2.49 (2 H, t, J
7), 2.81 (2 H, t, J 7) and 2.97–3.01 (4 H, m, 2 × CH2CH2), 3.48,
3.61, 3.84 and 3.87 (each 3 H, s, OMe), 3.60 (2 H, s, CH2CO2),
4.06 (2 H, s, 5-H2), 5.23 (2 H, s, CH2Ph), 7.29–7.33 (5 H, m, Ph),
10.07 (1 H, s, CHO) and 10.16 and 10.91 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 19.52, 20.53, 21.78, 29.43, 33.88 and 34.75
(CH2), 51.52, 51.89 and 52.97 (OMe), 65.76 (CH2Ph), 114.86,
118.42, 118.86, 123.50, 128.15, 128.52, 129.93, 131.24, 133.06,
132.90, 135.88, 136.15 and 137.31 (C᎐C) and 160.40, 160.53,
᎐
165.71, 166.35, 173.55, 173.61, 173.83, 174.42, 175.33 and
175.74 (C᎐O); m/z (FD) 1176 (Mϩ, 100%).
᎐
5-tert-Butoxycarbonyl-2-dimethylaminocarbonyl-4-(2-methoxy-
carbonylethyl)-3-methoxycarbonylmethylpyrrole 29
A solution of pyrrole 288 (2.0 g, 5.9 mmol) in dry tetrahydro-
furan (25 cm3) under argon at 0 ЊC was treated dropwise with
tert-butyl hypochlorite (2.15 cm3), stirred at room temperature
for 3 h, then evaporated under reduced pressure. A solution of
the residue in dry tetrahydrofuran (20 cm3) was stirred with 40%
methanolic dimethylamine (20 cm3) for 15 min and then evap-
orated under reduced pressure. The residue was dissolved in
benzene (10 cm3) and stirred overnight with water (10 cm3). The
organic layer was separated and the aqueous layer extracted
with dichloromethane (3 × 20 cm3). The combined organic
layers were dried and evaporated under reduced pressure. Puri-
fication by flash chromatography, eluting with 5% methanol in
diethyl ether, gave dimethylamide 29 (0.95 g, 81%), mp 111–
112 ЊC (from diethyl ether–hexane) (Found: C, 57.3; H, 7.1;
N, 7.1. C15H28N2O7 requires C, 57.55; H, 7.1; N, 7.1%);
νmax(CH2Cl2)/cmϪ1 3420, 3000, 1750, 1710, 1640, 1430, 1260
and 1180; δH(CDCl3, 400 MHz) 1.52 (9 H, s, But), 2.54 and 2.91
(each 2 H, t, J 8, CH2CH2), 3.00 (6 H, s, NMe2), 3.58 (2 H, s,
CH2CO2), 3.62 and 3.65 (each 3 H, s, OMe) and 9.35 (1 H, br s,
NH); δC(CDCl3, 100 MHz) 20.34 (CH2CH2CO2), 28.18 (CMe3),
29.82 (CH2CO2), 34.62 (CH2CH2CO2), 36.87 (NMe2), 51.32
and 51.86 (OMe), 81.54 (CMe3), 117.52, 121.28, 126.58 and
134.62 and 136.04 (C᎐C), 160.52, 164.50, 173.63, 174.36 and
᎐
175.46 (CO2) and 181.35 (CHO); m/z (FD) 610 (Mϩ, 100%).
9-Acetoxymethyl-1-benzyloxycarbonyl-8-methoxycarbonyl-2,7-
bis(2-methoxycarbonylethyl)-3-methoxycarbonylmethyl-
dipyrromethane 26
A solution of aldehyde 24 (95 mg, 0.156 mmol) in dry dichloro-
methane (1 cm3) and methanol (2 cm3) was stirred with
sodium borohydride (7 mg, 0.2 mmol) at room temperature for
10 min, then poured into water (10 cm3) and extracted with
dichloromethane (5 × 5 cm3). The combined extracts were dried
and evaporated under reduced pressure. A solution of the resi-
due in dry dichloromethane (3 cm3) was stirred at 0 ЊC while
triethylamine (45 µl, 0.3 mmol) followed by mesyl chloride (25
µl, 0.3 mmol) were added and after 30 min the mixture was
evaporated under reduced pressure. A solution of the residue
and sodium acetate (90 mg) in glacial acetic acid (3 cm3) was
heated at 70 ЊC for 1 h, then poured into water (25 cm3) and
extracted with dichloromethane (4 × 10 cm3). The combined
extracts were washed with water (2 × 10 cm3), dried and evap-
orated under reduced pressure. Purification by PLC, eluting
with diethyl ether, gave acetoxymethyldipyrromethane 26 (52
mg, 52%) as a gum (Found: Mϩ, 654.2411. C33H38N2O12
requires M, 654.2425); νmax(CH2Cl2)/cmϪ1 3300, 1720, 1700,
1350 and 1170; δH(CDCl3, 400 MHz) 2.10 (3 H, s, Ac), 2.48 and
2.78 (each 2 H, t, J 7) and 2.94–3.01 (4 H, m, 2 × CH2CH2),
3.60 (2 H, s, CH2CO2), 3.49, 3.61, 3.76 and 3.77 (each 3 H, s,
OMe), 3.90 (2 H, s, 5-H2), 5.23 and 5.29 (each 2 H, s, CH2O),
7.28–7.36 (5 H, m, Ph) and 10.13 and 10.22 (each 1 H, br s,
NH); δC(CDCl3, 100 MHz) 19.68, 20.56, 20.82, 21.54, 29.28,
128.42 (C᎐C) and 160.13, 163.99, 171.70 and 173.40 (C᎐O);
᎐
᎐
m/z (FD) 396 (Mϩ, 100%).
4-[5-Benzyloxycarbonyl-3-(2-methoxycarbonylethyl)-4-
(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-1-methoxy-2,8-
bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonylmethyl)-9-
(2,2,2-tribromoethoxycarbonyl)-4,5-dihydrodipyrrin 35
An equimolar mixture of lactam 34,10 trimethyloxonium
tetrafluoroborate and 1,8-bis(dimethylamino)naphthalene was
stirred in dichloromethane at room temperature under argon
for 28 h and then evaporated under reduced pressure. Purifica-
tion by flash chromatography, eluting with diethyl ether, gave
methoxypyrrolenine 35 (82%) as a foam (Found: Mϩ, 1169.0091.
C47H5479Br3N3O17 requires M, 1169.1001); νmax(CH2Cl2)/cmϪ1
3300, 2950, 1730s, 1450 and 1170; δH(CDCl3, 400 MHz) 2.31–
J. Chem. Soc., Perkin Trans. 1, 1998
1525

View Article Online
2.47 (10 H, m), 2.55 and 2.63 (each 2 H, t, J 7) and 3.00–3.05 (2
H, m, 3 × CH2CH2 and CH2CCH2), 3.32 and 3.42 (each 1 H, d,
J 17, CH2CO2), 3.49 (2 H, s, CH2CO2), 3.58, 3.59, 3.61 and 3.76
(21 H total, 4 × s, 7 × OMe), 3.73 and 3.85 (each 1 H, d, J 17,
CH2CO2), 5.02 and 5.11 (each 1 H, d, J 17, CH2CBr3), 5.17 and
5.25 (each 1 H, d, J 12, CH2Ph), 7.30–7.39 (5 H, m, Ph) and
10.31 (2 H, br s, 2 × NH); δC(CDCl3, 100 MHz) 19.27, 19.70,
20.54, 29.51, 30.45, 30.58, 30.73, 31.21, 31.54, 35.10 and 36.38
(CH2 and CBr3), 51.56, 51.71, 51.78, 51.93, 52.02, 53.12 and
55.49 (OMe), 65.93 (CH2Ph), 76.86 and 77.49 (CH2CBr3 and
C-4), 115.72, 116.31, 117.84, 121.98, 122.64, 128.32, 128.59,
126.13, 128.55, 128.65, 130.66, 132.13, 133.66 and 134.33 (C᎐C)
᎐
and 159.94, 171.93, 173.29, 173.75, 173.88 and 174.36 (C᎐O);
᎐
m/z (FD) 624 (Mϩ, 100%).
9-Acetoxymethyl-1-benzyloxycarbonyl-2,7-bis(2-methoxy-
carbonylethyl)-3,8-bis(methoxycarbonylmethyl)dipyrromethan-
5-one 40
A solution of dipyrroketone 39 (1.77 g, 3 mmol) in dry tetrahy-
drofuran (25 cm3) and dry diethyl ether (30 cm3) was stirred at
0 ЊC under argon while a solution of tert-butyl hypochlorite
(400 µl) in dry diethyl ether (10 cm3) was added dropwise and
then after a further 20 min evaporated under reduced pressure.
A solution of the residue and sodium acetate (1.5 g) in glacial
acetic acid (25 cm3) was heated at 60 ЊC for 1 h, cooled, poured
into water (300 cm3) and extracted with dichloromethane
(5 × 50 cm3). The combined extracts were washed with water
(50 cm3), dried and evaporated under reduced pressure. Purifi-
cation by flash chromatography, eluting with diethyl ether,
gave acetoxymethyl dipyrroketone 40 (1.93 g, 94%) as a gum
(Found: Mϩ, 682.2333. C34H38N2O13 requires M, 682.2374);
νmax(CH2Cl2)/cmϪ1 3400, 1710, 1350, 1160 and 1050; δH(CDCl3,
400 MHz) 1.96 (3 H, s, Ac), 2.47 and 2.57 (each 2 H, t) and
2.91–2.98 (4 H, m, 2 × CH2CH2), 3.54 and 3.67 (each 2 H, s,
CH2CO2), 3.57, 3.59, 3.65 and 3.70 (each 3 H, s, OMe), 4.99 (2
H, s, CH2OAc), 5.24 (2 H, s, CH2Ph), 7.30–7.41 (5 H, m, Ph)
and 9.90 and 10.20 (each 1 H, br s, NH); δC(CDCl3, 100 MHz)
20.00, 20.3, 20.3, 28.97, 29.83, 34.01 and 34.06 (6 × CH2 and
MeCO), 51.25, 51.32, 51.87 and 52.29 (OMe), 56.62 (CH2OAc),
66.51 (CH2Ph), 117.85, 120.04, 121.41, 127.29, 128.23, 128.38,
128.78, 129.60, 132.23, 134.55 and 136.29 (C᎐C) and 156.03,
᎐
158.73, 160.37, 171.37, 171.48, 172.13, 172.21, 173.06, 173.49
and 173.70 (C᎐O and N᎐C᎐C᎐C); m/z (FD) 1169, 1171, 1173
᎐
᎐
᎐
and 1175 (1:3:3:1, Mϩ, 100%).
4-[5-Benzyloxycarbonyl-3-(2-methoxycarbonylethyl)-4-
(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-1-methoxy-2,8-
bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonylmethyl)-
4,5-dihydrodipyrrin 36
Lactam 312 was methylated with trimethyloxonium tetra-
fluoroborate using the above procedure. Purification by flash
chromatography, eluting with diethyl ether, gave methoxy-
pyrrolenine 36 (69%) as a gum (Found: Mϩ, 863.3431.
C44H53N3O15 requires M, 863.3477); νmax(CH2Cl2)/cmϪ1 3300,
2950, 1735s, 1445 and 1180; δH(CDCl3, 400 MHz) 2.31–2.62
(12 H, m), 2.68 (2 H, t, J 7) and 2.96–3.03 (2 H, m,
3 × CH2CH2 and CH2CCH2), 3.28 and 3.37 (each 1 H, d, J 16,
CH2CO2), 3.43 and 3.49 (each 1 H, d, J 16, CH2CO2), 3.57,
3.58, 3.59, 3.61, 3.64 and 3.72 (21 H total, 6 × s, 7 × OMe), 3.73
and 3.82 (each 1 H, d, J 17, CH2CO2), 5.16 and 5.24 (each 1 H,
d, J 12, CH2Ph), 6.32 (1 H, d, J 2, 9-H), 7.28–7.38 (5 H, m, Ph)
and 9.01 and 10.24 (each 1 H, br s, NH); δC(CDCl3, 100 MHz)
19.16, 19.62, 20.82, 29.83, 30.06, 30.53, 31.09, 31.18, 31.42 and
35.06 (CH2), 51.54, 51.65, 51.76, 52.82 and 55.10 (OMe), 65.67
(CH2Ph), 77.65 (C-4), 112.06, 113.48, 117.49, 120.90, 121.63,
122.47, 125.23, 128.12, 128.44, 128.64, 130.00, 133.82 and
130.39, 131.36, 131.94 and 135.05 (C᎐C) and 159.93, 170.80,
᎐
171.52, 172.98, 173.34, 173.38 and 174.92 (C᎐O); m/z (FD) 682
᎐
(Mϩ, 100%).
1-tert-Butoxycarbonyl-2,7-bis(2-methoxycarbonylethyl)-3,8-
bis(methoxycarbonylmethyl)-9-(2,2,2-tribromoethoxycarbonyl)-
dipyrromethane 42
A solution of α-free pyrrole 128 (1.25 g, 3.85 mmol) and
acetoxymethylpyrrole 4110 (2.35 g, 3.85 mmol) in dry dichloro-
methane (50 cm3) was stirred with toluene-p-sulfonic acid (73
mg, 0.39 mmol) at room temperature under argon for 2.5 h,
then washed with 10% aqueous sodium hydrogen carbonate (15
cm3) followed by water (15 cm3), dried and evaporated under
reduced pressure. Purification by flash chromatography, eluting
with diethyl ether–hexane (3:2), gave the dipyrromethane 42
(2.85 g, 85%) as a foam (Found: Mϩ, 868.0054. C31H3979Br3-
N2O12 requires M, 868.0053); νmax(CH2Cl2)/cmϪ1 3350, 1730s,
1430, 1170 and 1040; δH(CDCl3, 400 MHz) 1.51 (9 H, s, But),
2.49, 2.57, 2.78 and 2.95 (each 2 H, t, J 7, 2 × CH2CH2), 3.54,
3.93 and 3.94 (each 2 H, s, 2 × CH2CO2 and 5-H2), 3.65, 3.66,
3.72 and 3.77 (each 3 H, s, OMe), 5.04 (2 H, s, OCH2) and 9.63
and 10.13 (each 1 H, br s, NH); δC(CDCl3, 100 MHz) 18.76,
20.70, 22.41, 29.50, 30.99, 34.28 and 35.18 (7 × CH2 and CBr3),
28.36 (CMe3), 51.45, 51.98, 52.17 and 52.69 (OMe), 76.69
(OCH2), 80.80 (CMe3), 114.27, 118.06, 120.24, 120.39, 123.48,
136.34 (C᎐C) and 156.28, 160.37, 171.08, 171.44, 172.14,
᎐
172.76, 173.15, 173.47 and 173.93 (C᎐O and N᎐C᎐C᎐C); m/z
᎐
᎐
᎐
(FD) 863 (Mϩ, 100%).
1-Benzyloxycarbonyl-2,7-bis(2-methoxycarbonylethyl)-3,8-
bis(methoxycarbonylmethyl)-9-methyldipyrromethan-5-one 39
A solution of dimethylamide 38 (3.20 g, 7.44 mmol), prepared
as for 29 above, in phosphorus oxychloride (3 cm3) was heated
at 60 ЊC for 30 min and then evaporated under reduced pres-
sure. Dry 1,2-dichloroethane (1 cm3) was added and the solu-
tion was re-evaporated. A solution of the residue and α-free
pyrrole 3713 (1.75 g, 7.40 mmol) in dry 1,2-dichloroethane (25
cm3) was heated at 70 ЊC with a stream of argon bubbling
through for 4 h. Aqueous sodium carbonate (25 cm3) was added
and the mixture heated under reflux for 1 h and then cooled.
The organic layer was separated and the aqueous layer was
extracted with dichloromethane (3 × 25 cm3). The combined
organic layers were washed with water (50 cm3), dried and
evaporated under reduced pressure. Purification by flash chro-
matography, eluting with diethyl ether, gave the dipyrroketone
39 (3.76 g, 81%) as a foam (Found: Mϩ, 624.2348. C32H36N2O11
requires M, 624.2319); λmax(CH2Cl2)/nm 343 (log10 ε 4.32),† 294
(4.08) and 240 (4.18); νmax(CH2Cl2)/cmϪ1 3400, 1730, 1590 and
1160; δH(CDCl3, 400 MHz) 2.17 (3 H, s, 9-Me), 2.50, 2.60, 2.95
and 3.01 (each 2 H, t, J 8, 2 × CH2CH2), 3.45 (2 H, s, CH2CO2),
3.61, 3.62, 3.67 and 3.76 (14 H total, 4 × s, 4 × OMe and
CH2CO2), 5.29 (2 H, s, CH2Ph), 7.30–7.37 (5 H, m, Ph) and 9.65
and 9.80 (each 1 H, br s, NH); δC(CDCl3, 100 MHz) 11.47 (9-
Me), 20.32, 20.86, 29.50, 30.30 and 34.23 (CH2), 51.46, 51.98
and 52.65 (OMe), 66.60 (CH2Ph), 116.29, 118.52, 121.34,
127.91, 130.44, 132.94 (C᎐C) and 158.90, 160.65, 171.69,
᎐
173.58, 173.75 and 174.24 (C᎐O); m/z (FD) 868, 870, 872 and
᎐
874 (1:3:3:1, Mϩ, 100%).
1-Iodo-2,7-bis(2-methoxycarbonylethyl)-3,8-bis(methoxy-
carbonylmethyl)-9-(2,2,2-tribromoethoxycarbonyl)dipyrro-
methane 44
The tert-butyl group of dipyrromethane 42 was cleaved using
stannic chloride following the standard procedure (see the
preparation of acid 43 in the preceding paper1). The resulting
acid was subjected to the standard iodination–decarboxylation
procedure (as for the preparation of iododipyrromethane 27
in the preceding paper1). Purification by flash chromatography,
eluting with diethyl ether, gave the iododipyrromethane 44
(90%) as an unstable light-sensitive gum; νmax(CH2Cl2)/cmϪ1
3350, 2950, 1740s, 1440 and 1170; δH(CDCl3, 400 MHz) 2.40,
† ε Values are measured in units of dm3 molϪ1 cmϪ1
.
1526
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
2.59, 2.65 and 2.77 (each 2 H, t, J 7, 2 × CH2CH2), 3.53, 3.87
and 3.91 (each 2 H, s, 2 × CH2CO2 and 5-H2), 3.64, 3.65, 3.68
and 3.75 (each 3 H, s, OMe), 5.02 (2 H, s, OCH2) and 9.36 and
10.28 (each 1 H, br s, NH); δC(CDCl3, 100 MHz) 18.64, 21.97,
22.34, 30.07, 31.03, 34.24 and 34.62 (CH2), 36.08 (CBr3), 51.50,
51.90, 52.00 and 52.62 (OMe), 63.77 (C᎐I), 76.62 (OCH2),
112.52, 114.43, 117.91, 119.75, 123.31, 125.44, 131.08 and
combined organic layers were dried and evaporated under
reduced pressure. A solution of the residual iodopyrrole 47 in
methanol (10 cm3) was stirred with sodium acetate (100 mg)
and Adams’ catalyst (30 mg) under an atmosphere of hydrogen
for 35 min, then filtered, diluted with water (100 cm3) and
extracted with dichloromethane (4 × 30 cm3). The combined
extracts were dried and evaporated under reduced pressure.
Purification by flash chromatography, eluting with 0% then 5%
methanol in diethyl ether, gave the α-free pyrrolic lactam 48
(193 mg, 69%) as a gum (Found: Mϩ, 1100.4119. C55H64N4O20
requires M, 1100.4114); λmax(CH2Cl2)/nm 340, 298 and 245;
νmax(CH2Cl2)/cmϪ1 3350, 2950, 1720, 1700, 1595 and 1180;
δH(CDCl3, 400 MHz) 2.34–2.52, 2.61–2.67 and 2.77–2.84 (15 H
total, 3 × m), 2.97 (2 H, t, J 8) and 3.02 (1 H, d, J 15,
4 × CH2CH2 and 4-CH2), 2.73 and 3.05 (each 1 H, d, J 15, 4-
CH2), 3.27 and 3.49 (each 1 H, d, J 17, CH2CO2), 3.37 (2 H, s,
CH2CO2), 3.56, 3.57, 3.60, 3.61, 3.64, 3.65, 3.68 and 3.71 (each
3 H, s, OMe), 3.56–3.71 (4 H, obscured, 2 × CH2CO2), 5.24 and
5.32 (each 1 H, d, J 12, CH2Ph), 6.46 (1 H, d, J 2, α-H), 7.30–
7.36 (6 H, m, Ph and lactam-NH) and 8.51, 10.06 and 10.20
(each 1 H, br s, NH); δC(CDCl3, 100 MHz) 19.43, 19.59, 20.26,
20.55, 29.41, 29.67, 30.46, 30.59, 31.32, 31.72, 32.05, 34.15,
34.40 and 34.84 (CH2), 51.49, 51.64, 51.70, 51.84, 52.16, 52.44
and 53.01 (OMe), 66.49 (CH2Ph), 113.84, 116.61, 117.11,
118.50, 120.54, 122.20, 127.59, 128.46, 128.60, 130.66, 130.95,
133.80 (C᎐C) and 158.50, 171.62, 173.24, 173.76 and 174.65
᎐
(C᎐O); m/z (FD) 894, 896, 898 and 900 (1:3:3:1, Mϩ, 100%).
᎐
14-Benzyloxycarbonyl-2,8,13-tris(2-methoxycarbonylethyl)-4-
[3-(2-methoxycarbonylethyl)-4-methoxycarbonylmethyl-5-
(2,2,2-tribromoethoxycarbonyl)pyrrol-2-ylmethyl]-3,7,12-
tris(methoxycarbonylmethyl)-4,5-dihydrotripyrrin-
1,10(15H,17H)-dione 45
A solution of acetoxymethyldipyrroketone 40 (1.03 g, 1.51
mmol) and iododipyrromethane 44 (1.35 g, 1.51 mmol) in
dry benzene (100 cm3) under argon at room temperature was
treated dropwise with stannic chloride (190 µl, 1.55 mmol)
and stirred for 45 min. Saturated aqueous sodium hydrogen
carbonate (30 cm3) was added and after 10 min the organic
layer was separated and the aqueous layer was extracted with
dichloromethane (3 × 20 cm3). The combined organic layers
were dried and evaporated under reduced pressure. A solution
of the residue in glacial acetic acid (10 cm3) was stirred at
room temperature under argon for 1 h, then poured into satur-
ated aqueous sodium carbonate (150 cm3) and extracted with
dichloromethane (5 × 20 cm3). The combined extracts were
washed with water (50 cm3), dried and evaporated under
reduced pressure. Purification by flash chromatography, eluting
with 0% then 5% methanol in diethyl ether, gave lactam 45 (605
mg, 29%) as a foam (Found: Mϩ, 1406.1598. C58H6579Br3N4O22
requires M, 1406.1638); λmax(CH2Cl2)/nm 341, 287 and 246;
νmax(CH2Cl2)/cmϪ1 3400, 2950, 1730, 1700, 1580, 1430 and
1080; δH(CDCl3, 400 MHz) 2.37–2.61 and 2.77–3.00 (18 H
total, 2 × m, 4 × CH2CH2 and CHAHBCCHAHB), 3.07 and 3.17
(each 1 H, J 15, CHAHBCCHAHB), 3.38 and 3.48 (each 1 H, d,
J 17, CH2CO2), 3.78 and 3.97 (each 1 H, d, J 17, CH2CO2),
3.53–3.80 (4 H, obscured, 2 × CH2CO2), 3.53, 3.58, 3.61, 3.64,
3.67, 3.68, 3.76 and 3.80 (each 3 H, s, OMe), 5.00 and 5.05 (each
1 H, d, J 17, CH2CBr3), 5.25 and 5.33 (each 1 H, d, J 12,
CH2Ph), 7.16 (1 H, br s, lactam-NH), 7.30–7.36 (5 H, m, Ph)
and 9.78, 10.00 and 10.24 (each 1 H, br s, NH); δC(CDCl3, 100
MHz) 19.01, 19.70, 20.28, 20.64, 29.58, 29.68, 29.75, 30.64,
30.73, 31.28, 32.84, 34.10, 34.31 and 34.43 (CH2), 35.92 (CBr3),
51.51, 51.65, 51.87, 52.00, 52.33, 52.50 and 53.26 (OMe), 65.91
and 66.54 (CH2Ph and C-4), 76.69 (CH2CBr3), 107.87, 117.58,
117.98, 120.23, 121.15, 122.69, 123.56, 127.79, 128.46, 128.63,
131.40, 131.73, 135.46, 137.28 and 149.65 (C᎐C) and 160.28,
᎐
171.53, 172.03, 172.72, 173.07, 173.32, 173.55, 174.28 and
175.53 (C᎐O); m/z (FD) 1100 (Mϩ, 100%).
᎐
14-Benzyloxycarbonyl-1-chloro-2,8,13-tris(2-methoxycarbonyl-
ethyl)-3,7,12-tris(methoxycarbonylmethyl)-4-methyl-4,5-
dihydrotripyrrin-10(17H)-one 51
Acetoxymethyldipyrroketone 40 and iodopyrrole 5010 were
coupled following the procedure for the synthesis of 45. Purifi-
cation by PLC, eluting with diethyl ether, gave the chloropyr-
rolenine 51 (20%) as a moisture sensitive gum; λmax(CH2Cl2)/nm
342, 296 and 245; δH(CDCl3, 400 MHz) 1.11 (3 H, s, 4-Me), 2.36
and 3.12 (each 1 H, d, J 15, 5-H2), 2.41–2.45, 2.53–2.58 and
2.94–3.03 (12 H total, 3 × m, 3 × CH2CH2), 3.46 and 3.55 (each
1 H, d, J 16, CH2CO2), 3.48 (2 H, s, CH2CO2), 3.59, 3.60, 3.62,
3.64, 3.66 and 3.67 (each 3 H, s, OMe), 3.69 and 3.77 (each 1 H,
d, J 17, CH2CO2), 5.25 and 5.32 (each 1 H, d, J 12, CH2Ph),
7.32–7.38 (5 H, m, Ph) and 9.74 and 10.07 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 19.66, 19.96, 20.23, 20.59, 29.50, 29.94,
31.69, 31.83, 32.46, 34.31, 34.41 (10 × CH2 and 4-Me), 51.41,
51.49, 51.78, 51.95, 52.08 and 52.49 (OMe), 66.53 (CH2Ph),
80.99 (C-4), 117.50, 120.80, 126.63, 128.39, 128.47, 128.58,
130.95, 131.52, 132.02, 132.19, 135.44 and 136.02 (C᎐C) and
᎐
129.11, 130.49, 130.70, 131.89, 135.49, 138.05 and 148.70 (C᎐C)
and 158.56, 160.25, 171.48, 171.67, 172.94, 173.26, 173.35,
160.05, 160.70, 169.54, 171.99, 172.36, 172.66, 173.29, 173.62
᎐
and 174.70 (C᎐O and C᎐N); m/z (FD) 895 and 897 (3:1, Mϩ,
᎐
᎐
173.44, 173.55, 174.07 and 175.53 (C᎐O); m/z (FD) 1406, 1408,
100%).
᎐
1410 and 1412 (1:3:3:1, Mϩ, 100%).
14-Benzyloxycarbonyl-2,8,13-tris(2-methoxycarbonylethyl)-
3,7,12-tris(methoxycarbonylmethyl)-4-methyl-10-oxo-4,5,10,17-
tetrahydrotripyrrin-1(15H)-thione 53
14-Benzyloxycarbonyl-2,8,13-tris(2-methoxycarbonylethyl)-4-
[3-(2-methoxycarbonylethyl)-4-(methoxycarbonylmethyl)pyrrol-
2-ylmethyl]-3,7,12-tris(methoxycarbonylmethyl)-4,5-
A solution of chloropyrrolenine 51 (200 mg, 0.22 mmol) in dry
dichloromethane (1 cm3) was added dropwise to a saturated
solution of hydrogen sulfide in dichloromethane (20 cm3).
Silver acetate (200 mg) was then added and the black mixture
was stirred at room temperature for 10 min and then evaporated
under a stream of argon. A solution of the residue in dichloro-
methane was filtered and evaporated under reduced pressure.
Purification by PLC, eluting with 5% methanol in diethyl ether,
gave thiolactam 53 (120 mg, 60%) as a gum (Found: Mϩ,
893.3081. C44H51N3O15S requires M, 893.3041); λmax(CH2Cl2)/
nm 340, 299 and 243; νmax(CH2Cl2)/cmϪ1 3350, 2950, 1720,
1695, 1580 and 1080; δH(CD3CN, 400 MHz) 1.29 (3 H, s,
4-Me), 2.38–2.51, 2.75–2.79 and 2.93–2.98 (14 H total, 3 × m,
3 × CH2CH2 and 5-H2), 3.44–3.50 (4 H, m, 2 × CH2CO2), 3.54,
3.56, 3.58, 3.59, 3.65 and 3.71 (each 3 H, s, OMe), 3.54–3.71
dihydrotripyrrin-1,10(15H,17H)-dione 48
A solution of tribromoethyl ester 45 (400 mg, 0.28 mmol) in
glacial acetic acid (5 cm3) was stirred with zinc dust (600 mg)
under argon at room temperature for 30 min, then filtered,
diluted with water (100 cm3) and extracted with dichlorometh-
ane (5 × 30 cm3). The combined extracts were dried and evap-
orated under reduced pressure. A solution of the residual acid
46 in dichloromethane (20 cm3) was stirred vigorously with 5%
aqueous sodium hydrogen carbonate (20 cm3) and an aqueous
solution (2.9 cm3) of iodine (0.1 mol dmϪ3) and potassium
iodide (0.2 mol dmϪ3) was added dropwise. After 25 min at
room temperature sodium metabisulfite was added to destroy
excess iodine. The organic layer was separated and the aqueous
layer was extracted with dichloromethane (4 × 10 cm3). The
J. Chem. Soc., Perkin Trans. 1, 1998
1527

View Article Online
(2 H, obscured, CH2CO2), 5.24 and 5.33 (each 1 H, d, J 12,
CH2Ph), 7.32–7.42 (5 H, m, Ph) and 9.02, 9.81 and 10.27 (each
1 H, br s, NH); δC(CD3COCD3, 100 MHz) 19.05, 19.52, 19.97,
29.72, 30.58, 31.06, 31.99, 33.09 and 33.14 (CH2 and 4-Me),
49.86, 49.93, 50.33, 50.56, 50.78 and 51.00 (OMe), 64.86
(CH2Ph), 70.61 (C-4), 116.19, 119.50, 120.03, 126.83, 127.25,
127.45, 127.94, 129.82, 120.03, 130.57, 130.97, 135.17, 139.23,
1075; δH(CD3COCD3, 400 MHz) 1.12 (3 H, s, 4-Me), 2.30–2.33
and 2.51–2.61 (9 H total, 2 × m), 2.68 (1 H, d, J 15) and 2.92
and 3.03 (each 2 H, t, J 7, 3 × CH2CH2 and 5-H2), 3.12 and 3.54
(each 1 H, d, J 17, CH2CO2), 3.15 and 3.30 (each 1 H, d, J 15,
NCH2), 3.57, 3.57, 3.58, 3.60, 3.61 and 3.63 (each 3 H, s, OMe),
3.57–3.63 (2 H, obscured, CH2CO2), 3.75 and 3.79 (each 1 H, d,
J 17, CH2CO2), 5.31 and 5.38 (each 1 H, d, J 12, CH2Ph) and
7.35–7.51 (5 H, m, Ph); δC(CD3COCD3, 100 MHz) 20.75, 21.28,
22.99, 24.85, 29.04, 30.50, 32.27, 33.88, 34.77 and 34.82 (4-Me
and 9 × CH2), 51.24, 51.35, 51.51, 51.71, 51.77, 52.01 and 53.19
(CH2N and 6 × OMe), 66.44 (CH2Ph), 72.18 (C-4), 107.04,
117.04, 120.75, 121.44, 127.56, 128.85, 129.15, 129.19, 131.65,
150.09 (C᎐C), 159.06, 168.97, 170.84, 171.72, 171.85, 172.01
᎐
and 174.75 (C᎐O) and 195.38 (C᎐S); m/z (FD) 893 (Mϩ,
᎐
᎐
100%).
14-Benzyloxycarbonyl-2,8,13-tris(2-methoxycarbonylethyl)-
3,7,12-tris(methoxycarbonylmethyl)-4-methyl-4,5-dihydro-
tripyrrin-10(17H)-one 52
131.80, 133.16, 134.11, 137.18 and 139.27 (C᎐C) and 160.87,
᎐
172.14, 172.68, 173.45, 173.71 and 175.70 (C᎐O); m/z (FD) 863
᎐
Thiolactam 53 was treated with nickel boride using the stand-
ard procedure (as for the synthesis of pyrrolenine 32 in the
preceding paper1). Purification by PLC, eluting with 5%
methanol in diethyl ether, gave a nickel complex of pyrrolenine
52 (45%) as a gum; λmax(CH2Cl2)/nm 359br, 319, 290 and 245;
νmax(CH2Cl2)/cmϪ1 3400, 1720 and 1580; δH(CD3COCD3, 400
MHz) 1.43 (3 H, s, 4-Me), 2.44–2.49 (3 H, m), 2.69–2.81 and
2.98–3.02 (10 H total, 2 × m) and 3.10 (1 H, d, J 15,
3 × CH2CH2 and 5-H2), 3.31 and 3.37 (each 1 H, d, J 17,
CH2CO2), 3.56, 3.57, 3.58, 3.60, 3.61 and 3.72 (each 3 H, s,
OMe), 3.56–3.72 (2 H, obscured, CH2CO2), 3.96 and 4.03 (each
1 H, d, J 17, CH2CO2), 5.39 and 5.48 (each 1 H, d, J 12, CH2Ph)
and 8.27 (1 H, s, 2-H); δC(CD3COCD3, 100 MHz) 19.43, 20.37,
21.03, 22.74, 31.67, 33.22, 33.68, 34.36 and 35.42 (CH2 and
4-Me), 51.23, 51.56, 51.62, 51.73, 52.63 and 54.93 (OMe), 70.61
(CH2Ph), 80.12 (C-4), 110.04, 113.52, 117.14, 118.56, 122.31,
129.04, 129.27, 129.49, 132.75, 135.94, 136.08, 137.49 and
(Mϩ, 100%).
14-Benzyloxycarbonyl-3,8,13-tris(2-methoxycarbonylethyl)-
2,7,12-tris(methoxycarbonylmethyl)-1-methyl-5,15-dihydro-
tripyrrin-10(17H)-one 55
A solution of pyrrolenine 52 (3.2 mmol dmϪ3) in dry degassed
acid-free dichloromethane was stirred with an equimolar
amount of toluene-p-sulfonic acid monohydrate at room
temperature under argon in the dark for 18 h, then washed with
5% aqueous sodium hydrogen carbonate followed by water,
dried and evaporated under reduced pressure. Purification by
PLC gave tripyrrole 55 (75%) as a gum (Found: Mϩ, 861.3297.
C44H51N3O15 requires M, 861.3320); λmax(CH2Cl2)/nm 340,
285 and 240; νmax(CH2Cl2)/cmϪ1 3350, 2950, 1720, 1575 and
1160; δH(CDCl3, 400 MHz) 2.09 (3 H, s, 1-Me), 2.46–2.55 (6 H,
m, 3 × CH2CH2CO2), 2.61, 2.71 and 2.94 (each 2 H, t,
3 × CH2CH2CO2), 3.31, 3.60, 3.61, 3.63, 3.64 and 3.75 (each 3
H, s, OMe), 3.31, 3.58, 3.72 and 3.84 (each 2 H, s, 3 × CH2CO2
and 5-H2), 5.30 (2 H, s, CH2Ph), 7.30–7.38 (5 H, m, Ph), 9.03,
9.62 and 10.05 (each 1 H, br s, NH); δC(CDCl3, 100.57 MHz)
11.08 (1-Me), 19.08, 20.15, 20.69, 27.22, 29.34, 29.79, 30.50,
34.30, 34.47 and 34.60 (10 × CH2), 51.32, 51.48, 51.52, 51.77,
52.21 and 52.48 (OMe), 66.60 (CH2Ph), 109.63, 115.57, 116.43,
120.85, 121.02, 122.33, 125.17, 127.02, 128.46, 128.55, 128.66,
138.07 (C᎐C) and 164.99, 169.82, 170.44, 171.75, 173.31,
᎐
173.40, 173.46, 173.78 and 174.52 (C᎐O and C᎐N); m/z (FD)
᎐
᎐
917, 918, 919, 920, 921 and 922 (Mϩ, 100%).
A solution of the nickel complex (23 mg, 25 µmol) in dry
dichloromethane (1 cm3) was stirred with ethylenediamine (18
mg, 0.3 mmol) at room temperature under argon for 5 min and
then evaporated under reduced pressure. Purification by PLC,
eluting with 5% methanol in diethyl ether, gave pyrrolenine 52
(17 mg, 80%) as a gum (Found: Mϩ, 861.3351. C44H51N3O15
requires M, 861.3320); λmax(CH2Cl2)/nm 342, 289 and 245;
νmax(CH2Cl2)/cmϪ1 3400, 2950, 1720, 1695, 1580 and 1180;
δH(CD3COCD3, 400 MHz) 1.09 (3 H, s, 4-Me), 2.05 (6 H,
obscured by solvent) and 2.48–2.61 (6 H, m, 3 × CH2CH2),
2.28 and 3.33 (each 1 H, d, J 15, 5-H2), 3.37 and 3.47 (each 1 H,
d, J 17, CH2CO2), 3.56 and 3.77 (each 2 H, s, 2 × CH2CO2),
3.57, 3.58, 3.59, 3.60, 3.63 and 3.66 (each 3 H, s, OMe), 5.32 and
5.38 (each 1 H, d, J 12, CH2Ph), 7.33–7.49 (5 H, m, Ph), 7.97
(1 H, s, 2-H), 10.60 (1 H, br s, NH) and 11.10 (1 H, v br s,
NH); δC(CD3COCD3 and Et3N, 100 MHz, some peaks
obscured by background noise) 19.36, 20.64, 20.95, 22.98,
32.98, 33.75, 34.39, 34.71 and 35.37 (CH2 and 4-Me),
50.97, 51.30, 51.47, 51.61, 52.36 and 54.69 (OMe), 70.60
(CH2Ph), 81.44 (C-4), 119.07, 126.67, 128.78, 129.05, 129.23,
130.86, 131.49, 132.10 and 135.20 (C᎐C) and 160.00, 172.86,
᎐
173.23, 173.62, 173.97, 174.84 and 174.97 (C᎐O); m/z (FD) 861
᎐
(Mϩ, 100%).
14-Benzyloxycarbonyl-4-[5-benzyloxycarbonyl-4-(2-methoxy-
carbonylethyl)-3-(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-
2,8,13-tris(2-methoxycarbonylethyl)-3,7,12-tris(methoxy-
carbonylmethyl)-4,5-dihydrotripyrrin-1,10(15H,17H)-dione 57
Iododipyrromethane 561 and acetoxymethyldipyrroketone 40
were coupled according to the procedure described above for
the synthesis of lactam 45. Purification by flash chroma-
tography, eluting with 0% then 5% methanol in diethyl ether,
gave lactam 57 (22%) as a gum (Found: Mϩ, 1234.4547.
C63H70N4O22 requires M, 1234.4482); λmax(CH2Cl2)/nm 342, 295
and 245; νmax(CH2Cl2)/cmϪ1 3400, 2950, 1725, 1575, 1445 and
1075; δH(CDCl3, 400 MHz) 2.35–2.59 and 2.75–3.04 (18 H
total, 2 × m, 4 × CH2CH2 and 4-CH2), 2.70 and 3.01 (each 1 H,
d, J 15, 4-CH2), 3.21 (1 H, d, J 16, CHAHBCO2), 3.38, 3.57,
3.57, 3.61, 3.62, 3.62, 3.64 and 3.73 (each 3 H, s, OMe), 3.38–
3.73 (1 H, obscured, CHAHBCO2), 3.48 (2 H, m, CH2CO2), 3.67
and 3.81 (each 1 H, d, J 17, CH2CO2), 5.05 and 5.50 (each 1 H,
d, J 12, CH2Ph), 5.17 and 5.31 (each 1 H, d, J 12, CH2Ph), 7.26–
7.39 (10 H, m, 2 × Ph) and 7.43, 9.59, 10.16 and 10.52 (each
1 H, br s, NH); δC(CDCl3, 100 MHz) 19.73, 20.08, 20.36, 20.62,
28.86, 29.47, 29.53, 29.74, 30.16, 30.78, 33.20, 33.96, 34.29 and
34.70 (14 × CH2), 51.37, 51.46, 51.51, 51.60, 52.20, 52.28, 52.62
and 53.12 (OMe), 65.66 and 66.27 (CH2Ph), 115.19, 117.94,
118.12, 121.10, 121.38, 127.79, 127.97, 128.25, 128.35, 128.43,
128.52, 128.60, 129.61, 130.59, 130.98, 131.31, 132.26, 135.98,
135.69, 142.24 (C᎐C), 159.90, 172.07, 172.74, 172.88, 173.17,
᎐
173.36, 174.29 and 175.32 (C᎐O and C᎐N); m/z (FD) 861 (Mϩ,
᎐
᎐
100%).
14-Benzyloxycarbonyl-2,8,13-tris(2-methoxycarbonylethyl)-
3,7,12-tris(methoxycarbonylmethyl)-4-methyl-1,4,5,15-
tetrahydrotripyrrin-10(17H)-one 54
A solution of pyrrolenine 52 (10 mg, 11 µmol) in dry methanol
was stirred with sodium borohydride (10 mg) at room temper-
ature for 30 min under argon, then diluted with water (10 cm3)
and extracted with dichloromethane (4 × 5 cm3). The combined
extracts were dried and evaporated under reduced pressure.
Purification by PLC, eluting with 5% methanol in diethyl ether,
gave amine 54 (8 mg, 80%) as a gum (Found: Mϩ, 863.3490.
C44H53N3O15 requires M, 863.3477); λmax(CH2Cl2)/nm 345, 295
and 245; νmax(CH2Cl2)/cmϪ1 3400, 3250, 2950, 1720, 1580 and
136.16, 138.24 and 149.00 (C᎐C) and 159.85, 160.07, 171.56,
᎐
171.96, 172.49, 172.97, 173.36, 173.53, 173.59, 174.23 and
175.45 (C᎐O); m/z (FD) 1234 (Mϩ, 100%).
᎐
1528
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
14-Benzyloxycarbonyl-4-[5-benzyloxycarbonyl-4-(2-methoxy-
carbonylethyl)-3-(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-
2,8,13-tris(2-methoxycarbonylethyl)-3,7,12-tris(methoxycarb-
onylmethyl)-4,5-dihydrotripyrrin-1,10(15H,17H)-dithione 59
A solution of lactam 57 in dry dimethoxyethane (1 cm3) was
stirred with an equimolar quantity of Davy’s reagent 6 at room
temperature under argon for 10 min and then evaporated under
reduced pressure. Purification by PLC, eluting with 5% meth-
anol in diethyl ether, gave the dipyrrothioketone thiolactam
59 (52%) as a gum; λmax(CH2Cl2)/nm 426, 285 and 250;
νmax(CH2Cl2)/cmϪ1 3300, 2950, 1730, 1700, 1440 and 1180;
δH(CDCl3, 400 MHz) 2.35–2.56, 2.67–2.73 and 2.90–2.98 (18 H
total, 3 × m, 4 × CH2CH2 and 4-CH2), 2.83 and 3.09 (each 1 H,
d, J 15, 4-CH2), 3.34 and 3.42 (each 1 H, d, J 17, 2 × CHA-
HBCO2), 3.53, 3.55, 3.58, 3.61, 3.62, 3.63, 3.64 and 3.76 (each
3 H, s, OMe), 3.53–3.76 (6 H, obscured, 2 × CHAHBCO2 and
2 × CH2CO2), 5.20 and 5.28 (each 1 H, d, J 12, CH2Ph), 5.27
and 5.35 (each 1 H, d, J 12, CH2Ph), 7.26–7.39 (10 H, m,
2 × Ph) and 9.27, 9.78, 9.85 and 9.94 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 20.35, 20.43, 20.73, 20.88, 29.49, 29.65,
29.92, 30.51, 30.66, 31.45, 31.85, 33.78, 34.31 and 34.62 (CH2),
51.41, 51.48, 51.52, 51.60, 52.12, 52.48, 52.66 and 53.21 (OMe),
65.73 and 66.35 (CH2Ph), 73.23 (C-4), 115.34, 118.37, 119.35,
119.67, 120.54, 127.70, 128.04, 128.25, 128.28, 128.37, 128.43,
128.54, 129.99, 131.61, 133.19, 135.69, 136.03, 138.03, 138.30,
Purification by PLC, eluting with 2% methanol in diethyl
ether, gave methylthiopyrrolenine 60 (28 mg, 56%) as a gum
(Found: Mϩ, 1264.4421. C64H72N4O21S requires M, 1264.4410);
λmax(CH2Cl2)/nm 343, 290 and 240; νmax(CH2Cl2)/cmϪ1 3300,
2950, 1720, 1695, 1580 and 1175; δH(CDCl3, 400 MHz) 2.02
(3 H, s, SMe), 2.21–2.23, 2.32–2.54 and 2.85–3.05 (20 H total,
3 × m, 4 × CH2CH2 and CH2CCH2), 3.32 and 3.43 (each 1 H,
d, J 16, CH2CO2), 3.36 and 3.44 (each 2 H, s, 2 × CH2CO2),
3.56, 3.58, 3.59, 3.59, 3.61, 3.62, 3.63 and 3.66 (each 3 H, s,
OMe), 3.56–3.66 (2 H, obscured, CH2CO2), 5.19 and 5.26 (each
1 H, d, J 12, CH2Ph), 5.26 and 5.32 (each 1 H, d, J 12, CH2Ph),
7.27–7.39 (10 H, m, 2 × Ph) and 9.81, 10.04 and 10.24 (each
1 H, br s, NH); δC(CDCl3, 100 MHz) 12.42 (SMe), 19.65, 20.28,
20.36, 20.44, 29.36, 29.50, 29.61, 30.29, 30.60, 31.12, 31.74,
34.34 and 34.68 (CH2), 51.41, 51.51, 51.76, 51.94, 52.04 and
52.71 (OMe), 65.84 and 66.46 (CH2Ph), 84.07 (C-4), 115.25,
117.01, 117.22, 120.55, 126.75, 128.21, 128.42, 128.47, 128.51,
128.59, 128.68, 130.01, 130.27, 130.75, 131.54, 131.83, 132.68,
135.51, 136.06, 139.14 and 155.20 (C᎐C) and 160.13, 160.23,
᎐
170.93, 171.91, 172.17, 172.29, 172.61, 173.27, 173.35, 173.49
and 174.90 (C᎐O and C᎐N); m/z (FD) 1264 (Mϩ, 100%).
᎐
᎐
1-Carboxy-2,7-bis(2-methoxycarbonylethyl)-3,8-bis(methoxy-
carbonylmethyl)-9-methyldipyrromethan-5-one 64
A solution of benzyl ester 39 (1.06 g, 1.70 mmol) in dry tetra-
hydrofuran (10 cm3) was stirred with triethylamine (80 µl) and
10% palladium-on-charcoal (100 mg) under an atmosphere of
hydrogen for 45 min, then filtered and evaporated under
reduced pressure. Purification by flash chromatography, eluting
with methanol–ethyl acetate (1:6), gave acid 64 (815 mg, 90%)
as a gum (Found: Mϩ, 534.1865. C25H30N2O11 requires M,
534.1849); λmax(CH2Cl2)/nm 344 (log10 ε 4.25), 289 (3.95) and
238 (4.04); νmax(CH2Cl2)/cmϪ1 3400, 3300–2500, 1720, 1590 and
1050; δH(CDCl3, 400 MHz) 2.18 (3 H, s, 9-Me), 2.57, 2.61, 2.77
and 3.02 (each 2 H, t, J 7, 2 × CH2CH2), 3.56, 3.61, 3.63 and
3.65 (each 3 H, s, OMe), 3.46 and 3.75 (each 2 H, s, CH2CO2)
and 9.88 and 10.00 (each 1 H, br s, NH); δC(CDCl3, 100 MHz)
11.25 (9-Me), 20.13, 20.50, 29.40, 30.00 and 34.20 (CH2), 51.28,
51.80 and 52.22 (OMe), 115.78, 119.20, 126.27, 129.59, 131.16,
138.56, 144.26 and 147.03 (C᎐C), 160.11, 160.23, 171.55,
᎐
172.70, 172.77, 173.08, 173.46 and 173.57 (C᎐O) and 197.81
᎐
and 198.52 (C᎐S); m/z (FD) 1266 (Mϩ, 100%).
᎐
1-Benzyloxycarbonyl-2,7-bis(2-methoxycarbonylethyl)-3,8-bis-
(methoxycarbonylmethyl)-9-methyldipyrromethane-5-thione 62
A solution of dipyrroketone 39 (50 mg, 80 µmol) in dry
dimethoxyethane (1 cm3) was stirred with Davy’s reagent 6
(14 mg, 45 µmol) at room temperature under argon for 10 min
and then evaporated under reduced pressure. Purification by
PLC, eluting with diethyl ether, gave dipyrrothioketone 62 (35.5
mg, 69%) as a gum; λmax(CH2Cl2)/nm 425, 261 and 226;
νmax(CH2Cl2)/cmϪ1 3350, 2950, 1725 and 1170; δH(CDCl3, 400
MHz) 2.17 (3 H, s, 9-Me), 2.50–2.56 (4 H, m, 2 × CH2-
CH2CO2), 2.91 and 2.97 (each 2 H, t, J 7, CH2CH2CO2), 3.45
and 3.47 (each 2 H, s, CH2CO2), 3.59, 3.61, 3.67 and 3.69 (each
3 H, s, OMe), 5.29 (2 H, s, CH2Ph), 7.33–7.40 (5 H, m, Ph) and
9.44 and 9.51 (each 1 H, br s, NH); δC(CDCl3, 100 MHz) 11.71
(9-Me), 20.47, 21.25, 29.67, 30.26, 33.63 and 34.11 (CH2),
51.48, 52.06 and 52.34 (OMe), 66.50 (CH2Ph), 116.80, 119.63,
121.49, 128.38, 128.47, 128.59, 131.23, 135.28, 135.46, 137.31,
132.95 and 134.16 (C᎐C) and 164.08, 171.97, 173.69, 173.74
᎐
and 174.64 (C᎐O); m/z (FD) 534 (Mϩ, 100%).
᎐
1-Dimethylaminocarbonyl-2,7-bis(2-methoxycarbonylethyl)-3,8-
bis(methoxycarbonylmethyl)-9-methyldipyrromethan-5-one 65
A solution of carboxylic acid 64 (486 mg, 0.91 mmol) and
1,1Ј-carbonyldiimidazole (162 mg, 1.0 mmol) in dry dichloro-
methane (5 cm3) was stirred at room temperature under argon
for 15 min, then treated with dimethylamine (40% in industrial
methylated spirits; 5 cm3) and after a further 1 h evaporated
under reduced pressure. Purification by PLC, eluting with 10%
methanol in diethyl ether, gave dimethylamide 65 (335 mg, 66%)
as a gum (Found: Mϩ, 561.2326. C27H35N3O10 requires, M,
561.2322); λmax(CH2Cl2)/nm 345, 295 and 229; νmax(CH2Cl2)/
cmϪ1 3400, 2950, 1710, 1585 and 1150; δH(CDCl3, 400 MHz)
2.14 (3 H, s, 9-Me), 2.44, 2.56, 2.73 and 2.97 (each 2 H, t, J 7,
2 × CH2CH2), 2.99 (6 H, s, NMe2), 3.43 and 3.56 (each 2 H, s,
CH2CO2), 3.59, 3.61, 3.65 and 3.71 (each 3 H, s, OMe) and 9.98
and 10.00 (each 1 H, br s, NH); δC(CDCl3, 100 MHz) 11.34
(9-Me), 19.89, 20.68, 29.49, 30.43, 34.30 and 34.41 (CH2), 37.0
(NMe2), 51.39, 51.54, 51.92 and 52.42 (OMe), 115.70, 118.37,
137.67 and 138.24 (C᎐C), 160.08, 171.41, 173.30 and 173.34
᎐
(C᎐O) and 194.08 (C᎐S); m/z (FD) 640 (Mϩ, 100%).
᎐
᎐
The above product 62 was reconverted into the starting
dipyrroketone 39, 82%, without full purification of the inter-
mediate 63, by the standard method developed for hydrolysis of
thioketones. This is described below for the conversion of 59
into 60.
14-Benzyloxycarbonyl-4-[5-benzyloxycarbonyl-4-(2-methoxy-
carbonylethyl)-3-(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-
2,8,13-tris(2-methoxycarbonylethyl)-3,7,12-tris(methoxycarb-
onylmethyl)-1-methylthio-4,5-dihydrotripyrrin-10(17H)-one 60
A solution of dipyrrothioketone thiolactam 59 (50 mg, 40
µmol) in distilled trifluoroacetic acid (2 cm3) and trimethyl
orthoformate (2 cm3) was stirred at room temperature under
argon for 1 h and then evaporated under reduced pressure. A
solution of the residue in dichloromethane (5 cm3) was washed
with aqueous sodium hydrogen carbonate (10 cm3), dried and
evaporated under reduced pressure. A solution of the residue in
tetrahydrofuran (3 cm3) was stirred with water (20 drops) and
toluene-p-sulfonic acid (10 mg, 50 µmol) at room temperature
under argon for 16 h, then poured into water (20 cm3) and
extracted with dichloromethane (4 × 5 cm3). The combined
extracts were dried and evaporated under reduced pressure.
124.30, 126.04, 126.09, 129.97, 132.61, 133.69 (C᎐C) and
᎐
164.26, 172.05, 173.19, 173.82 and 174.42 (C᎐O); m/z (FD) 561
᎐
(Mϩ, 100%).
2,7-Bis(2-methoxycarbonylethyl)-3,8-bis(methoxycarbonyl-
methyl)-9-methyl-1-phenylselenocarbonyldipyrromethan-5-one
66
A solution of acid 64 (50 mg, 94 µmol) in dry dichloromethane
(1 cm3) was stirred with 1,1Ј-carbonyldiimidazole (18 mg, 120
µmol) at room temperature under argon for 15 min and then a
J. Chem. Soc., Perkin Trans. 1, 1998
1529

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solution of sodium phenylselenide17 (54 mg, 0.30 mmol) in
diglyme (0.5 cm3) was added. After a further 1 h the solution
was poured into water (15 cm3) and extracted with dichloro-
methane (4 × 10 cm3). The combined extracts were washed with
water (10 cm3), dried and evaporated under reduced pressure.
Purification by PLC, eluting with diethyl ether, gave the seleno-
ester 66 (29 mg, 46%) as a gum (Found: C, 55.0; H, 4.9; N,
4.15. C31H34N2O10Se requires C, 55.3; H, 5.1; N, 4.15%);
λmax(CH2Cl2)/nm 354 (log10 ε 4.42), 257 (4.19) and 220 (4.20);
νmax(CH2Cl2)/cmϪ1 3400, 1720, 1570, 1330 and 1030; δH(CDCl3,
400 MHz) 2.19 (3 H, s, 9-Me), 2.56, 2.64, 2.96 and 3.06 (each
2 H, t, J 7, 2 × CH2CH2), 3.37, 3.64, 3.68 and 3.78 (each 3 H, s,
OMe), 3.47 and 3.65 (each 2 H, s, CH2CO2), 7.39–7.43 and
7.55–7.57 (5 H total, 2 × m, Ph) and 9.70 and 9.89 (each 1 H, br
s, NH); δC(CDCl3, 100 MHz) 11.54 (9-Me), 20.47, 20.94, 29.49,
30.29, 33.90 and 34.18 (CH2), 51.51, 51.64, 52.04 and 52.79
(OMe), 116.59, 119.22, 124.70, 126.10, 129.33, 129.46, 133.25,
Acknowledgements
Grateful acknowledgement is made to the Commissioners for
the Exhibition of 1851 for an Overseas Scholarship (to C. J. H.).
We also thank Zeneca, Roche Products, F. Hoffmann-La Roche
and the EPSRC for financial support.
References
1 Part 48. C. J. Hawker, A. C. Spivey, F. J. Leeper and A. R. Battersby,
J. Chem. Soc., Perkin Trans. 1, 1998, 1509.
2 C. J. Hawker, W. M. Stark, A. C. Spivey, P. R. Raithby, F. J. Leeper
and A. R. Battersby, J. Chem. Soc., Perkin Trans. 1, 1998, 1493.
3 F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp,
M. Lipton, C. Caufield, G. Chang, T. Hendrickson and W. C. Still,
J. Comput. Chem., 1990, 11, 440.
4 F. J. Leeper, D. H. C. Smith, M. J. Doyle and P. R. Raithby, J. Chem.
Soc., Perkin Trans. 2, 1995, 777.
5 P. M. Petersen, C. J. Hawker, F. J. Leeper and A. R. Battersby,
J. Chem. Soc., Perkin Trans. 1, 1998, 1531.
134.22, 134.95 and 136.38 (C᎐C) and 171.86, 173.16, 173.50,
᎐
173.75, 174.30 and 181.09 (C᎐O); m/z (FD) 674 (Mϩ, 100%).
6 T. Mukaiyama, Angew. Chem., Int. Ed. Engl., 1979, 18, 707.
7 G. Lajoie, F. Lepine, L. Maziak and B. Belleau, Tetrahedron Lett.,
1983, 24, 3815.
᎐
3,7,12-Tris(2-methoxycarbonylethyl)-2,8,13-tris(methoxycarb-
onylmethyl)-1,14-dimethyltripyrrin-5,10(15H,17H)-dione 67
A solution of selenoester 66 (1 equiv.) and α-free pyrrole 3713
(1.1 equiv.) in dichloromethane was stirred with calcium car-
bonate (1.25 equiv.) and a solution of copper() triflate–benzene
complex (0.5 equiv.) in benzene at room temperature for 30
min,15,16 then poured into saturated aqueous sodium carbonate,
shaken vigorously and extracted four times with dichloro-
methane. The combined extracts were washed with water, dried
and evaporated under reduced pressure. Purification by PLC,
eluting with 5% methanol–diethyl ether, gave the dioxotripyrrin
67 (5%) as a gum (Found: Mϩ, 755.2853. C37H45N3O14 requires
M, 755.2901); λmax(CH2Cl2)/nm 343, 294 and 227; νmax(CH2Cl2)/
cmϪ1 3400, 1740, 1700, 1600 and 1180; δH(CDCl3, 400 MHz)
2.26 and 2.29 (each 3 H, s, C-Me), 2.57, 2.93, 2.97 and 3.03
(each 2 H, t, J 7) and 2.61–2.64 (4 H, m, 3 × CH2CH2), 3.47
(4 H, s, 2 × CH2CO2), 3.67 (2 H, s, CH2CO2), 3.61, 3.63, 3.63,
3.68, 3.68 and 3.77 (each 3 H, s, OMe) and 9.63 (2 H, br s,
2 × NH); δC(CDCl3, 100.57 MHz, some peaks obscured by
background noise) 11.63 and 11.84 (CMe), 19.96, 20.60, 20.80,
29.56, 29.67, 30.16, 34.45 and 34.53 (CH2), 51.53, 51.59, 52.03
and 52.44 (OMe), 107.90, 115.98, 120.12, 126.68, 131.80 and
8 A. R. Battersby, M. H. Block, C. J. R. Fookes, P. J. Harrison,
G. B. Henderson and F. J. Leeper, J. Chem. Soc., Perkin Trans. 1,
1992, 2175.
9 B. Harrell and A. H. Corwin, J. Am. Chem. Soc., 1956, 78, 3135.
10 W. M. Stark, C. J. Hawker, G. J. Hart, A. Philippides, P. M. Petersen,
J. D. Lewis, F. J. Leeper and A. R. Battersby, J. Chem. Soc., Perkin
Trans. 1, 1993, 2875; W. M. Stark, G. J. Hart and A. R. Battersby,
J. Chem. Soc., Chem. Commun., 1986, 465.
11 A. M. van Leusen, J. Wildeman and O. H. Oldenziel, J. Org. Chem.,
1977, 42, 1153.
12 J. A. Ballentine, A. H. Jackson, G. W. Kenner and G. McGillivray,
Tetrahedron, Suppl. 7, 1966, 241.
13 W. M. Stark, M. G. Baker, F. J. Leeper, P. R. Raithby and A. R.
Battersby, J. Chem. Soc., Perkin Trans. 1, 1988, 1187.
14 P. S. Clezy and G. A. Smythe, Aust. J. Chem., 1969, 22, 239.
15 A. P. Kozikowski and A. Ames, J. Am. Chem. Soc., 1980, 102, 860.
16 C. J. Hawker, A. Philippides and A. R. Battersby, J. Chem. Soc.,
Perkin Trans. 1, 1991, 1833.
17 H. J. Reich and M. L. Cohen, J. Org. Chem., 1979, 44, 3148.
Paper 7/08134K
Received 11th November 1997
Accepted 12th January 1998
139.47 (C᎐C); m/z (FD) 755 (Mϩ, 100%).
᎐
1530
J. Chem. Soc., Perkin Trans. 1, 1998