Biosynthesis of porphyrins and related macrocycles. Part 47. Synthesis and chemistry of 2H-pyrroles (pyrrolenines) related to the proposed spiro-intermediate for porphyrin biosynthesis

Article abstract of DOI:10.1039/a708132d

It is proposed that the biosynthesis of uroporphyrinogen III 3, the parent precursor of the natural porphyrins, chlorins and corrins, involves a pyrrolenine 2 as a key intermediate, yet methods for the synthesis of such systems are not available. Novel routes for the synthesis of pyrrolenines by desulfurisation of unsaturated thiolactams have now been devised and the chemistry of such compounds has been explored. Enzymic experiments are carried out using a model pyrrolenine indicating that deletion of one of the pyrrole rings of the putative intermediate 2 leads to loss of tight binding.

Full text of DOI:10.1039/a708132d

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Biosynthesis of porphyrins and related macrocycles. Part 47.1,2
Synthesis and chemistry of 2H-pyrroles (pyrrolenines) related to
the proposed spiro-intermediate for porphyrin biosynthesis
Craig J. Hawker, W. Marshall Stark, Alan C. Spivey, Paul R. Raithby,
Finian J. Leeper and Alan R. Battersby*
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
It is proposed that the biosynthesis of uroporphyrinogen III 3, the parent precursor of the natural
porphyrins, chlorins and corrins, involves a pyrrolenine 2 as a key intermediate, yet methods for
the synthesis of such systems are not available. Novel routes for the synthesis of pyrrolenines by
desulfurisation of unsaturated thiolactams have now been devised and the chemistry of such
compounds has been explored. Enzymic experiments are carried out using a model pyrrolenine
indicating that deletion of one of the pyrrole rings of the putative intermediate 2 leads to loss of
tight binding.
Uroporphyrinogen III synthase (E.C. 4.2.1.75), usually called
cosynthetase, catalyses the conversion of hydroxymethylbilane
1 into uroporphyrinogen III 3, shortened to uro’gen III. This
macrocycle is the parent from which haem, chlorophyll and
vitamin B12 are all biosynthesised and much interest has centred
on the mechanism of its formation. Intriguingly, the cyclisation
of hydroxymethylbilane 1 to produce uro’gen III 3 is accom-
panied by a rearrangement which leads to inversion of ring D in
the product 3. Extensive earlier studies have been made both
of the biosynthesis of hydroxymethylbilane 1 and of its ring-
closure by cosynthetase; this work has been reviewed.3 Of cen-
tral importance for the present paper was the discovery4,5 that
the inversion of ring D occurs by an intramolecular mechanism
that only involves ring D of the bilane 1. An attractive sequence
for this inversion involves the spiro-pyrrolenine 2 as a key
intermediate, Scheme 1. Such pyrrolylmethylpyrrolenines are
known6 to undergo the indicated fragmentation and this step
could be followed by formation of a new carbon᎐carbon bond
as illustrated. This proposed mechanism is based on a sugges-
tion by Mathewson and Corwin,7 as shown in Scheme 1 in a
simplified form.
The intermediacy of the spiro-pyrrolenine 2 for the bio-
synthesis of uro’gen III 3 was given strong support by syn-
thesis8 of the racemic spirolactam 4 and the finding that it
RP
AR
P
A
RA
PR
A
P
P
A
B
NH
HN
HN
NH
NH
HN
HN
RA
D
C
AR
A
RP
NH
PR
A
P
O
Spirolactam 4 R = H
5 R = Me
Uro'gen I 6
A
R = CH2CO2R, PR = CH2CH2CO2R
A
P
A
P
P
A
P
P
A
A
A
B
A
B
inhibits strongly the action of cosynthetase in cyclising
hydroxymethylbilane 1 to uro’gen III 3. This support was
further strengthened by preparing both enantiomers of the
spirolactam 4 and demonstrating that one enantiomer com-
petitively inhibits cosynthetase over twenty times more strongly
than the other.9 Finally, the strongly inhibiting enantiomer of 4
has been shown10 to have the R-configuration and therefore, if
the spiro-intermediate 2 is in fact formed in the enzymic pro-
cess, the evidence points to its absolute configuration also being
R, as illustrated in Scheme 1.
HN
HN
NH
HN
HN
NH
HO
NH
D
C
C
A
A
D
P
16
N
15
A
P
P
H+
Spiro-pyrrolenine 2
Hydroxymethylbilane 1
Cosynthetase
A synthesis of the spiro-pyrrolenine 2 itself, even as a racem-
ate, would allow a decisive test of the mechanism in Scheme 1,
since cosynthetase should convert one enantiomer of the syn-
thetic product into uro’gen III 3 without formation of any
significant amount of uro’gen I 6. In contrast, non-enzymic
rearrangement of 2 would be expected to yield a mixture of the
type III 3 and type I 6 isomers (see the second in this series of
four papers11). An earlier paper6 described our first experi-
ments aimed at developing chemistry necessary for the syn-
thesis of 2. The central problem was to devise routes to what
were expected to be rather labile pyrrolylmethylpyrrolenines
and bis(pyrrolylmethyl)pyrrolenines exemplified by the ring
A–ring D–ring C system of 2. In that earlier paper6 the
pyrrolenine ring of a model pyrrolenine was built up by conju-
gate addition of a nitro alkane to an acetylenic ester, followed
P
A
P
P
A
A
A
P
A
A
P
A
B
C
NH
NH
HN
HN
NH
NH
HN
+
HN
D
A
A
P
P
P
Uro'gen III 3
A = CH2CO2H, P = CH2CH2CO2H
Scheme 1 Mechanism proposed for the production of uro’gen III by
cosynthetase; some 13C-labelling experiments which established the
intramolecular rearrangement4 are illustrated by the black spots and
squares
J. Chem. Soc., Perkin Trans. 1, 1998
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by reduction of the ester and nitro groups and cyclisation. This
route does not permit substituents at C-4 of the pyrrolenine.
Although a methyl group at C-4 was introduced in a round-
about fashion by alkylation of an enolate, such chemistry
would clearly be incompatible with the ester side-chains
required for the synthesis of 2. Furthermore, we were keen to
exploit the coupling of iodopyrroles with acetoxymethyl-
pyrroles to give 2-(pyrrolylmethyl)-5-halopyrrolenines (e.g.
11 ϩ 12→13, Scheme 3), which has been so successful in the
formation of mono- and bis-(pyrrolylmethyl)lactams, culmin-
ating in the synthesis of spirolactam 4.8 The present paper
describes how these 2,2,3,4-tetra-substituted pyrrolenines can
be constructed and also some studies of their chemistry.
was obtained, albeit in 19% yield, by changing the Lewis acid
catalyst for the reaction of 11 with 12 to boron trifluoride.
Sufficient iodo derivative 14 was obtained to allow it to be
photolysed in the presence of triphenyltin hydride but the
major product, 59%, was the pyrrole 2712 together with a small
amount of the α-free pyrrole13 25. These arise either by the
cationic fragmentation pathway (e.g. see Scheme 8; also fully
exemplified in the following paper11), with reduction of the
intermediate azafulvene by triphenyltin hydride, or by an
analogous process involving radicals. Essentially the same
result was obtained when the iodo derivative 14 was heated with
triphenyltin hydride and a catalytic amount of 2,2Ј-azobis-
isobutyronitrile (AIBN).
The phenylseleno group has been widely used for the gener-
ation of radicals14 and so attention now focused on the
selenopyrrolenine 16, Scheme 3. Despite the lack of reactivity
of chloropyrrolenine 13 towards iodide ion, we expected that
displacement of chloride by selenophenol or its anion might be
successful. It was also important to develop a way to prepare
chloropyrrolenines e.g. 13, from lactams, e.g. 21, since the final
application of any reductive method would be to the spiro-
lactam ester 5.
Results and discussion
Exploration of radical and other methods to reduce 5-substituted
pyrrolenines
Our first approach to 5-unsubstituted mono- and bis-
(pyrrolylmethyl)pyrrolenines 10, Scheme 2, was by reduction of
Lactam 21 had been synthesised earlier8 from pyrroles 11
and 12, as in Scheme 3. An improved procedure described for a
close relative10 has now doubled the yield of 21 from the earlier
ca. 30% to 62%. The best conversion of lactam 21 into the
chloropyrrolenine 13 was by treatment with phosgene15 but
importantly with 4-dimethylaminopyridine (DMAP) in place
of the originally used pyridine; use of triphosgene rather than
phosgene gave identical results and was experimentally prefer-
able. The reaction was not straightforward in that three com-
pounds were formed in differing amounts depending on the
conditions. All three materials were unstable but could be
separated under argon for spectroscopic characterisation. The
rapidly formed kinetic product appeared to be the enolised
N-chloroformyl lactam 24, the second product was thought to
be the O-chloroformyl derivative 15, and the chloropyrrolenine
13 only predominated after heating at reflux in CH2Cl2. The
presence of an N-chloroformyl species was supported by the
results of attempted reductions of the crude reaction mixture
with ZnBH4; reaction for 3 h followed by aqueous work-up gave
the N-methyl lactam 22, 44%, whereas reaction for 12 h fol-
lowed by treatment with acetic acid gave the N-methyl dihydro-
pyrrole 23, 25%.
Treatment of chloropyrrolenine 13 (prepared from lactam 21
using phosgene) with selenophenol (prepared by reduction of
diphenyl diselenide)16 or with thiophenol gave the phenyl-
selenopyrrolenine 16, 92%, and the sulfur analogue 17, 81%,
respectively. Interestingly, these reactions occurred more
rapidly and were higher yielding if no base (triethylamine) was
added, presumably because the initial addition step is catalysed
by protonation of the pyrrolenine nitrogen by the two phenols
under the non-basic conditions.
Irradiation of the phenylseleno compound 16 in benzene
with triphenyltin hydride or heating it at reflux in benzene with
AIBN and either triphenyltin hydride or tributyltin hydride
gave the same two products, pyrroles 26 and 27, in good yield.
Again these had been formed by fragmentation followed by
reduction.
Strictly analogous steps to those just described were also
carried out in the dipyrrolic series on lactam 288 (Scheme 4).
The chloropyrrolenine 30 was derived from it using phosgene
and reacted with selenophenol to give the phenyl selenide 31 in
low yield (34%) because the now familiar fragmentation also
occurred. One of the products of this competing process was
the phenylselenomethylpyrrole17 33 but the analogue 34 that
would arise by the alternative fragmentation was not formed,
no doubt due to the significant electron-withdrawing effect of
the tribromoethyl group.
MeA
MeP
MeA
MeP
MeA
MeP
MeA
MeP
–X•
H•
NH
N
N
N
•
O
X
H
7
8
9
10
AMe = CH2CO2Me, PMe = CH2CH2CO2Me,
Scheme 2
5-substituted pyrrolenines 8 (X = I or PhSe), derived from
lactams 7. It was hoped that generation of radicals 9 with
quenching by hydrogen abstraction might afford the desired
pyrrolenines.
When the reaction of acetoxymethylpyrrole 11 with iodo-
pyrrole 12 is catalysed by stannic chloride,8 the product is
mainly the chloropyrrolenine 13 with lesser amounts of the
iodide 14, Scheme 3. The iodo analogue 14 was the preferred
MeA
PMe
CO2Bn
11
AMe
MeP
MeP
CO2Bn
NH
CO2Bn
NH
MeA
MeA
N
H
AcO
iii
iv
i
MeA
MeP
MeA
MeP
+
or ii
MeP
I
Me
Me
N
NR
Me
X
N
H
X
12
21 X = O, R = H
22 X = O, R = Me
23 X = H,H, R = Me
13 X = Cl
14 X = I
15 X = OCOCl
16 X = SePh
17 X = SPh
v
18 X = OMe
19 X = OCH2p-C6H4NO2
20 X = OCH2p-C6H4Br
MeP
vi
CO2Bn
MeA
NH
Me
MeP
MeA
Me
AMe
Me
PMe
CO2Bn
MeO2C
MeP
+
X
N
H
N
H
N
O
HO
25 X = H
26 X = SePh
27
Cl
24
Scheme 3 Reagents: i, SnCl4; ii, BF3; iii, AgOAc, H3Oϩ or SmI2, THF,
H2O; iv, COCl2 or triphosgene; v, PhSeH (or PhSH); vi, Ph3SnH, AIBN
(or hν)
material for radical generation yet under none of the wide
variety of conditions tested was it possible to displace chloride
from 13 by iodide. The rather unstable iodopyrrolenine 14
The same chemistry was also performed on lactam 29 which
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J. Chem. Soc., Perkin Trans. 1, 1998

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allow selective reduction using Raney nickel18 or some similar
MeP
MeP
CO2R
NH
CO2R
NH
reagent. Alternatively alkylation of the sulfur atom might be
used to increase the reactivity of the thiolactam towards differ-
ent reducing agents. The pyrrole rings of spiro-lactam 5, how-
ever, lack any electron-withdrawing ester groups to deactivate
them and it was necessary to test out the required chemistry on
simpler model pyrrolylmethyllactams having similarly electron-
rich pyrrole rings.
MeA
MeA
i
CO2Bn
AMe
CO2Bn
AMe
HN
HN
MeA
MeA
MeP
MeP
PMe
PMe
NH
N
O
X
We therefore explored thionation of bis(pyrrolylmethyl)-
lactams having non-deactivated α-free pyrrole group(s). Hydro-
genolysis of the previously synthesised8 lactam dibenzyl ester
35 gave the diacid 37 which was decarboxylated using trifluoro-
acetic acid (TFA), Scheme 5. The product 38 was then treated
28 R = CH2CBr3
29 R = Bn
30 R = CH2CBr3, X = Cl
31 R = CH2CBr3, X = SePh
32 R = Bn, X = SePh
ii
MeP
MeA
AMe
CO2Bn
33
PMe
CO2CH2CBr3
34
N
H
N
H
MeP
MeP
PhSe
PhSe
R
R
MeA
MeA
NH
NH
Scheme 4 Reagents: i, COCl2; ii, PhSeH
R
CO2Bn
AMe
PMe
HN
HN
MeA
MeP
MeA
MeP
PMe
only differs from isomer 35 synthesised earlier8 (Scheme 5) in
the arrangement of the side-chains on one pyrrole ring. This
change made the synthesis, described in the following paper,11
easier and more reproducible than the earlier one. The phenyl-
selenopyrrolenine 32 was prepared from lactam 29 in the usual
way but without isolation of the chloro intermediate. Similar
studies using tin hydrides to those described above for the
monopyrrolic series were also carried out briefly with the
dipyrrolic system 32 but here too, appreciable fragmentation
occurred under all conditions tested, so this work is not further
described.
AMe
NH
NH
X
X
35 R = CO2Bn, X = O
36 R = CO2Bn, X = S
37 R = CO2H, X = O
38 R = H, X = O
28 R = CO2CH2CBr3, X = O
40 R = CO2CH2CBr3, X = S
41 R = H, X = O
v,
i
iv
ii
iii
iii
X
42 R = H, X = S
X
39 R = H, X = S
S
S
S
R
S
43 R = p-C6H4OMe
44 R = SMe
P
P
45 R = S-p-C6H4Me
R
The conclusion from these experiments was that either the
desired radical is formed but the molecule then undergoes rapid
homolytic fragmentation or that heterolytic fragmentation
dominates the chemistry under the conditions used.
Reduction of the monopyrrolic chloropyrrolenine 13 under
many conditions with a wide variety of hydride and other
reducing agents was also attempted. These experiments usually
led either to recovery of starting material or only to reduction
of the side-chain ester(s). A few reactions did occur, however.
Thus treatment of the halopyrrolenine mixture 13/14 with
samarium() iodide and water gave the lactam 21, Scheme 3,
whereas treatment with lithium triethylborohydride resulted in
the formation of a boronic acid complex of 21.
We then aimed to replace the chlorine atom of 13 by another
group for further reductive experiments. It proved impossible to
displace the chlorine using methoxide or cyanide ions but the
methoxy derivative 18 was available by methylation of lactam
21 with either trimethyloxonium tetrafluoroborate (Meerwein’s
reagent), in 83% yield, or methyl iodide and silver carbonate,
75% yield. Similarly, p-nitrobenzyl bromide or p-bromo-
benzyl bromide together with silver carbonate and 18-crown-6
afforded the imino ethers 19 and 20, respectively, in yields of
71 and 62%. Earlier work6 had shown that a close analogue
of 18 lacking the acetate and propionate side chains could be
smoothly reduced with DIBAL but the use of this reducing
agent is precluded in the case of 18 by the presence of the ester
groups. Many other reducing agents were tested but again they
either left 18 unchanged or just reduced one or more of the
side-chain esters. The only exception was the high-yielding con-
version of 18 into the original lactam 21 by samarium() iodide,
with or without tributyltin hydride.
Scheme 5 Reagents: i, 43; ii, Pd/C, H2; iii, TFA; iv, 44; v, Zn, AcOH
with Lawesson’s reagent19 43 in tetrahydrofuran, conditions
that had been found to allow relatively mild conversion of 35
into the thiolactam 36. However, the bis-α-free system 38 did
not react and even more forcing conditions left it largely
unaffected; the thiolactam 39 was not produced. This may be
due to association of the two electron-rich pyrrole rings with
the lactam residue by π–π interaction and hydrogen bonding, a
phenomenon previously observed.6
One final hope for this approach was to use Davy’s reagent 44
for thionation20 since it is milder than Lawesson’s reagent 43.
Indeed, this reagent converted the closely related bis(pyrrolyl-
methyl)lactam 28 into thiolactam 40 at room temperature in
94% yield. Because of the foregoing results with 38, just one
α-free pyrrolylmethyl group was generated by removal of the
tribromoethyl group from 28 using zinc and acetic acid and
then decarboxylation of the resultant acid using TFA. The
product 41 was treated directly with 44 under the same condi-
tions as before; 42 was not formed and there was essentially
complete decomposition of the material. Thus, on the one
hand, there was insufficient reactivity for the system 38 with
two α-free pyrroles whereas, on the other hand, there was
destructive lability for the analogue 41 with one α-free pyrrole.
Synthesis of pyrrolenines
Because of the failure to thionate pyrrolylmethyl lactams hav-
ing a non-deactivated pyrrole ring, we changed to studying
thionation of systems having deactivated pyrroles, with the
thought that it might be possible to remove or use the deactivat-
ing groups at a later stage and further steps would then allow
formation of the macrocycle. Our initial studies were performed
on the more readily available monopyrrolic lactams before we
progressed to dipyrrolic systems.
Lactam 21 was smoothly converted into the thiolactam 46
using Lawesson’s reagent (Scheme 6), which clearly demon-
strates the difference that the deactivating ester groups can
make. An alternative procedure for the preparation of this thio-
lactam was found to be treatment of halopyrrolenine mixture
13/14 with H2S. Desulfurisation of thiolactam 46 with Raney
Exploration of the thionation route
The obvious and apparently simple way to prepare the spiro-
pyrrolenine 2 would be to reduce the spiro-lactam ester 5, fol-
lowed by a final hydrolysis step. Clearly the reduction of the
lactam would have to be effected in the presence of the eight
more reactive ester groups and therefore some means of acti-
vation of the lactam would be required. We thought that con-
version of a lactam into the corresponding thiolactam might
J. Chem. Soc., Perkin Trans. 1, 1998
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MeA
MeA
MeA
MeP
MeP
CO2CH2CBr3
NH
53
CO2R
NH
CO2R
MeP
MeP
MeP
CO2Bn
NH
CO2Bn
NH
MeA
MeA
21
i
NH
AcO
i
iv
MeA
MeP
MeA
MeP
ii
MeA
MeP
MeA
MeP
+
13/14
Me
Me
N
Me
Me
NH
NH
N
12
SMe
X
X
X
iii
54 R = CH2CBr3, X = O
55 R = CH2CBr3, X = S
56 R = H, X = S
57 R = CH2CBr3
58 R = H
46 X = S
48 X = SMe
ii
iii
iii
v
iv
iv or v
47 X = H,H
49 X = H
MeP
R
MeA
MeP
R
AMe
Me
MeP
MeP
vii
NH
CO2Bn
CO2Bn
NH
MeA
MeA
N
H
NH
v
MeA
MeP
CO2Bn
R1
CO2Bn
R1
v
HN
HN
25 R = H
MeA
MeP
MeA
MeP
Me
N
OMe
59 R = CHO
60 R = CH=S
61 R = CO2H
62 R = SMe
ii
iv or vi
R2
R2
NH
N
viii
63 R = CO2H
64 R = H
36 R1 = PMe, R2 = AMe
50 R1 = AMe, R2 = PMe
51 R1 = PMe, R2 = AMe
52 R1 = AMe, R2 = PMe
S
vii
Scheme 7 Reagents: i, SnCl4 then AgOAc, H3Oϩ; ii, 43; iii, Zn, AcOH;
Scheme 6 Reagents: i, 43; ii, H2S; iii, TMOF, TFA; iv, Raney nickel; v,
nickel boride
iv, TFA, TMOF; v, TFA; vi, DMF, POCl3; vii, TsOH; viii, KI3,
(NH2)2C᎐S then KOH, MeI
᎐
nickel, or more reproducibly with nickel boride,21 then yielded
the desired pyrrolenine 49, 45%. Alternatively, methylation of
the thiolactam with trimethyl orthoformate (TMOF) and tri-
fluoroacetic acid (TFA) afforded the thioimino ether 48,
95%, which was desulfurised using Raney nickel yielding the
pyrrolenine 49, 41%. When nickel boride replaced Raney nickel
in the foregoing experiment, the yield of 49 was only 10–16%
and a second product proved to be the amine 47. The latter
became the sole product when either 46 or 48 was treated with
nickel boride for 15–24 h, yields 51 and 37%, respectively.
The pyrrolenine 49 was reasonably stable if handled carefully
but it decomposed completely after storage for one month at
0 ЊC under argon. It was thought that an adduct of the
pyrrolenine with a nucleophile might produce a more stable
compound, amenable to further synthetic steps. However,
neither thiols, selenophenol nor cyanide could be added to
the imine residue of pyrrolenine 49 by any of the many
methods tested, including e.g. trimethylsilyl cyanide–zinc
iodide.22 Clearly the 5-position of these 2,2,3,4-substituted
pyrrolenines is strongly hindered.
acid 56. Unexpectedly, this underwent fragmentation under
standard decarboxylation–formylation conditions, TMOF and
TFA, to afford the monopyrrole 59 in 75% yield and the same
product was also formed under Vilsmeier conditions (Me2-
NCHO, POCl3). Thiolactam 56 was also broken down by TFA
alone, the major product being pyrrole 25. The two pyrroles
25 and 59 were identified by comparison with authentic sam-
ples prepared by published methods.13,23 A rationalisation of
the outcome of these reactions is shown in Scheme 8; acid-
MeA
MeA
MeA
MeP
MeP
MeP
+
NH
NH
Me
NH
Me
H+
H+
56
+
–CO2
MeA
MeP
MeA
MeP
MeP AMe
NH
NH
+
Me
HS
N
H
S
SH
In the dipyrrolic series, the synthesis of pyrrolenines was just
as successful as in the monopyrrolic series. Reduction of thio-
lactam 36 with nickel boride gave pyrrolenine 51 (46%). Similar
reduction of the isomeric thiolactam 50 to give the correspond-
ing pyrrolenine 52 (52%) is reported in the following paper.11
H+
MeP AMe
MeP AMe
MeP AMe
TFA,
TMOF
R'SH
HS
OHC
Me
Me
Me
+
or
DMF,
POCl3
N
H
N
H
N
H
H
Chemistry of thiolactams
59
25
Having established an effective route to pyrrolenines such as 49
and 51 from the corresponding thiolactams, we wished to
explore some of the chemistry that would be necessary if a
thiolactam similar to 51 were to be converted into the thio-
lactam corresponding to spirolactam 5. For this to be possible it
would be necessary to make a bis(pyrrolylmethyl)thiolactam
with a pyrrolic α-formyl group to allow attachment of the third
pyrrole ring. The chemistry was first explored in the mono-
(pyrrolylmethyl) series.
The initial approach was to make the thiolactam first and
then cleave the pyrrolic α-ester group, decarboxylate and
formylate. This demanded a different ester, as it would probably
not be possible to hydrogenolyse a benzyl group in a sulfur-
containing molecule. Because tribromoethyl ester 53 was avail-
able,8 lactam tribromoethyl ester 54, with a reversed substitu-
tion pattern on the pyrrolic ring, was synthesised as before,
Scheme 7. It was converted into the thiolactam 55 and the ester
was cleaved with zinc and acetic acid to yield the thiolactam
Scheme 8 Proposed mechanism for the formation of pyrroles 25 and
59 from thiolactam 56
catalysed decarboxylation of 56 is probably the first step, gener-
ating an undeactivated pyrrole, which upon protonation of the
sulfur atom would fragment as shown. A similar fragmentation
by a related mechanism occurred when the thioimino ether 58,
prepared from thiolactam 55 by methylation followed by reduc-
tive ester cleavage, was treated with toluene-p-sulfonic acid. The
sole product, apart from polymeric material, was the methyl-
thiopyrrole 62, 49%, identified by comparison with authentic
material synthesised24 from the acid 61,25 Scheme 7.
Surprisingly, treatment of acid 63, prepared by hydro-
genolysis of imino ether 18, with either TFA or toluene-p-
sulfonic acid gave the α-free pyrrole 64 in up to 87% yield
whereas only fragmentation was observed with the sulfur
analogue 58. This result is somewhat puzzling but does fit in
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with the greater stability of pyrrolylmethyl lactams compared
with the corresponding thiolactams.
version. For example, if the explanation offered for the lack of
reactivity of the bis-α-free pyrrole system 38 is correct (i.e. steric
hindrance from the pyrrole rings), then the spirolactam 5
should not be similarly affected because the pyrrole rings are
tied back away from the lactam. The foregoing results with the
mono-α-free pyrrole model 41 and the acid 56 forewarned of
possible problems but even the smallest chance for the prepar-
ation of the spirothiolactam 70 could not be ignored. Accord-
ingly, the spirolactam ester 5 was heated with Lawesson’s
reagent or with phosphorus pentasulfide. However the only
products, in each case after aerial oxidation, were uroporphyrin
Concurrently with the above studies in the monopyrrolic
series, analogous experiments were also tried in the dipyrrolic
series. Thus treatment of lactam 65, synthesised earlier,8 with
Lawesson’s reagent afforded the thiolactam 66, from which the
tribromoethyl group was reductively removed, Scheme 9. The
MeP
CO2Bn
NH
MeA
1
octamethyl esters, 48% yield, shown by HPLC and H NMR
CO2R
AMe
HN
MeA
MeP
spectroscopy to contain the statistical mixture of the four pos-
sible isomers, i.e. type III 72, 50%, type I, 12.5%, type II, 12.5%
and type IV, 25%. Presumably these arise, Scheme 10, by frag-
mentation analogous to that shown in Scheme 8 followed by
recyclisation and loss of sulfur (also similar to that in Scheme 8)
to give uro’gen esters of both type I and type III (only the type
III one 71 is shown). Then scrambling of the pyrrole rings at the
uro’gen stage under the acidic conditions leads to the statistical
mixture of isomers.26 Davy’s reagent 44 at room temperature
only caused slow decomposition of 5, and raising the temper-
ature simply increased the rate of decomposition. The p-tolyl
analogue27 45 left the lactam 5 unchanged up to 50 ЊC and
decomposition set in at 60 ЊC. At roughly the half-way point of
MeP
BnO2C
MeA
AMe
PMe
R
PMe
NH
N
H
N
H
X
65 R = CH2CBr3, X = O
66 R = CH2CBr3, X = S
67 R = H, X = S
i
68 R = H
69 R = I
iv
ii
iii
Scheme 9 Reagents: i, 43; ii, Zn, AcOH; iii, TsOH; iv, PtO2, H2
resultant acid 67, on treatment with acid, underwent frag-
mentation as in the simpler mono-pyrrolyl case, to yield the
dipyrromethane 68. The mechanism of its formation is clearly
analogous to that shown in Scheme 8; 68 was identified by
comparison with a standard sample prepared from iodide 6911
by hydrogenolysis.
It was clear from the foregoing experiments that, due to the
lability under acidic conditions of pyrrolylmethyl thiolactams
having an undeactivated pyrrole ring, it would not be possible
to set up the thiolactam system early in the synthesis and carry
it forward through the remaining steps necessary8 to generate
the spirothiolactam ester 70, Scheme 10.
1
the last experiment, it was shown by H NMR spectroscopy
that the undecomposed substance was unchanged starting
material.
Thus we were reluctantly forced to conclude that the route
to pyrrolylmethylpyrrolenines from lactams by thionation fol-
lowed by reduction, so successful when the pyrrole rings are
deactivated, cannot be used for synthesis of the spiro-
pyrrolenine 2 itself.
Synthesis of á-formyl- and á-cyano-pyrrolic pyrrolenines
Finally, in view of the fact that the the spiro-pyrrolenine 2 itself
was not yet synthetically accessible, we wanted to make altern-
ative pyrrolenines in which the necessary electron-withdrawing
groups on the pyrrolic ring(s) are smaller than the benzyloxy-
carbonyl residue of 49 and 51. This was because, in addition
to studying the chemistry of pyrrolenines, a further aim was to
explore how they interacted with the enzyme, cosynthetase.
Formyl and cyano groups were chosen as being suitable for the
envisaged enzymic experiments.
AMe
PMe
MeP
MeA
HN
HN
+
NH
NH
HN
MeA
AMe
MeA
MeP
MeP
PMe
SH
AMe
NH
PMe
H+
X
5
X = O
70 X = S
+
NH
HN
As in previous cases, we initially investigated the required
chemistry in the monopyrrolic series. In view of the fragmen-
tation that occurred upon attempted decarboxylation–formyl-
ation of thiolactam acid 56, we investigated the alternative
sequence of reactions, i.e. formylation first then thionation.
Hydrogenolysis of lactam benzyl ester 21 gave the acid 73
which was treated with TMOF and TFA to afford the aldehyde
74 (Scheme 11). However, thionation using Lawesson’s reagent
converted this into a mixture of the lactam thioaldehyde 75 and
the corresponding thiolactam thioaldehyde 79. It was clear that
the monothio product was thioaldehyde 75 and not the desired
thiolactam 80 from the 1H NMR chemical shift of the aldehyde
proton, which had moved to δ 10.57 from 9.51 in the starting
aldehyde 74.
MeA
AMe
MeP
PMe
SH
MeP
AMe
RSH
MeA
PMe
NH
N
O2
N
HN
NH
HN
MeA
MeA
AMe
AMe
MeP
PMe
MeP
PMe
72 Uroporphyrin III ester
71 Uro'gen III ester
H+
O2
Since thioketones can be hydrolysed to give ketones,28 we
hoped to hydrolyse the bis-thio system 79 to the thiolactam
aldehyde 80. Trial experiments were carried out by converting
the aldehyde 59 into the thioaldehyde 60 using Lawesson’s
reagent, Scheme 7. This thioaldehyde 60 crystallised as red
rhombohedra and its structure, shown in Fig. 1, was deter-
mined by X-ray analysis.† It is monomeric in contrast to the case
Uroporphyrin I, II and IV esters
Uro'gen I, II and IV esters
Scheme 10 Proposed mechanism for the formation of uroporphyrin
octamethyl esters upon thionation of spirolactam ester 5
The alternative to early formation of the thiolactam system
was to attempt the transformation of the spirolactam ester 5
into the thiolactam 70 at the end of the synthesis; all the
experiments were carried out with racemic material. Naturally
this conversion was tried as soon as the thiolactam route to
pyrrolenines was developed, indeed before some of the studies
described above, but without success. All the experience gained
from the subsequent work led us to return to this desired con-
† The experimental details and coordinates for the crystal structure
determinations of 60 and 77 have been deposited with the Cambridge
Crystallographic Data Centre (CCDC). Deposition numbers: 60,
100546; 77, 100545.
J. Chem. Soc., Perkin Trans. 1, 1998
1497

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Fig. 2 X-Ray crystal structure of anti-O-acetyloxime 77
products, some of them inseparable. However, mass spec-
trometry showed that the mixture contained the nitrile 78 and
the acetylated oxime 77. The latter was obtained pure by frac-
tional crystallisation and an X-ray structure determination was
carried out.† Fig. 2 shows that this product is the anti-isomer,
which is understandable since the syn-isomer presumably
undergoes rapid elimination of acetic acid to give the nitrile.
This structure fully confirms all the features of this molecule
and indeed of the entire monopyrrolic series, previously
dependent on spectroscopic evidence. An alternative method
for dehydration of oximes30 (Me2NCHO and POCl3) smoothly
converted the mixture of isomeric oximes 76 into the nitrile 78
in good yield. Preparation of the corresponding thiolactam 81,
as earlier, and desulfurisation with nickel boride then readily
afforded the cyanopyrrolenine 83.
Turning to the dipyrrolic series, hydrogenolysis of the benzyl
groups of lactam 29 gave the diacid 85, which with TMOF and
TFA was converted into the required dialdehyde 86. However, it
was not possible to prepare the corresponding thiolactam
dithioaldehyde cleanly using Lawesson’s reagent and attempted
hydrolysis (as in the monopyrrolic series) of the product mix-
ture aiming to produce some of the thiolactam dialdehyde was
unsuccessful. Attention therefore turned to the dinitrile 87
which was synthesised smoothly from dialdehyde 86 by form-
ing the mixture of oximes followed by dehydration as earlier.
Further, the lactam dinitrile 87 was converted into the thio-
lactam 88 by Lawesson’s reagent ready for desulfurisation with
nickel boride. Unlike the monopyrrolic case 81→83, desulfuris-
ation generated a mixture and caused serious loss of material.
In order to obtain pure pyrrolenine 89 for the enzymic experi-
ments, purification by HPLC was needed and we had to accept
a yield of 14%.
Fig. 1 X-Ray crystal structure of thioaldehyde 60
MeP
MeP
MeP
MeA
MeA
MeA
R
R
R
NH
NH
NH
v
viii
MeA
MeP
MeA
MeP
MeA
MeP
Me
Me
Me
NH
NH
N
O
S
21 R = CO2Bn
73 R = CO2H
74 R = CHO
75 R = CH=S
79 R = CH=S
80 R = CHO
81 R = CN
82 R = CHO
83 R = CN
vii
i
ii
v
iii
R
S
R
76 R = CH=NOH
77 R = CH=NOAc
78 R = CN
vi
iv
MeA PMe
S
S
CO2Bn
84 R =
N
H
R
MeP
RP
R
CN
MeA
RA
NH
NH
R
CN
AR
HN
HN
MeA
RA
RP
AMe
MeP
PMe
PR
NH
N
X
29 R = CO2Bn, X = O
85 R = CO2H, X = O
86 R = CHO, X = O
87 R = CN, X = O
88 R = CN, X = S
89 R = Me
90 R = H
i
x
ii
ix
iii, vi
v
Enzymic studies
The plan was to hydrolyse the six ester groups of the dicyano-
pyrrolenine 89 under conditions that left the cyano and
pyrrolenine systems unaffected. These conditions were devel-
oped using the simpler monopyrrolic analogue 83, Scheme 11,
which on treatment with aqueous methanolic potassium
hydroxide gave a homogeneous solution. Part of this solution
was repeatedly evaporated and redissolved in deuterium oxide;
A
R = CH2CO2R, PR = CH2CH2CO2R
Scheme 11 Reagents: i, Pd/C, H2; ii, TFA, TMOF; iii, NH2OH; iv,
Ac2O; v, 43; vi, DMF, POCl3; vii, morpholine, H2O; viii, Raney nickel;
ix, nickel boride; x, KOH
1
studied by Baker29 which existed as the trimer 84. Presumably
the greater electron release from the pyrrole ring to the thio-
aldehyde residue in the case of 60 accounts for its greater
stability.
Thioaldehyde 60 could be hydrolysed in aqueous morpholine
to yield the starting aldehyde 59. These conditions were then
applied to the thiolactam thioaldehyde 79 and gave the thio-
lactam aldehyde 80. Desulfurisation by Raney nickel then gave
the desired formylpyrrolenine 82.
The second target in the monopyrrolic series was the nitrile
83, Scheme 11. Treatment of aldehyde 74 with hydroxylamine
yielded a mixture of syn- and anti-oximes 76 and subsequent
reaction with hot acetic anhydride then gave a mixture of
the final solution gave a 400 MHz H NMR spectrum fully
consistent with the tetrapotassium salt derived from 83. The
remainder of the hydrolysate was re-esterified using diazo-
methane to give almost pure starting material 83, together with
trace amounts of higher Rf fragmentation products. Thus, the
hydrolytic conditions met the requirements and were used to
prepare the hexapotassium salt of the acid 90 from the ester 89.
Hart studied the effect of the hexaacid 90 in buffered solution
on the rate of conversion of synthetic hydroxymethylbilane12
1
into uro’gen III 3 by purified cosynthetase31 using kinetic
experiments exactly as had been used8 to demonstrate strong
inhibition of the enzyme by the spirolactam 4. The outcome
was that, even at high concentrations (500 µmol dmϪ3), the acid
1498
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
90 had no effect on the enzymic rate and is thus not an inhibitor
of cosynthetase. This interlocks with earlier results8 which
showed that molecules lacking some part or all of the lactam
ring present in the inhibitory spirolactam 4 did not inhibit the
enzyme. The present results suggest either that the entire
macrocyclic system is also necessary for strong binding to occur
or that 90 cannot readily adopt the same conformation as that
of rings A, D and C of 4.
dichloromethane (2 cm3) was heated at reflux under argon for
1 h. The mixture was rapidly cooled in ice, filtered through a
plug of Celite and evaporated under reduced pressure to give
the crude 5-chloropyrrolenine 13 as an oil (52 mg), which was
generally used without further purification.
TLC of this material (diethyl ether–methanol, 20:1) showed
that it contained, in addition to 13, two minor components.
Their relative proportions were roughly equal after equi-
libration at room temperature for a few hours but strongly
favoured 13 after heating at reflux. The three very air- and
moisture-sensitive components were separated by PLC, eluting
with diethyl ether–methanol (20:1) in the dark under argon, to
give: (i) a compound thought to be O-chloroformylimidate 15
(Rf 0.6); δH(CDCl3, 400 MHz) 1.61 (3 H, s, 4-Me), 2.44–2.94
(8 H, 2 × CH2CH2), 2.79 and 3.41 (each 1 H, d, J 16, 5-H2), 3.44
(2 H, s, CH2CO2), 3.53 and 3.84 (each 1 H, d, J 18, CH2CO2),
3.59, 3.62, 3.63 and 3.77 (each 3 H, s, OMe), 5.17 and 5.31 (each
1 H, d, J 12.5, CH2Ph), 7.25–7.40 (5 H, m, Ph) and 10.02 (1 H,
Conclusions
The probable involvement of a 2,2-disubstituted pyrrolenine
(2H-pyrrole) in the biosynthesis of uro’gen III 3, the parent of
all the natural porphyrins, chlorins and corrins, has focused
attention on the chemistry of such systems. However, methods
for synthesis of close analogues of the proposed natural system
were not available. The novel methods described in this paper
have provided a variety of the required pyrrolenines carry-
ing one or two pyrrolylmethyl groups at the disubstituted
2-position of the 3,4-substituted pyrrolenine ring. This has
allowed extensive study of the chemistry of these systems and
also of how one example interacted with the enzyme cosyn-
thetase. It was found that whereas the spirolactam 4 strongly
inhibited cosynthetase, the open-chain pyrrolenine 90, lacking
ring B of 4, did not.
1
br s, NH); (ii) chloropyrrolenine 13 (Rf 0.8); H NMR data
identical to those previously8 reported; (iii) a compound
thought to be enolised N-chloroformyl lactam 24 (Rf 0.9);
λmax(CH2Cl2)/nm 277 and 332; νmax(CHCl3)/cmϪ1 3443, 3338,
3029, 2954, 1734, 1583, 1453 and 1175; δH(CDCl3, 400 MHz)
2.00 (3 H, s, 4-Me), 1.93–2.01 (1 H, m), 2.10–2.17 (1 H, m),
2.33–2.52 (5 H, m) and 2.86 (2 H, t, J 8, 2 × CH2CH2CO2 and
OH), 3.38 (2 H, s, CH2CO2), 3.58, 3.62, 3.64 and 3.73 (each 3 H,
s, OMe), 3.73 and 4.12 (each 1 H, d, J 15.5, 5-H2), 5.21 and 5.30
Experimental
(each 1 H, d, J 12.5, CH Ph), 5.59 (1 H, s, C᎐CHCO ), 7.33–
᎐
2
2
7.36 (5 H, m, Ph) and 8.61 (1 H, br s, NH); δC(CDCl3, 100
MHz) 19.4 and 20.7 (2 × CH2CH2CO2), 22.1 (4-Me), 29.3, 30.6,
31.6 and 34.6 (3 × CH2CO2 and C-5), 51.5, 51.9, 52.0 and 52.0
General directions
General directions are as in ref. 32. Coupling constants, J, are
quoted in Hz. For 13C NMR spectra in which the numbers
of hydrogens attached to carbons were determined, this was
achieved by heteronuclear J-resolved 2D spectra, off-resonance
decoupling or DEPT experiments.
(OMe), 66.0 (CH Ph), 78.5 (C-4), 105.7 (C᎐CHCO ), 116.6,
᎐
2
2
118.3, 125.0, 129.4, 130.5, 136.4, 136.5 and 142.5 (C᎐C), 128.3
᎐
and 128.7 (C᎐CH) and 158.7, 160.1, 166.4, 172.0, 172.4 and
᎐
173.5 (C᎐O); m/z (ϩFAB) 689 (MHϩ, 4%) and 372 (C H NO ,
᎐
20 22
6
100).
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-
bis(methoxycarbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-
1(10H)-one 21
9-Benzyloxycarbonyl-1-iodo-2,8-bis(2-methoxycarbonylethyl)-
3,7-bis(methoxycarbonylmethyl)-4-methyl-4,5-dihydrodipyrrin
14
A mixture of a solution of 3-(2-methoxycarbonylethyl)-4-
methoxycarbonylmethyl-5-methylpyrrole-2-carboxylic acid25
(25, X = CO2H) (200 mg, 0.7 mmol) in dichloromethane (10
cm3) and a solution of sodium hydrogen carbonate (119 mg, 1.4
mmol) in water (8 cm3) was stirred vigorously under argon and
an aqueous solution (7.1 cm3) of iodine (0.1 mol dmϪ3) and
potassium iodide (0.2 mol dmϪ3) was added over 5 min. The
resulting mixture was stirred for a further 2 min and then solid
sodium metabisulfite was added to destroy the excess iodine.
The organic layer was separated and the aqueous layer was
extracted with dichloromethane (3 × 15 cm3). The combined
organic layers were dried and evaporated under reduced pres-
sure to give the crude iodopyrrole 12. To this was added a
solution of acetoxymethylpyrrole 1133 (305 mg, 0.7 mmol) in
anhydrous dichloromethane (10 cm3) and the resulting solution
was cooled to Ϫ78 ЊC under argon. Stannic chloride (83 mm3,
0.7 mmol) was added dropwise and the stirring continued for
3 h, during which time the solution was allowed to warm up to
0 ЊC. The solution was then re-cooled to Ϫ78 ЊC and a solution
of samarium() iodide in THF (0.1 mol dmϪ3; 14 cm3, 1.4
mmol) was added, followed by water (100 mm3). The solution
was allowed to warm to room temperature over 1 h and then
evaporated under reduced pressure. Purification by PLC, elut-
ing with ethyl acetate–hexane (1:1) and then ethyl acetate, gave
lactam 21 as an oil (238 mg, 54%), with physical characteristics
identical to those reported.8
A solution of acetoxymethylpyrrole 1133 (75 mg, 175 µmol) and
iodopyrrole 128 (64 mg, 175 µmol) in dry dichloromethane
(3 cm3) was stirred with boron trifluoride–diethyl ether (50 mg,
175 µmol) at 0 ЊC under argon for 1 h. Saturated aqueous
sodium hydrogen carbonate (3 cm3) was added and then, after
5 min, the organic layer was separated and the aqueous layer
extracted with dichloromethane (3 × 5 cm3). The combined
organic layers were dried and evaporated under reduced pres-
sure. Purification by PLC, eluting with diethyl ether, gave
iodopyrrolenine 14 (19 mg, 13%) as a moisture-sensitive gum;
physical data were as previously8 described; m/z (FD) 736 (Mϩ,
100%).
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis-
(methoxycarbonylmethyl)-4-methyl-1-phenylseleno-4,5-dihydro-
dipyrrin 16
A solution of chloropyrrolenine 13 (400 mg, 0.62 mmol) in dry
degassed dichloromethane (10 cm3) was added under argon to
selenophenol16 (471 mg, 3.0 mmol), stirred under argon for 30
min, poured into saturated aqueous sodium carbonate (50 cm3)
and extracted with dichloromethane (4 × 25 cm3). The com-
bined extracts were dried and evaporated under reduced pres-
sure. Purification by column chromatography, eluting with
diethyl ether, gave phenylselenopyrrolenine 16 (452 mg, 95%) as
a gum (Found: Mϩ, 766.2015. C38H42N2O1080Se requires M,
766.2005); νmax(CH2Cl2)/cmϪ1 3350, 1720, 1700, 1160 and 1070;
δH(CDCl3, 400 MHz) 1.10 (3 H, s, 4-Me), 2.33 and 3.09 (each
1 H, d, J 15, 5-H2), 2.47–2.58 and 2.92–3.01 (8 H, m, 2 ×
CH2CH2), 3.30 and 3.38 (each 1 H, d, J 16, CH2CO2), 3.43 (2 H,
s, CH2CO2), 3.59, 3.62, 3.65 and 3.69 (each 3 H, s, OMe), 5.27
9-Benzyloxycarbonyl-1-chloro-2,8-bis(2-methoxycarbonylethyl)-
3,7-bis(methoxycarbonylmethyl)-4-methyl-4,5-dihydrodipyrrin
13
A suspension of triphosgene (50 mg, 160 µmol), DMAP (920
mg, 160 µmol) and lactam 21 (50 mg, 80 µmol) in anhydrous
J. Chem. Soc., Perkin Trans. 1, 1998
1499

View Article Online
(2 H, s, CH2Ph), 7.28–7.37 and 7.53–7.57 (10 H, m, 2 × Ph) and
9.94 (1 H, m, NH); δC(CDCl3, 100 MHz) 20.30, 20.58, 20.65,
29.59, 31.37, 32.44 and 32.81 (7 × CH2 and 4-Me), 51.40, 51.76,
51.89 and 52.52 (OMe), 65.38 (OCH2Ph), 83.37 (C-4), 115.28,
117.19, 125.75, 127.92, 128.04, 128.44, 128.60, 129.50, 131.19,
3.67 and 3.69 (each 3 H, s, OMe), 5.18 and 5.29 (each 1 H, d,
J 12, CH2Ph), 7.31–7.40 (5 H, m, Ph) and 10.61 (1 H, br s, NH);
δC(CDCl3, 100 MHz) 20.5 (4-Me), 19.51, 20.5, 29.56, 31.26,
31.93, 32.85 and 34.68 (7 × CH2), 51.23, 51.46, 51.73, 52.18 and
54.74 (OMe), 65.63 (OCH2Ph), 74.51 (C-4), 128.00 and 128.36
134.86, 136.55 and 138.72 (C᎐C) and 157.05, 160.33, 167.99,
(C᎐CH), 115.02, 116.74, 130.00, 131.12, 131.88 and 136.18
᎐
᎐
170.40, 172.32, 172.86 and 173.74 (C᎐O and N᎐C᎐C᎐C); m/z
(C᎐C) and 158.30, 160.26, 169.86, 170.46, 172.08, 172.98 and
᎐
᎐
᎐
᎐
(FD) 766 (Mϩ for 80Se, 100%).
173.61 (C᎐O and N᎐C᎐C᎐C); m/z (FD) 640 (Mϩ, 100%).
᎐
᎐
᎐
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-
bis(methoxycarbonylmethyl)-4-methyl-1-(4-nitrobenzyloxy)-4,5-
dihydrodipyrrin 19‡
Attempted reduction of phenylselenopyrrolenine 16
A solution of phenylselenopyrrolenine 16 (31 mg, 42 µmol) in
dry degassed toluene (5 cm3) was added dropwise via a syringe
pump to a solution of triphenyltin hydride (100 mg, 0.27 mmol)
in dry degassed toluene (10 cm3), which was being irradiated by
UV light. After 4 h the solution was evaporated under reduced
pressure. Purification by PLC, eluting with diethyl ether–hexane
(1:1), gave at lower Rf methylpyrrole 27 (13 mg, 84%), identical
with authentic material,12 and at higher Rf phenylselenopyrrole
26 (10.5 mg, 67%) (Found: Mϩ, 395.0639. C18H21NO480Se
requires M, 395.0636); νmax(CH2Cl2)/cmϪ1 3400, 2975, 1725,
1260 and 1170; δH(CDCl3, 400 MHz) 2.21 (3 H, s, C-Me), 2.45
and 2.83 (each 2 H, t, J 7, CH2CH2), 3.46 (2 H, s, CH2CO2),
3.61 and 3.68 (each 3 H, s, OMe), 7.07–7.25 (5 H, m, Ph) and
7.93 (1 H, br s, NH); m/z (FD) 395 (Mϩ for 80Se, 100%).
Reduction was also attempted by dropwise addition of 16 to
a solution of triphenyltin hydride (4 equiv.) and AIBN in reflux-
ing dry, degassed benzene. Again 27 (56%) and 26 (59%) were
isolated.
A solution of 18-crown-6 (42 mg, 0.16 mmol) in benzene (2
cm3) was stirred with silver carbonate (400 mg, 1.5 mmol) at
room temperature for 30 min and then lactam 21 (100 mg, 0.16
mmol) and p-nitrobenzyl bromide (340 mg, 1.6 mmol) were
added. The mixture was stirred overnight and then evaporated
under reduced pressure. Purification by PLC, eluting with
diethyl ether, gave imino ether 19 (37 mg, 72%) (Found: Mϩ,
761.2799. C39H43N3O13 requires M, 761.2796); δH(CDCl3, 400
MHz) 1.03 (s, 4-Me), 2.16 (1 H, d, J 15, 5-HA), 2.50–2.60 and
2.97–3.02 (9 H total, 2 × m, 2 × CH2CH2 and 5-HB), 3.41 and
3.43 (each 2 H, s, CH2CO2), 3.60, 3.62, 3.63 and 3.71 (each 3 H,
s, OMe), 5.24 and 5.31 (each 1 H, d, J 12, OCH2Ar) and 5.28
(2 H, s, OCH2Ar), 7.23–7.46 (5 H, m, Ph), 8.15 and 8.17 (each
2 H, d, Ar) and 10.41 (1 H, br s, NH); δC(CDCl3) 19.67 (4-Me),
20.57, 20.65, 29.73, 31.47, 32.18, 32.85 and 34.92 (7 × CH2),
51.44, 51.72, 51.94 and 52.46 (OMe), 65.77 (OCH2Ph), 68.16
(OCH2Ar), 75.11 (C-4), 123.76, 128.18, 128.42 and 128.58
(C᎐CH), 115.36, 117.13, 122.75, 127.02, 127.71, 130.03, 131.10,
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-
bis(methoxycarbonylmethyl)-4-methyl-1-phenylthio-4,5-
dihydrodipyrrin 17
᎐
131.93, 136.38, 143.60, 147.69 (C᎐C) and 159.38, 160.69,
᎐
169.44, 169.96, 172.22, 173.01 and 173.74 (C᎐O and N᎐C᎐
᎐
᎐
C᎐C); m/z (FD) 761 (Mϩ, 100%).
A solution of chloropyrrolenine 13 (62 mg, 96 µmol) in dry
dichloromethane (3 cm3) was stirred with thiophenol (110 mg, 1
mmol) at room temperature for 90 min, then added to saturated
aqueous sodium hydrogen carbonate (10 cm3) and extracted
with dichloromethane (3 × 10 cm3). The combined extracts
were dried and evaporated under reduced pressure. Purification
by PLC, eluting with diethyl ether, gave the phenylthiopyrrol-
enine 17 (56 mg, 81%) as a gum (Found: Mϩ, 718.2562.
C38H42N2O10S requires M, 718.2560); νmax(CH2Cl2)/cmϪ1 3300,
1720, 1700 and 1170; δH(CDCl3, 400 MHz) 1.06 (3 H, s, 4-Me),
2.28 and 3.04 (each 1 H, d, J 15, 5-H2), 2.45–2.64 and 2.90–2.99
(8 H, m, 2 × CH2CH2), 3.29 and 3.37 (each 1 H, d, J 16,
CH2CO2), 3.36 and 3.43 (each 1 H, d, J 16, CH2CO2), 3.59,
3.61, 3.66 and 3.70 (each 3 H, s, OMe), 5.24 (2 H, s, CH2Ph),
7.29–7.38 and 7.48–7.50 (10 H, m, 2 × Ph) and 9.91 (1 H, br s,
NH); δC(CDCl3, 100 MHz) 20.02, 20.26, 20.55, 29.66, 31.41,
32.56, 32.67 and 34.86 (7 × CH2 and 4-Me), 50.75, 51.28, 51.64
and 52.41 (OMe), 65.38 (OCH2Ph), 81.71 (C-4), 115.20, 117.23,
127.90, 128.34, 128.61, 129.25, 129.56, 131.40, 133.77, 136.62
᎐
9-Benzyloxycarbonyl-1-(4-bromobenzyloxy)-2,8-bis(2-methoxy-
carbonylethyl)-3,7-bis(methoxycarbonylmethyl)-4-methyl-4,5-
dihydrodipyrrin 20‡
A solution of the lactam 21 (238 mg, 0.38 mmol) in dry benzene
(4 cm3) was stirred with silver carbonate (315 mg, 1.14 mmol)
and 18-crown-6 (99 mg, 0.38 mmol) at room temperature for
1.5 h and then p-bromobenzyl bromide (946 mg, 3.8 mmol) was
added. The mixture was stirred for 3 h, then heated at reflux for
1.5 h and then evaporated under reduced pressure. Purification
by PLC, eluting with 2% methanol in diethyl ether, gave the
imino ether 20 (187 mg, 62%) as an oil (Found: Mϩ, 794.2039.
C39H4379BrN2O11 requires M, 794.2050); δH(CDCl3, 400 MHz)
1.07 (3 H, s, 4-Me), 2.22–2.25 (7 H, m), 2.68 (2 H, t, J 7) and
2.92 (1 H, d, J 15, 2 × CH2CH2 and 5-H2), 3.37–3.45 (4 H, m,
2 × CH2CO2), 3.59, 3.60, 3.60 and 3.66 (each 3 H, s, OMe), 5.01
and 5.06 (each 1 H, d, J 12, OCH2Ar), 5.22–5.26 (2 H, m,
OCH2Ar), 6.95 and 7.46 (each 2 H, d, J 8, Ar), 7.20–7.30 (5 H,
m, Ph) and 10.50 (1 H, br s, NH); m/z (FD) 794 and 796 (1:1;
Mϩ, 100%).
and 137.72 (C᎐C) and 157.49, 160.36, 169.57, 170.42, 172.35,
᎐
173.03 and 173.81 (C᎐O and N᎐C᎐C᎐C); m/z (FD) 718 (Mϩ,
᎐
᎐
᎐
100%).
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-
bis(methoxycarbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-
1(10H)-one N,NЈ-boronate
9-Benzyloxycarbonyl-1-methoxy-2,8-bis(2-methoxycarbonyl-
ethyl)-3,7-bis(methoxycarbonylmethyl)-4-methyl-4,5-dihydro-
dipyrrin 18
A solution of crude 5-chloropyrrolenine 13 (52 mg, 80 µmol;
from reaction of lactam 21 with triphosgene) in dry THF
(3 cm3) was stirred with a solution of lithium triethylboro-
hydride in THF (1.0 mol dmϪ3; 160 mm3, 160 µmol) initially at
0 ЊC and then at room temperature for 1 h. Saturated aqueous
ammonium chloride (2 cm3) and ethyl acetate (10 cm3) were
added and the organic phase was separated, dried and evapor-
ated under reduced pressure. Purification by flash chrom-
atography on silica, eluting with diethyl ether, gave the N,NЈ-
boronate of lactam 21 (28 mg, 53%) as an oil (Found: MHϩ,
653.2490. C32H37BN2O12 requires MH, 653.2518); λmax(CH2Cl2)/
A mixture of the lactam 21 (1.44 g, 2.3 mmol), trimethyloxo-
nium tetrafluoroborate (340 mg, 2.3 mmol) and 1,8-bis-
(dimethylamino)naphthalene (492 mg, 2.3 mmol) was stirred in
dry dichloromethane (20 cm3) under argon for 28 h and then
evaporated under reduced pressure. Purification on a flash
chromatography column (25 × 2 cm), eluting with diethyl ether,
gave methoxypyrrolenine 18 (1.22 g, 83%) as a gum (Found: Mϩ,
640.2634. C33H40N2O11 requires M, 640.2632); νmax(CH2Cl2)/
cmϪ1 3300, 2950, 1730s, 1690, 1450, 1380, 1250, 1170 and 1100;
δH(CDCl3, 250 MHz) 1.03 (3 H, s, 4-Me), 2.15 and 2.96 (each
1 H, d, J 15, 5-H2), 2.46–2.59 and 3.00–3.04 (8 H, m, 2 × CH2-
CH2), 3.38 and 3.44 (each 2 H, s, CH2CO2), 3.61, 3.63, 3.64,
‡ With Dr A. Philippides.
1500
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
nm 282; νmax(CHCl3)/cmϪ1 3691, 2954, 1778, 1736, 1438, 1345,
1173 and 1117; δH(CDCl3, 400 MHz) 1.23 (3 H, s, 4-Me), 2.42–
2.56 (2 H, m), 2.63 (4 H, m) and 2.71–2.87 (2 H, m,
2 × CH2CH2), 2.63 and 3.11 (each 1 H, d, J 16, 5-H2), 3.39 (2 H,
s, CH2CO2), 3.52 and 3.57 (each 1 H, d, J 16, CH2CO2), 3.60,
3.63, 3.66 and 3.74 (each 3 H, s, OMe), 5.17 and 5.43 (each 1 H,
d, J 12.5, OCH2Ph) and 7.28–7.41 (5 H, m, Ph); δC(CDCl3,
100 MHz) 19.5 and 19.9 (CH2CH2CO2), 21.8 (4-Me), 29.4,
30.9, 31.1, 31.1 and 34.5 (5 × CH2), 51.6, 51.7, 52.3 and 52.8
(OMe), 65.0 (OCH2Ph), 67.2 (C-4), 116.0, 121.6, 130.1,
(CO Bn) and 171.1, 172.3, 173.1 and 173.7 (C᎐O); m/z
᎐
2
(ϩFAB) 627 (MHϩ, 40%), 372 (C20H22NO6, 10) and 254
(100).
4-[5-Benzyloxycarbonyl-3-(2-methoxycarbonylethyl)-4-
(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-1-chloro-2,8-bis-
(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonylmethyl)-9-
(2,2,2-tribromoethoxycarbonyl)-4,5-dihydrodipyrrin 30
A stirred solution of dipyrrolic lactam 288 (250 mg, 215 µmol)
and 4-(dimethylamino)pyridine (80 mg, 650 µmol) in dry
dichloromethane (15 cm3) was treated dropwise with a solution
of phosgene (0.65 mmol) in toluene (0.5 cm3) at room temper-
ature under argon, then stirred for 2 h and the solvent evapor-
ated under a stream of argon. Purification by PLC, eluting with
diethyl ether, gave chloropyrrolenine 30 (200 mg, 86% based
on unrecovered starting material) as a water-sensitive gum;
νmax(CH2Cl2)/cmϪ1 3350, 2950, 1740, 1700, 1245 and 1150;
δH(CDCl3, 400 MHz) 2.31–2.62 (12 H, m), 3.03 (2 H, t, J 8) and
3.16 and 3.19 (each 1 H, d, J 15, 3 × CH2CH2 and CH2CCH2),
3.34 and 3.45 (each 1 H, d, J 17, CH2CO2), 3.57 (2 H, s,
CH2CO2), 3.58, 3.60, 3.60, 3.62, 3.63 and 3.79 (each 3 H, s,
OMe), 3.71 and 3.80 (each 1 H, d, J 17, CH2CO2), 5.01 and 5.13
(each 1 H, d, J 12, OCH2CBr3), 5.21 and 5.29 (each 1 H, d, J 12,
OCH2Ph), 7.30–7.41 (5 H, m, Ph) and 9.80 and 10.10 (each 1 H,
br s, NH); δC(CDCl3, 100 MHz) 19.01, 20.05, 20.27, 29.28,
29.66, 30.21, 30.42, 31.39, 31.52, 34.68, 34.83 and 36.72 (11 ×
CH2 and CBr3), 51.39, 51.53, 51.75, 51.92 and 53.09 (OMe),
65.59 (OCH2Ph), 76.49 (OCH2CBr3), 83.38 (C-4), 116.07,
116.34, 118.29, 122.04, 122.33, 127.84, 130.49, 131.20, 136.11
134.4, 135.8, 141.3 and 153.7 (C᎐C), 128.2, 128.5 and 128.6
᎐
(C᎐CH), 160.8 (CO Bn), 162.2, 166.8, 170.8, 173.1 and 173.2
᎐
᎐
2
(C᎐O); m/z (ϩFAB) 653 (MHϩ, 55%) and 545 (MH Ϫ BnOH,
100).
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis-
(methoxycarbonylmethyl)-4,10-dimethyl-4,5-dihydrodipyrrin-
1(10H)-one 22
A solution of crude 5-chloropyrrolenine 13 (60 mg, 90 µmol;
produced, as described above, by the action of triphosgene on
lactam 21) in dry THF (2 cm3) was stirred with a solution of
zinc borohydride34 in diethyl ether (0.14 mol dmϪ3; 1.32 cm3,
180 µmol) at room temperature for 3 h. Saturated aqueous
ammonium chloride (1 cm3) was added and the phases were
separated. The organic phase was dried and evaporated under
reduced pressure. Purification by flash chromatography on
silica, eluting with diethyl ether–methanol (20:1), gave N-
methyl lactam 22 (27 mg, 44%) as an oil (Found: MHϩ,
641.2715. C33H40N2O11 requires MH, 641.2710); λmax(CH2Cl2)/
nm 277; νmax(CHCl3)/cmϪ1 3319, 2954, 2930, 1731, 1689, 1438,
1252 and 1174; δH(CDCl3, 400 MHz) 1.30 (3 H, s, 4-Me), 2.33–
3.01 (11 H, 2 × CH2CH2, 2 × CHAHBCO2 and 5-HAHB), 2.68
(3 H, s, NMe), 3.30 (1 H, d, J 19.5, CHAHBCO2), 3.37 (1 H, d,
J 18, CHAHBCO2), 3.50 (1 H, d, J 16, 5-HAHB), 3.59, 3.60, 3.64
and 3.69 (each 3 H, s, OMe), 5.17 and 5.33 (each 1 H, d, J 12.5,
OCH2Ph), 7.25–7.42 (5 H, m, Ph) and 9.70 (1 H, br s, NH);
δC(CDCl3, 100 MHz) 20.1 and 20.4 (2 × CH2CH2CO2), 22.4
(4-Me), 24.5, 29.7, 29.8, 30.4, 31.0 and 34.5 (5 × CH2 and
NMe), 51.4, 51.6, 52.1 and 52.9 (OMe), 65.7 (OCH2Ph), 66.1
and 138.80 (C᎐C) and 158.10, 160.11, 161.81, 170.82, 171.12,
᎐
172.12, 172.45, 173.39 and 173.47 (C᎐O and C᎐N); m/z (FD)
᎐
᎐
1173, 1175, 1177, 1179 and 1181 (Mϩ, 100%).
4-[5-Benzyloxycarbonyl-3-(2-methoxycarbonylethyl)-4-
(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-2,8-bis(2-methoxy-
carbonylethyl)-3,7-bis(methoxycarbonylmethyl)-1-phenyl-
seleno-9-(2,2,2-tribromoethoxycarbonyl)-4,5-dihydrodipyrrin 31
A solution of chloropyrrolenine 30 (210 mg, 178 µmol) in dry
degassed dichloromethane (5 cm3) was stirred with a solution
of selenophenol16 (314 mg, 2.0 mmol) in dichloromethane
(3 cm3) at room temperature under argon for 30 min, then
added to saturated aqueous sodium hydrogen carbonate (20
cm3) and extracted with dichloromethane (4 × 15 cm3). The
combined extracts were dried and evaporated under reduced
pressure. Purification by PLC, eluting with diethyl ether, gave
phenylselenopyrrolenine 31 (78 mg, 34%) as a gum (Found: C,
47.7; H, 4.55; N, 3.3. C52H56Br3N3O16Se requires C, 48.1; H,
4.35; N, 3.25%); νmax(CH2Cl2)/cmϪ1 3300, 1715, 1695, 1160 and
1070; δH(CDCl3, 400 MHz) 2.28–2.58 (14 H, m, 3 × CH2CH2
and CHAHBCCHAHB), 3.09–3.17 (6 H, m, 2 × CH2CO2 and
CHAHBCCHAHB), 3.53, 3.58, 3.62 and 3.76 (18 H, 4 × s,
6 × OMe), 3.66 and 3.82 (each 1 H, d, J 17, CH2CO2), 5.07 and
5.12 (each 1 H, d, J 12, CH2CBr3), 5.22 and 5.28 (each 1 H, d,
J 12, CH2Ph), 7.26–7.37 and 7.41–7.43 (10 H, m, 2 × Ph) and
9.67 and 9.96 (each 1 H, br s, NH); δC(CDCl3, 100 MHz) 18.98,
20.43, 20.55, 29.19, 30.08, 30.33, 30.61, 31.07, 32.22, 34.83,
35.00 (11 × CH2), 51.39, 51.49, 51.72, 53.02 (OMe), 65.41
(OCH2Ph), 76.68 (OCH2CBr3), 85.72 (C-4), 115.88, 116.09,
118.17, 121.73, 122.07, 127.93, 128.10, 128.35, 129.00, 129.65,
(C-4), 128.0 and 128.4 (C᎐CH), 115.2, 116.4, 128.2, 129.8,
᎐
136.2, 136.5 and 146.5 (C᎐C), 160.1 (CO Bn) and 169.3, 171.1,
᎐
᎐
2
172.1, 173.6 and 173.8 (C᎐O); m/z (ϩFAB) 641 (Mϩ, 40%) and
372 (C20H22NO6, 100).
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis-
(methoxycarbonylmethyl)-4,10-dimethyl-1,4,5,10-tetrahydro-
dipyrrin 23
A solution of crude 5-chloropyrrolenine 13 (140 mg, 0.2 mmol;
produced, as described above, by the action of triphosgene on
lactam 21) in dry THF (2.5 cm3) was stirred with a solution of
zinc borohydride34 in diethyl ether (0.15 mol dmϪ3; 1.45 cm3, 0.2
mmol) at room temperature for 12 h, then cooled to 0 ЊC.
Glacial acetic acid (0.5 cm3) was dripped in over a period of 30
min, then saturated aqueous disodium EDTA (1 cm3) was
added and the phases were separated. The organic phase was
dried and evaporated under reduced pressure. Purification by
PLC, eluting with ethyl acetate, gave N-methyl amine 23 (37 mg,
25%) as an oil; λmax(CH2Cl2)/nm 281; νmax(CHCl3)/cmϪ1 3030,
2953, 1732, 1696, 1437, 1248 and 1171; δH(CDCl3, 400 MHz)
0.96 (3 H, s, 4-Me), 2.18–2.34 and 2.49–2.62 (each 4 H, m,
2 × CH2CH2), 2.30 (3 H, s, NMe), 2.66 and 2.88 (each 1 H, d,
J 16), 2.86–2.91 and 3.00–3.04 (each 1 H, m), 3.19, 3.37 and
3.43 (each 1 H, d, J 13) and 3.50–3.63 (1 H, obscured, 4 × CH2),
3.50, 3.57, 3.60 and 3.63 (each 3 H, s, OMe), 5.18 and 5.24
(each 1 H, d, J 12.5, CH2Ph), 7.30–7.39 (5 H, m, Ph) and 11.02
(1 H, br s, NH); δC(CDCl3, 100 MHz) 18.5 (4-Me), 20.4 and
22.4 (CH2CH2CO2), 29.4, 29.9, 30.6, 31.7 and 38.7 (5 × CH2),
34.8 (NMe), 51.4, 51.6, 52.0 and 52.0 (OMe), 59.9 (CH2N),
65.4 (OCH2Ph), 71.6 (C-4), 113.5, 116.4, 129.4, 132.6, 133.1,
136.2 and 136.4 (C᎐C), 128.0, 128.1 and 128.4 (C᎐CH), 160.3
130.53, 131.46, 135.32, 136.36, 141.50 and 154.90 (C᎐C) and
᎐
158.53, 160.15, 171.28, 171.86, 172.11, 172.57, 173.30 and
173.54 (C᎐O and C᎐N); m/z (FD) 1295, 1296, 1297, 1298, 1299,
᎐
᎐
1300, 1301, 1302, 1303 and 1304 (ratio 4:11:5:14:12:20:14:
9:7:4, Mϩ, 100%).
9-Benzyloxycarbonyl-4-[5-benzyloxycarbonyl-3-(2-methoxy-
carbonylethyl)-4-(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-
2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonyl-
methyl)-1-phenylseleno-4,5-dihydrodipyrrin 32
Dipyrrolic lactam 2911 (80 mg, 80 µmol) was reacted with phos-
᎐
᎐
J. Chem. Soc., Perkin Trans. 1, 1998
1501

View Article Online
gene, as described above for the synthesis of 30, followed by
selenophenol, as described above for the synthesis of 31. Purifi-
cation by PLC, eluting with methanol–diethyl ether (1:40), gave
the phenylselenopyrrolenine 32 (42 mg, 49%) as a gum (Found:
Mϩ, 1123.3248. C57H61N3O1680Se requires M, 1123.3217);
νmax(CH2Cl2)/cmϪ1 3300, 1715, 1700, 1170 and 1065; δH(CDCl3,
400 MHz) 2.26–2.35, 2.40–2.52 and 2.80–3.22 (18 H, m,
3 × CH2CH2, CH2CCH2 and CH2CO2), 3.47 (2 H, s, CH2CO2),
3.53, 3.54, 3.57, 3.59, 3.61 and 3.70 (each 3 H, s, OMe), 3.65 and
3.83 (each 1 H, d, J 17, CH2CO2), 5.22 and 5.28 (each 1 H, d,
J 13, CH2Ph), 5.22 and 5.31 (each 1 H, d, J 13, CH2Ph), 7.27–
7.39 (15 H, m, 3 × Ph) and 9.68 and 9.71 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 19.00, 20.50, 29.20, 30.18, 30.31, 30.62,
31.07, 32.17, 34.69 and 34.84 (CH2), 51.32, 51.44, 51.68, 51.74
and 52.87 (OMe), 65.38 and 65.45 (OCH2Ph), 85.85 (C-4),
115.49, 117.16, 118.16, 121.72, 122.11, 125.00, 127.91, 128.09,
128.36, 128.38, 129.65, 129.70, 129.80, 135.34, 136.43 and
2 × α-H), 7.57 (1 H, br s, lactam-NH) and 8.75 (2 H, br s,
2 × pyrrole-NH); m/z (FD) 715 (Mϩ, 100%).
4-[5-Benzyloxycarbonyl-3-(2-methoxycarbonylethyl)-4-
(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-2,8-bis(2-methoxy-
carbonylethyl)-3,7-bis(methoxycarbonylmethyl)-9-(2,2,2-tri-
bromoethoxycarbonyl)-4,5-dihydrodipyrrin-1(10H)-thione 40
A solution of lactam 288 (120 mg, 104 µmol) and Davy’s
reagent20 44 (16.3 mg, 57 µmol) in dry 1,2-dimethoxyethane
(1 cm3) was stirred at room temperature for 20 min and then
evaporated under reduced pressure. Purification by PLC, elut-
ing with methanol–diethyl ether (1:40), gave the thiolactam 40
(114 mg, 94%) as a gum (Found: C, 47.3; H, 4.65; N, 3.55.
C46H52Br3N3O16S requires C, 47.0; H, 4.5, N, 3.6%); νmax(CH2-
Cl2)/cmϪ1 3400, 2960, 1730, 1700, 1430 and 1170; δH(CDCl3,
400 MHz) 2.46–2.58 and 2.71–2.76 (12 H, m, 3 × CH2CH2),
2.89 and 3.20 (each 1 H, d, J 15) and 3.06 and 3.12 (each 1 H,
d, J 15, CH2CCH2), 3.21 and 3.45 (each 1 H, d, J 17, CH2CO2),
3.57, 3.58, 3.59, 3.60, 3.61 and 3.81 (each 3 H, s, OMe), 3.57–
3.81 (4 H, obscured, 2 × CH2CO2), 5.04 and 5.12 (each 1 H, d,
J 12, CH2CBr3), 5.19 and 5.24 (each 1 H, d, J 12, CH2Ph), 7.27–
7.39 (5 H, m, Ph) and 9.29, 9.44 and 10.26 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 19.16, 20.34, 20.85, 29.20, 30.34, 30.54,
31.42, 31.79, 34.59 and 34.93 (CH2 and CBr3), 51.48, 51.86,
52.23, 52.53 and 53.31 (OMe), 65.64 (OCH2Ph), 73.49 (C-4)
and 76.67 (CH2CBr3), 115.62, 119.46, 122.14, 122.51, 129.53,
141.51 (C᎐C) and 154.89, 160.12, 160.18, 171.27, 171.88,
᎐
172.17, 172.60, 173.29 and 173.61 (C᎐O and C᎐N); m/z (FD)
᎐
᎐
1123 (Mϩ for 80Se, 100%).
9-Benzyloxycarbonyl-4-[5-benzyloxycarbonyl-4-(2-methoxy-
carbonylethyl)-3-(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-
2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonyl-
methyl)-4,5-dihydrodipyrrin-1(10H)-thione 36
A solution of lactam 358 (52 mg, 53 µmol) in benzene (3 cm3)
was heated at reflux with Lawesson’s reagent (12 mg, 29 µmol)
under argon for 45 min and then evaporated under reduced
pressure. Purification on a column of silica gel PF254 (5 × 1 cm),
eluting with dichloromethane and then diethyl ether, gave thio-
lactam 36 (43 mg, 81%) as an oil (Found: Mϩ, 999.3428.
C51H57N3O16S requires M, 999.3459); λmax(EtOH)/nm 281;
νmax(CHCl3)/cmϪ1 3430, 3300, 2950, 1720s, 1690, 1570, 1435,
1180 and 1075; δH(CDCl3, 400 MHz) 2.45–2.51 (8 H, m) and
2.89–3.01 (4 H, m, 3 × CH2CH2), 2.82 and 3.06 (each 2 H, d,
J 15, 2 × 4-CH2), 3.32 and 3.50 (each 2 H, d, J 17, CH2CO2),
3.49 (2 H, s, CH2CO2), 3.55 and 3.72 (each 3 H, s, OMe), 3.60
and 3.64 (each 6 H, s, 2 × OMe), 5.20 and 5.27 (each 2 H, d,
J 12, CH2Ph), 7.28–7.39 (10 H, m, Ph), 9.46 (1 H, br s, NH) and
9.62 (2 H, br s, NH); δC(CDCl3, 100.57 MHz, DEPT) 20.68
(3 C), 29.61 (2 C), 31.01 (3 C), 31.67 and 34.64 (2 C, CH2), 51.45
(2 C), 52.27 (2 C) and 52.99 (1 C, OMe), 66.00 (2 × OCH2),
74.16 (C-4), 115.90, 118.33, 128.90 (br) and 130.24 (each 2 C,
pyrrole-C), 128.00, 128.15 and 128.40 (phenyl-CH), 135.98
131.11, 135.25, 144.07 and 147.29 (C᎐C), 160.16, 161.99,
᎐
171.70, 171.78, 171.95, 172.05 and 173.70 (C᎐O) and 197.73
᎐
(C᎐S); m/z (FD) 1171, 1173, 1175, 1177 (1:3:3:1, Mϩ, 100%).
᎐
4-[5-Benzyloxycarbonyl-3-(2-methoxycarbonylethyl)-4-
(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-2,8-bis(2-methoxy-
carbonylethyl)-3,7-bis(methoxycarbonylmethyl)-4,5-dihydro-
dipyrrin-1(10H)-one 41
A solution of tribromoethyl ester 288 (100 mg, 86 µmol) in
glacial acetic acid (2 cm3) was stirred with zinc dust (200 mg)
under argon at room temperature for 20 min and then filtered.
The filtrate was added to aqueous sodium carbonate (15 cm3)
and extracted with dichloromethane (4 × 10 cm3). The com-
bined extracts were dried and evaporated under reduced pres-
sure. A solution of the residue in freshly distilled trifluoroacetic
acid (1 cm3) was stirred at room temperature under argon
for 7 h, then poured into water (20 cm3) and extracted with
dichloromethane (4 × 15 cm3). The combined extracts were
dried and evaporated under reduced pressure. Purification by
PLC, eluting with 5% methanol in diethyl ether, gave the α-free
pyrrolic lactam 41 (62 mg, 85%) as a foam (Found: C, 60.8; H,
6.0; N, 4.8. C43H51N3O15 requires C, 60.8; H, 6.05; N, 4.9%);
νmax(CH2Cl2)/cmϪ1 3400, 2950, 1720, 1685, 1435 and 1175;
δH(CDCl3, 400 MHz) 2.39–2.50 (8 H, m) and 2.63–2.68 (4 H, m,
3 × CH2CH2), 2.74 and 3.11 (each 1 H, d, J 15) and 2.81 and
2.99 (each 1 H, d, J 15, CH2CCH2), 3.20 and 3.38 (each 1 H, d,
J 16, CH2CO2), 3.47 and 3.55 (each 1 H, d, J 16, CH2CO2), 3.57,
3.59, 3.60, 3.63, 3.64 and 3.77 (each 3 H, s, 6 × OMe), 3.57–3.77
(2 H, obscured, CH2CO2), 5.17 and 5.27 (each 1 H, d, J 12,
CH2Ph), 6.34 (1 H, d, J 2, α-H), 7.28–7.38 (5 H, m, Ph)
and 7.41, 8.91 and 9.54 (each 1 H, br s, NH); δC(CDCl3, 100
MHz) 19.14, 19.62, 20.61, 29.80, 30.43, 30.59, 30.74, 31.62,
34.69 and 34.74 (CH2), 51.45, 51.54, 51.75, 52.04 and 52.95
(OMe), 65.68 and 66.68 (C-4 and OCH2Ph), 112.25, 114.61,
118.99, 120.87, 121.87, 122.28, 123.25, 127.98, 128.19, 128.33,
(phenyl-C), 143.23 and 147.84 (C᎐C), 160.65 (2 C), 171.05,
᎐
172.80 (2 C), 173.44 and 173.57 (2 C, C᎐O) and 197.50 (C᎐S);
᎐
᎐
m/z (FD) 999 (Mϩ, 100%).
4-[4-(2-Methoxycarbonylethyl)-3-(methoxycarbonylmethyl)-
pyrrol-2-ylmethyl]-2,8-bis(2-methoxycarbonylethyl)-3,7-bis-
(methoxycarbonylmethyl)-4,5-dihydrodipyrrin-1(10H)-one 38
A solution of lactam dibenzyl ester 358 (100 mg) in methanol
(5 cm3) was stirred with 10% palladium-on-charcoal (10 mg)
under an atmosphere of hydrogen until uptake of gas ceased
(45 min), then filtered through Celite and evaporated. A solu-
tion of the residue in trifluoroacetic acid (5 cm3) was allowed to
stand for 7 h at room temperature under argon, then added to
water (50 cm3) and extracted with dichloromethane (3 × 10
cm3). The extract was washed with 5% aqueous sodium hydro-
gen carbonate (30 cm3), dried and evaporated. Purification on a
short column of silica gel PF254 (5 × 2.5 cm diam.), eluting
with diethyl ether–methanol (19:1), gave lactam 38 (59 mg,
81%) as a gum (Found: Mϩ, 715.2950. C35H45N3O13 requires M,
715.2952); λmax end absorption only; νmax(CHCl3)/cmϪ1 3450,
3350br, 2950, 1720, 1685, 1440, 1175 and 1010; δH(CDCl3, 400
MHz) 2.41 and 2.46 (each 2 H, m, 2-CH2CH2), 2.49 and 2.66
(each 4 H, m, 2 × CH2CH2CO2), 2.72 and 2.95 (each 2 H,
d, J 15, CH2CCH2), 3.25 and 3.38 (each 2 H, d, J 16, 2 ×
CH2CO2), 3.48 (2 H, s, 3-CH2), 3.62 and 3.79 (each 3 H, s,
OMe), 3.64 and 3.66 (each 6 H, s, 2 × OMe), 6.33 (2 H, d, J 3,
136.00, 137.21 and 149.83 (C᎐C) and 160.48, 171.86, 172.38,
᎐
173.29, 173.40, 173.51 and 173.62 (C᎐O); m/z (FD) 849 (Mϩ,
᎐
100%).
General procedure for the conversion of lactams into thiolactams
A solution of the lactam (0.44 mmol) in dry benzene (24 cm3)
was heated at reflux under argon with Lawesson’s reagent (95
mg, 0.23 mmol) for 45 min and then evaporated under reduced
pressure. Purification by chromatography gave the thiolactam.
1502
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-
bis(methoxycarbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-
1(10H)-thione 46
requires M, 612.2683); νmax(CH2Cl2)/cmϪ1 3280, 2940, 1740s,
1700, 1450, 1260, 1160 and 1090; δH(CDCl3, 250 MHz) 1.16
(3 H, s, 4-Me), 2.29–2.36 (4 H, m) and 2.51 and 2.99 (each 2 H,
t, J 7, 2 × CH2CH2), 2.48 and 2.58 (each 1 H, d, J 15, 5-H2),
3.09–3.15 (3 H, m, CH2CO2 and NCHAHB), 3.37 and 3.49 (each
1 H, d, J 16, CH2CO2), 3.52 (1 H, d, J 15, NCHAHB), 3.59, 3.61,
3.64 and 3.65 (each 3 H, s, OMe), 5.21 and 5.32 (each 1 H, d,
J 12, CH2Ph), 7.27–7.42 (5 H, m, Ph) and 10.74 (1 H, br s,
pyrrole-NH); δC(CDCl3, 100 MHz) 20.38 (4-Me), 22.33, 25.74,
29.33, 29.97, 31.56, 33.86 and 34.61 (CH2), 50.82, 51.09, 51.37
and 51.72 (OMe), 53.07 (C-2), 65.15 (PhCH2), 70.88 (C-4),
Method A. Lactam 21 was reacted with Lawesson’s reagent
according to the above general procedure. Purification by flash
chromatography, eluting with diethyl ether, gave thiolactam 46
(72%) which crystallised from aqueous methanol, mp 114–
116 ЊC (Found: C, 60.2; H, 6.2; N, 4.3%; Mϩ, 642.2251. C32H38-
N2O10S requires C, 59.8; H, 6.0; N, 4.35%; M, 642.2247);
νmax(CH2Cl2)/cmϪ1 3300, 2950, 1740s, 1710, 1680, 1585, 1490,
1450, 1200 and 1065; δH(CDCl3, 250 MHz) 1.38 (3 H, s, 4-Me),
2.45–2.60 (6 H, m) and 2.68–2.80 (2 H, m, 2 × CH2CH2), 2.81
and 3.00 (each 1 H, d, J 15, 5-H2), 3.32 and 3.70 (each 1 H, d,
J 17, CH2CO2), 3.35 and 3.58 (each 1 H, d, J 17, CH2CO2), 3.59,
3.62, 3.71 and 3.77 (each 3 H, s, OMe), 5.19 and 5.30 (each 1 H,
d, J 12, CH2Ph), 7.27–7.41 (5 H, m, Ph) and 9.13 and 10.17
(each 1 H, br s, NH); δC(CDCl3, 62.5 MHz) 22.43 (4-Me), 20.47,
20.53, 29.75, 31.92, 31.98, 32.72 and 34.73 (CH2), 51.29, 51.39,
52.56 and 52.80 (OMe), 65.75 (PhCH2), 70.86 (C-4), 127.90,
128.11 and 128.34 (phenyl-CH), 115.12, 118.24, 128.80, 130.00,
136.12 and 149.95 (C᎐C), 160.53, 170.94 and 173.55 (C᎐O) and
114.80, 116.93, 132.44, 132.55, 136.43 and 138.99 (C᎐C),
᎐
127.65, 128.15 and 129.60 (C᎐CH) and 160.28, 171.75, 172.03,
᎐
172.74 and 173.23 (C᎐O); m/z (FD) 612 (Mϩ, 100%).
᎐
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-
bis(methoxycarbonylmethyl)-4-methyl-1-methylthio-4,5-
dihydrodipyrrin 48
Thiolactam 46 (375 mg, 0.584 mmol) was dissolved in redis-
tilled trifluoroacetic acid (10 cm3) and distilled trimethyl ortho-
formate (10 cm3) was immediately added. The solution was
stirred in the dark under argon for 30 min and then evaporated
under reduced pressure. The residue was twice dissolved in
dichloromethane (20 cm3) and evaporated under reduced pres-
sure and then purified by flash chromatography (40 × 2.5 cm),
eluting with diethyl ether, to give the thioimidate 48 (365 mg,
95%) as a gum (Found: Mϩ, 656.2404. C33H40N2O10S requires
M, 656.2403); νmax(CH2Cl2)/cmϪ1 3300, 2950, 1720s, 1690, 1440,
1190 and 1075; δH(CDCl3, 400 MHz) 1.05 (3 H, s, 4-Me), 2.28
(3 H, s, S-Me), 2.30 and 2.99 (each 1 H, d, J 15, 5-H2), 2.53–2.58
and 2.98–3.00 (8 H, m, 2 × CH2CH2), 3.39 and 3.44 (each 2 H,
s, CH2CO2), 3.61, 3.64, 3.64 and 3.69 (each 3 H, s, OMe), 5.22
and 5.29 (each 1 H, d, J 12, CH2Ph), 7.33–7.40 (5 H, m, Ph) and
10.67 (1 H, br s, NH); δC(CDCl3, 62.5 MHz) 12.75 (SMe), 19.9
(4-Me), 19.9, 20.55, 29.70, 31.42, 32.55, 32.77 and 34.81 (CH2),
51.21, 51.54, 51.72 and 52.19 (OMe), 65.70 (CH2Ph), 81.40
᎐
᎐
196.52 (C᎐S); m/z (FD) 642 (Mϩ, 100%).
᎐
Method B. Dichloromethane (3 cm3) at 0 ЊC was saturated
with hydrogen sulfide and then stirred with a solution of the
halopyrrolenines 13/14 (36 mg, 50 µmol) in dichloromethane
(2 cm3) for 1 h at room temperature. The solvent was evaporated
in a stream of nitrogen. Purification by chromatography gave
the thiolactam 46 (25 mg, 80%).
General procedure for desulfurisation with nickel boride
A stirred solution of nickel() chloride hexahydrate (1.19 g,
5 mmol) and boric acid (4.0 g) in methanol (70 ml) was cooled
in ice and a solution of sodium borohydride (380 mg, 10 mmol)
in water (5 ml) was added over 1 min. After 5 min the black
precipitate was allowed to settle and the supernatant was
decanted. The precipitate of nickel boride was washed with
methanol (3 × 20 ml) decanting excess methanol after each
washing and used immediately without drying.
(C-4), 128.08 and 128.50 (C᎐CH), 115.21, 130.22, 136.38,
᎐
136.44 and 157.82 (C᎐C) and 160.39, 169.76, 172.06, 172.74
᎐
A solution of the thiolactam (0.2 mmol) in methanol (6 cm3)
and acetic acid (0.6 cm3) was added to a suspension of the
above nickel boride in methanol (15 cm3). The mixture was
stirred under hydrogen at room temperature for 30 min, then
filtered, washing the residue with methanol (15 cm3). The fil-
trate was mixed with 5% aqueous sodium hydrogen carbonate
(200 cm3), and extracted with dichloromethane (4 × 50 cm3).
The combined extracts were dried, evaporated under reduced
pressure and purified by chromatography as described.
and 173.61 (C᎐O and C-2); m/z (FD) 656 (Mϩ, 100%).
᎐
9-Benzyloxycarbonyl-4-[5-benzyloxycarbonyl-4-(2-methoxy-
carbonylethyl)-3-(methoxycarbonylmethyl)pyrrol-2-ylmethyl]-
2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxycarbonyl-
methyl)-4,5-dihydrodipyrrin 51
Thiolactam 36 was reduced with nickel boride following the
general procedure described above. Purification by PLC, eluting
with diethyl ether–methanol (19:1), gave pyrrolenine 51 (33 mg,
46%) as a gum; λmax(EtOH)/nm 281; νmax(CHCl3) 3420, 3320,
2950, 1725, 1685, 1445, 1435, 1255, 1175 and 1080; δH(CDCl3,
400 MHz) 2.33 (2 H, m), 2.48 (6 H, m) and 2.87–3.00 (4 H,
m, 3 × CH2CH2), 2.40 and 3.10 (each 2 H, d, J 15, 2 × 4-CH2),
3.32 and 3.37 (each 2 H, d, J 16, 2 × CH2CO2), 3.45 (2 H, s,
CH2CO2), 3.58 and 3.59 (each 6 H, s, 2 × OMe), 3.58 and 3.71
(each 3 H, s, OMe), 5.26 and 5.30 (each 2 H, d, J 12, CH2Ph),
7.30–7.42 (10 H, m, 2 × Ph), 7.80 (1 H, s, 2-H) and 10.03 (2 H,
br s, NH); δC(CDCl3, 100.57 MHz) 20.60, 20.65 (2 C), 29.56
(2 C), 30.14, 31.13, 32.42 (2 C) and 34.92 (2 C, CH2), 51.50
(2 C), 51.87, 51.98 (2 C) and 52.99 (OMe), 65.71 (2 × OCH2),
86.13 (C-4), 115.62, 117.37, 129.85 and 130.11 (each 2 C,
pyrrole-C), 128.14, 128.34, 128.57 and 136.48 (2 × Ph), 140.47
9-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis-
(methoxycarbonylmethyl)-4-methyl-4,5-dihydrodipyrrin 49
The thiolactam 46 was reduced with nickel boride according to
the general procedure above. Purification by PLC, eluting with
ethanol–diethyl ether (1:9), gave pyrrolenine 49 (45%) as a gum
(Found: Mϩ, 610.2535. C32H38N2O10 requires M, 610.2527);
νmax(CH2Cl2)/cmϪ1 3320, 2960, 2850, 1730s, 1700, 1430, 1210
and 1160; δH(CDCl3, 400 MHz) 1.10 (3 H, s, 4-Me), 2.23 and
3.10 (each 1 H, d, J 15, 5-H2), 2.46–2.53 and 2.96–3.02 (6 H, m)
and 2.61 (2 H, t, J 7, 2 × CH2CH2), 3.37 and 3.47 (each 1 H, d,
J 17, CH2CO2), 3.38 and 3.48 (each 1 H, d, J 16, CH2CO2), 3.60,
3.64 and 3.69 (12 H, each s, 4 × OMe), 5.23 and 5.32 (each 1 H,
d, J 12, CH2Ph), 7.30–7.42 (5 H, m, Ph), 7.92 (1 H, s, 2-H) and
10.20 (1 H, br s, NH); δC(CDCl3, 100 MHz) 19.60 (4-Me),
20.43, 20.53, 29.61, 31.12, 32.15, 32.68 and 34.72 (CH2), 51.23,
51.61, 51.76 and 52.29 (OMe), 65.46 (PhCH2), 83.30 (C-4),
and 156.04 (C᎐C), 166.33 (C-2) and 160.42 (2 C), 171.36, 172.42
᎐
(2 C), 172.77 and 173.79 (2 C, C᎐O); m/z (FD) 967 (Mϩ, 100%).
᎐
2,7-Bis(2-methoxycarbonylethyl)-3,8-bis(methoxycarbonyl-
methyl)-4-methyl-9-(2,2,2-tribromoethoxycarbonyl)-4,5-
dihydrodipyrrin-1(10H)-one 54
115.22, 117.15, 129.72, 131.20, 137.41 and 157.85 (C᎐C),
᎐
127.89, 128.07 and 128.38 (C᎐CH), 160.46, 172.20 and 173.66
᎐
(C᎐O) and 164.78 (C-2); m/z (FD) 610 (Mϩ, 100%).
Iodopyrrole 12 and acetoxymethylpyrrole 538 were reacted by
the procedure described11 for the synthesis of 29 except that the
hydrolysis of the halopyrrolenines required 15 h. Purification
by flash chromatography, eluting with 0–3% ethanol in diethyl
᎐
Amine 47 (ca. 5%) was also found at lower Rf. When the
reaction time was extended to 15 h, amine 47 (51%) became
the only product isolated (Found: Mϩ, 612.2682. C32H40N2O10
J. Chem. Soc., Perkin Trans. 1, 1998
1503

View Article Online
ether, gave lactam 54 (29%) as a gum (Found: Mϩ, 797.9630.
C27H3379Br3N2O11 requires M, 797.9635); νmax(CH2Cl2)/cmϪ1
3250, 2960, 1720s, 1430, 1210 and 1040; δH(CDCl3, 400 MHz)
1.40 (3 H, s, 4-Me), 2.46–2.67 (6 H, m) and 2.72 (2 H, t, J 7,
2 × CH2CH2), 2.78 and 3.14 (each 1 H, d, J 15, 5-H2), 3.36 and
3.72 (each 1 H, d, J 17, CH2CO2), 3.63, 3.65, 3.68 and 3.79
(each 3 H, s, OMe), 3.63–3.79 (1 H, obscured) and 4.09 (1 H, d,
J 17, CH2CO2), 4.99 and 5.13 (each 1 H, d, J 17, CH2CBr3),
6.54 (1 H, br s, lactam-NH) and 10.08 (1 H, br s, pyrrole-NH);
δC(CDCl3, 62.5 MHz) 24.27 (4-Me), 19.22, 19.82, 30.66, 30.93,
31.33, 33.29, 34.42 and 36.11 (CH2 and CBr3), 51.52, 51.85,
51.91 and 52.93 (OMe), 63.11 (C-4), 76.68 (CH2O), 117.93,
2 × CH2CH2 and 5-HA), 2.81 (3 H, s, SMe), 3.43 (1 H, d, J 15,
5-HB), 3.55 and 3.66 (each 1 H, d, J 16, CH2CO2), 3.64, 3.64,
3.65 and 3.74 (each 3 H, s, OMe), 3.74 and 3.93 (each 1 H, d,
J 17, CH2CO2), 5.02 and 5.14 (each 1 H, d, J 12, CH2CBr3) and
10.05 (1 H, br s, NH); δC(CDCl3, 100.57 MHz) 14.71 (SMe),
19.18, 19.36, 20.19, 30.54, 31.55, 31.81, 33.04, 34.91 and 36.20
(7 × CH2, 4-Me and CBr3), 51.71, 51.80, 51.89 and 52.87
(OMe), 80.10 (C-4), 118.19, 122.52, 123.34, 128.22, 136.95 and
158.59 (C᎐C) and 159.76, 168.31, 171.42, 172.14, 173.28 and
᎐
180.03 (C᎐O and C-2); m/z (FD) 828, 830, 832 and 834
᎐
(1:3:3:1, Mϩ, 100%).
122.60, 123.55, 129.96, 135.89 and 150.89 (C᎐C) and 158.78,
᎐
9-Carboxy-2,7-bis(2-methoxycarbonylethyl)-3,8-bis(methoxy-
carbonylmethyl)-4-methyl-1-methylthio-4,5-dihydrodipyrrin 58
Tribromoethyl ester 57 was cleaved using zinc and acetic acid
following the same procedure as for the preparation of 56.
Purification by PLC, eluting with 5% methanol in diethyl ether,
gave the carboxylic acid 58 (95%) as a gum (Found: Mϩ,
566.1851. C26H34N2O10S requires M, 566.1822); νmax(CH2Cl2)/
cmϪ1 3400–2700, 3300, 1730, 1650 and 1180; δH(CDC13, 400
MHz) 1.13 (3 H, s, 4-Me), 2.26 and 3.06 (each 1 H, d, J 15,
5-H2), 2.37–2.39 (2 H, m), 2.50–2.58 (4 H, m) and 2.68 (2 H, t,
J 8, 2 × CH2CH2), 2.56 (3 H, s, SMe), 3.44 (2 H, s, CH2CO2),
3.63, 3.65, 3.66 and 3.71 (each 3 H, s, OMe), 3.75 and 3.89
(each 1 H, d, J 17, CH2CO2) and 10.70 (1 H, br s, NH); m/z (FD)
566 (Mϩ, 100%).
170.82, 171.44, 171.62 and 174.07 (C᎐O); m/z (FD) 798, 800,
᎐
802 and 804 (1:3:3:1, Mϩ, 100%).
2,7-Bis(2-methoxycarbonylethyl)-3,8-bis(methoxycarbonyl-
methyl)-4-methyl-9-(2,2,2-tribromoethoxycarbonyl)-4,5-dihydro-
dipyrrin-1(10H)-thione 55
Lactam 54 was reacted with Lawesson’s reagent according to
the above general procedure. The residue was purified by flash
chromatography, eluting with diethyl ether, to give thiolactam
55 as a foam (Found: Mϩ, 813.9374. C27H3379Br3N2O10S
requires M, 813.9406); νmax(CH2Cl2)/cmϪ1 3300, 2950, 1725s,
1430, 1200 and 1160; δH(CDCl3, 400 MHz) 1.45 (3 H, s, 4-Me),
2.57–2.80 (8 H, m, 2 × CH2CH2), 2.83 and 3.24 (each 1 H, d,
J 15, 5-H2), 3.38 and 3.72 (each 1 H, d, J 17, CH2CO2), 3.64,
3.65, 3.74 and 3.79 (each 3 H, s, OMe), 3.75 and 4.08 (each 1 H,
d, J 17, CH2CO2), 5.01 and 5.11 (each 1 H, d, J 17, CH2CBr3),
8.74 (1 H, br s, thiolactam-NH) and 10.12 (1 H, br s, pyrrole-
NH); δC(CDCl3, 62.5 MHz) 23.04 (4-Me), 19.11, 21.08, 31.02,
31.92, 32.76, 34.13 and 36.17 (CH2 and CBr3), 51.51, 51.93,
52.21 and 53.02 (OMe), 70.87 (C-4), 76.74 (CH2O), 118.14,
3-(2-Methoxycarbonylethyl)-4-methoxycarbonylmethyl-5-
methyl-2-methylthiopyrrole 62
A solution of carboxylic acid 6125 (1.00 g, 3.53 mmol) and
thiourea (270 mg, 3.55 mmol) in ethanol–water (1:1; 20 cm3)
was stirred at room temperature under argon and a solution of
iodine (0.1 mol dmϪ3) in aqueous potassium iodide (0.2 mol
dmϪ3; 36 cm3) was added dropwise. After a further 30 min,
sodium hydrogen carbonate (2.0 g) was added and the mixture
was extracted with dichloromethane (4 × 15 cm3). The com-
bined extracts were washed with water (30 ml), dried and evap-
orated to dryness. Without further purification, the intermedi-
ate thiourea derivative was dissolved in methanol–water (1:1)
and sodium hydroxide (150 mg, 3.75 mmol) was added. The
solution was stirred for 30 min at room temperature under
argon and then methyl iodide was added. The solution was
stirred for 15 h and then extracted with chloroform (4 × 15
cm3). The combined extracts were washed with water (30 cm3),
dried and evaporated under reduced pressure. Purification by
PLC, eluting with diethyl ether, gave the methylthiopyrrole 62
(275 mg, 27%) as an oil (Found: Mϩ, 285.1038. C13H19NO4S
requires M, 285.1035); νmax(CH2Cl2)/cmϪ1 3450, 2940, 1730,
1435, 1300, 1270 and 1165; δH(CDCl3, 400 MHz) 2.17 and 2.21
(each 3 H, s, SMe and 5-Me), 2.53 and 2.82 (each 2 H, t, J 8,
CH2CH2), 3.38 (2 H, s, CH2CO2), 3.66 and 3.67 (each 3 H, s,
OMe) and 7.88 (1 H, br s, NH); m/z (EI) 285 (Mϩ, 100%), 238
(55), 226 (35) and 212 (55).
122.61, 123.80, 129.27, 141.96 and 149.44 (C᎐C), 158.80,
᎐
170.79, 171.52, 173.55 and 174.77 (C᎐O) and 196.55 (C᎐S);
᎐
᎐
m/z (FD) 814, 816, 818 and 820 (1:3:3:1, Mϩ, 100%).
9-Carboxy-2,7-bis(2-methoxycarbonylethyl)-3,8-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-1(10H)-thione 56
A solution of thiolactam 55 (500 mg, 0.61 mmol) in glacial
acetic acid (30 cm3) was stirred with zinc dust (1.30 g) for 20
min, then filtered, mixed with water (50 cm3) and extracted with
dichloromethane (4 × 50 cm3). The combined extracts were
washed with water (100 cm3), dried and evaporated under
reduced pressure. Purification by flash chromatography (20 × 2
cm), eluting with ethanol–diethyl ether (1:9), gave acid 56 (302
mg, 90%) as a gum (Found: Mϩ, 552.1772. C25H32N2O10S
requires M, 552.1776); νmax(CH2Cl2)/cmϪ1 3300, 3400–2700,
1730s, 1650, 1450 and 1160; δH(CDCl3, 400 MHz) 1.23 (3 H, s,
4-Me), 2.45–2.52 and 2.67–2.72 (8 H, m, 2 × CH2CH2), 2.71
and 3.19 (each 1 H, d, J 15, 5-H2), 3.52 and 3.58 (each 1 H, d,
J 16, CH2CO2), 3.64, 3.64, 3.68 and 3.74 (each 3 H, s, OMe),
3.83 (2 H, s, CH2CO2) and 9.99 and 10.49 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 20.70 (4-Me), 19.37, 20.92, 30.94, 31.42,
32.11, 32.31 and 34.69 (CH2), 51.65, 51.82, 52.12, 52.73 (OMe),
72.09 (C-4), 119.42, 123.13, 123.98, 129.66, 140.35, 151.99
9-Carboxy-1-methoxy-2,8-bis(2-methoxycarbonylethyl)-3,7-
bis(methoxycarbonylmethyl)-4-methyl-4,5-dihydrodipyrrin 63
A solution of benzyl ester 18 (126 mg, 197 µmol) in methanol
(10 cm3) was stirred with 10% palladium-on-charcoal (20 mg)
under hydrogen until uptake of gas ceased (ca. 1.5 h), then
filtered and evaporated under reduced pressure. Purification
by PLC, eluting with 5% ethanol in diethyl ether, gave acid 63
(94 mg, 87%) as a gum (Found: Mϩ, 550.2149. C26H34N2O11
requires M, 550.2163); νmax(CH2Cl2)/cmϪ1 3400–2400, 2940,
1730, 1660, 1435, 1260 and 1170; δH(CDCl3, 400 MHz) 1.11
(3 H, s, 4-Me), 2.30 and 3.02 (each 1 H, d, J 15, 5-H2), 2.44–2.61
(6 H, m) and 2.99–3.03 (2 H, m, 2 × CH2CH2), 3.40 (2 H, s,
CH2CO2), 3.42 and 3.47 (each 1 H, d, J 17, CH2CO2), 3.63,
3.63, 3.64, 3.70 and 3.95 (each 3 H, s, OMe) and 10.54 (1 H, br
s, NH); m/z (FD) 550 (Mϩ, 100%).
(C᎐C), 164.35, 169.83, 172.55 and 173.64 (C᎐O) and 196.19
᎐
᎐
᎐
(C᎐S); m/z (FD) 552 (Mϩ, 100%).
2,7-Bis(2-methoxycarbonylethyl)-3,8-bis(methoxycarbonyl-
methyl)-4-methyl-1-methylthio-9-(2,2,2-tribromoethoxy-
carbonyl)-4,5-dihydrodipyrrin 57
Thiolactam 55 was treated with trifluoroacetic acid and tri-
methyl orthoformate according to the procedure described
above for the synthesis of 48. Purification by flash chrom-
atography, eluting with diethyl ether, gave thioimidate 57 (92%)
as a gum (Found: Mϩ, 827.9551. C28H3579Br3N2O10S requires
M, 827.9562); νmax(CH2Cl2)/cmϪ1 3350, 2970, 1725 and 1180;
δH(CDCl3, 400 MHz) 1.50 (3 H, s, 4-Me), 2.27–2.63 (9 H, m,
1504
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
1-Methoxy-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin 64
aqueous layer was further extracted with dichloromethane
(3 × 10 cm3). The combined organic layers were dried and
evaporated under reduced pressure. Purification by PLC, elut-
ing with diethyl ether, gave the α-free dipyrromethane 68 (62
mg, 67%) as a light-sensitive gum (Found: Mϩ, 596.2351.
C31H36N2O10 requires M, 596.2370); νmax(CH2Cl2)/cmϪ1 3350,
2950, 1730, 1690, 1430, 1250 and 1170; δH(CDCl3, 400 MHz)
2.47–2.53 (4 H, m), 2.72 (2 H, t, J 8) and 3.00 (2 H, t, J 8,
2 × CH2CH2), 3.49 and 3.64 (each 2 H, s, CH2CO2), 3.57, 3.57,
3.60 and 3.74 (each 3 H, s, OMe), 3.79 (2 H, s, 5-H2), 5.23 (2 H,
s, CH2Ph), 6.42 (1 H, d, J 2, 9-H), 7.26–7.40 (5 H, m, Ph) and
9.35 and 10.20 (each 1 H, br s, NH); m/z (FD) 596 (Mϩ, 100%).
A solution of carboxylic acid 63 (77 mg, 0.14 mmol) in dry
dichloromethane (5 cm3) was stirred with toluene-p-sulfonic
acid (39 mg, 0.21 mmol) under argon at room temperature for
24 h, then washed with water (3 × 5 cm3), dried and evaporated
under reduced pressure. Purification by PLC, eluting with 10%
ethanol in diethyl ether, gave the methoxypyrrolenine 64 (62 mg,
88%) as a gum (Found: Mϩ, 506.2354. C25H34N2O9 requires M,
506.2264); νmax(CH2Cl2)/cmϪ1 3400, 2950, 1725s, 1680, 1440,
1265 and 1165; δH(CDCl3, 250 MHz) 1.02 (3 H, s, 4-Me), 2.18
and 2.96 (each 1 H, d, J 15, 5-H2), 2.41–2.57 and 2.70–2.76
(8 H, m, 2 × CH2CH2), 3.37 (4 H, s, 2 × CH2CO2), 3.62, 3.62,
3.63, 3.68 and 3.90 (each 3 H, s, OMe), 6.41 (1 H, d, J 2, 9-H)
and 9.44 (1 H, br s, NH); m/z (FD) 506 (Mϩ, 100%).
9-Carboxy-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-1(10H)-one 73
A solution of benzyl ester 21 (3.95 g, 6.31 mmol) in methanol
(50 cm3) was stirred with 10% palladium-on-charcoal (100 mg)
in the dark under hydrogen until uptake of gas ceased (4 h),
then filtered through Celite, washing with methanol (20 cm3),
and evaporated under reduced pressure to give the acid 73 (2.80
g, 83%), mp 177–178 ЊC (from methanol) (Found: C, 55.8; H,
6.0; N, 5.1. C25H32N2O11 requires C, 56.0; H, 6.0; N, 5.2%);
νmax(CH2Cl2)/cmϪ1 3300, 3200–2400, 2950, 1730s, 1680 and
1420; δH(CDCl3, 250 MHz) 1.01 (3 H, s, 4-Me), 2.59–2.64
and 3.04–3.07 (8 H, m, 2 × CH2CH2), 2.35 and 3.17 (each 1 H,
d, J 15, 5-H2), 3.47 (2 H, s, CH2CO2), 3.47 and 3.55 (each 1 H,
d, J 16, CH2CO2), 3.62, 3.64, 3.65 and 3.72 (each 3 H, s, OMe)
and 9.45 and 10.30 (each 1 H, br s, NH); δC(CDCl3, 62.5 MHz)
19.99 (4-Me), 19.56, 20.72, 30.01, 31.01, 31.57, 34.23 and 34.77
(CH2), 51.33, 51.54, 51.94 and 52.50 (OMe), 65.01 (C-4),
9-Benzyloxycarbonyl-4-[3-(2-methoxycarbonylethyl)-4-methoxy-
carbonylmethyl-5-(2,2,2-tribromoethoxycarbonyl)pyrrol-2-yl-
methyl]-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4,5-dihydrodipyrrin-1(10H)-thione 66
Lactam 658 was reacted with Lawesson’s reagent as described
in the general procedure above. Purification by flash chrom-
atography, eluting with 2% ethanol in diethyl ether, gave thio-
lactam 66 (71%) as a gum (Found: C, 47.1; H, 4.5; N, 3.5.
C46H52Br3N3O16S requires C, 47.0; H, 4.5; N, 3.6%); νmax
-
(CH2Cl2)/cmϪ1 3440, 3300, 2960, 1730s, 1700, 1430, 1250 and
1170; δH(CDCl3, 400 MHz) 2.44–2.52 (9 H, m), 2.68–2.72 (2 H,
m) and 2.89–2.94 (2 H, m, 4-CHAHB and 2 × CH2CH2), 2.91
and 3.11 (each 1 H, d, J 15, 4-CH2), 3.24 (1 H, d, J 15,
4-CHAHB), 3.41 (1 H, d, J 17, CHAHBCO2), 3.58, 3.58, 3.64,
3.65, 3.70 and 3.74 (each 3 H, s, OMe), 3.58–3.74 (3 H,
obscured, CHAHBCO2 and CH2CO2), 3.87 and 3.90 (each 1 H,
d, J 17, CH2CO2), 5.00–5.03 (2 H, m, CH2CBr3), 5.18 and 5.26
(each 1 H, d, J 12, CH2Ph), 7.27–7.37 (5 H, m, Ph) and 9.35,
10.00 and 10.20 (each 1 H, br s, NH); δC(CDCl3, 100 MHz)
19.15, 20.62, 29.26, 29.52, 29.58, 30.68, 30.92, 31.00, 31.18,
31.51, 34.50, 34.61 and 35.93 (CH2 and CBr3), 51.93, 51.48,
51.77, 51.93, 52.42 and 53.03 (OMe), 66.06 (CH2Ph), 73.99 and
76.76 (C-4 and OCH2CBr3), 115.63, 118.11, 118.33, 122.72,
117.42, 120.34, 129.92, 130.90, 133.86 and 154.67 (C᎐C) and
᎐
165.44, 169.34, 171.95, 173.16, 173.71 and 174.25 (C᎐O);
᎐
m/z (FD) 536 (Mϩ, 100%).
9-Formyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-1(10H)-one 74
A solution of carboxylic acid 73 (950 mg, 1.77 mmol) in redis-
tilled trifluoroacetic acid (20 cm3) under argon in the dark was
stirred at room temperature for 75 min, then cooled to 0 ЊC and
treated with trimethyl orthoformate (20 cm3). After a further 40
min at 0 ЊC the solution was poured into 10% aqueous sodium
carbonate (200 cm3) and extracted with dichloromethane
(4 × 75 cm3). The combined extracts were dried and evaporated
under reduced pressure. Purification by flash chromatography
(25 × 2 cm), eluting with 0–4% ethanol in diethyl ether, gave
aldehyde 74 (664 mg, 72%), which crystallised from dichloro-
methane–diethyl ether, mp 84–85 ЊC (Found: C, 57.4; H, 6.45;
123.54, 128.79, 130.10, 135.82, 143.41 and 147.56 (C᎐C),
᎐
127.94, 128.09 and 128.32 (phenyl-CH), 158.52, 171.49, 173.36,
173.46 and 173.54 (C᎐O) and 197.40 (C᎐S); m/z (FD) 1171, 1173,
᎐
᎐
1175 and 1177 (1:3:3:1, Mϩ, 100%).
Acid-catalysed fragmentation of the thiolactam acid 67 derived
from tribromoethyl ester 66
A solution of the tribromoethyl ester 66 (126 mg, 0.107 mmol)
in acetic acid (3 cm3) was stirred with zinc dust (260 mg) for
20 min and then filtered. The filtrate was diluted with water
(10 cm3) and extracted with dichloromethane (5 × 10 cm3). The
combined extracts were washed with water (2 × 10 cm3), dried
and evaporated under reduced pressure. Purification by PLC,
using methanol–diethyl ether (3:17), gave the acid 67 (87 mg,
89%); m/z (FD) 909.
A solution of acid 67 (50 mg) in dry dichloromethane (5 ml)
was stirred at room temperature with toluene-p-sulfonic acid
(13.6 mg) under argon in the dark for 20 h. TLC then showed
essentially one product in addition to baseline material. The
product was isolated by PLC, eluting with ethanol–diethyl ether
(1:9), and identified as the dipyrromethane 68 by comparison
with an authentic sample synthesised as below.
N, 5.1. C25H32N2O10 requires C, 57.7; H, 6.2; N, 5.4%); νmax
-
(CH2Cl2)/cmϪ1 3300, 2950, 1740s, 1690, 1440 and 1100;
δH(CDCl3, 250 MHz) 1.31 (3 H, s, 4-Me), 2.49–2.57 (6 H, m)
and 2.99 (2 H, t, J 8, 2 × CH2CH2), 2.76 and 3.05 (each 1 H, d,
J 15, 5-H2), 3.37 and 3.49 (each 1 H, d, J 16, CH2CO2), 3.40 and
3.58 (each 1 H, d, J 17, CH2CO2), 3.63, 3.72 and 3.77 (12 H,
each s, 4 × OMe), 7.41 (1 H, br s, lactam-NH), 9.51 (1 H, s,
CHO) and 10.62 (1 H, br s, pyrrole-NH); δC(CDCl3, 62.5 MHz)
23.25 (4-Me), 19.25, 19.67, 29.65, 30.74, 31.37, 33.85 and 35.77
(CH2), 51.46, 51.52, 52.27 and 52.66 (OMe), 63.44 (C-4),
116.15, 128.75, 133.39, 133.85, 135.38 and 151.36 (C᎐C),
᎐
170.39, 171.69, 172.50, 172.78 and 173.39 (C᎐O) and 177.38
᎐
(CHO); m/z (FD) 520 (Mϩ, 100%).
Reaction of formyl lactam 74 with Lawesson’s reagent
1-Benzyloxycarbonyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis-
(methoxycarbonylmethyl)dipyrromethane 68
Formyl lactam 74 (27 mg, 52 µmol) was reacted with Law-
esson’s reagent following the general procedure described
above. The residue was purified by PLC, eluting with ethanol–
ether (1:9), to give two higher Rf compounds: (i) at lower Rf,
thioformyl lactam 75 (15 mg, 53%) as an oil; νmax(CH2Cl2)/cmϪ1
3300, 2950, 1735s, 1700, 1440 and 1150; δH(CDCl3, 250 MHz)
1.38 (3 H, s, 4-Me), 2.46–2.60 (6 H, m) and 2.97 (2 H, t, J 7,
2 × CH2CH2), 2.81 and 3.00 (each 1 H, d, J 15, 5-H2), 3.33 and
A solution of iodide 6911 (112 mg, 155 µmol) in methanol
(10 cm3) was stirred with Adams catalyst (10 mg) and sodium
acetate (100 mg) under hydrogen until uptake of gas ceased (ca.
2 h). The catalyst was then filtered off and the filtrate evapor-
ated under reduced pressure. The residue was partitioned
between dichloromethane (20 cm3) and water (20 cm3) and the
J. Chem. Soc., Perkin Trans. 1, 1998
1505

View Article Online
3.70 (each 1 H, d, J 17, CH2CO2), 3.38 and 3.54 (each 1 H, d,
J 16, CH2CO2), 3.64, 3.75 and 3.80 (12 H, each s, 4 × OMe),
7.15 (1 H, br s, lactam-NH), 10.21 (1 H, br s, pyrrole-NH) and
10.57 (1 H, s, CHS); m/z (FD) 536 (Mϩ, 100%); (ii) at higher Rf,
thioformyl thiolactam 79 (7 mg, 24%) as a gum (Found: Mϩ,
522.1543. C25H32N2O8S2 requires M, 552.1600); νmax(CH2Cl2)/
cmϪ1 3250, 2950, 1730s, 1450, 1300, 1140 and 990; δH(CDCl3,
250 MHz) 1.43 (3 H, s, 4-Me), 2.49–2.82 and 2.93–2.98 (8 H, m,
2 × CH2CH2), 2.87 and 3.03 (each 1 H, d, J 15, 5-H2), 3.34 and
3.58 (each 1 H, d, J 17, CH2CO2), 3.39 and 3.79 (each 1 H, d,
J 16, CH2CO2), 3.65, 3.81 and 3.82 (12 H, each s, 4 × OMe),
9.03 and 10.23 (each 1 H, br s, NH) and 10.60 (1 H, s, CHS);
m/z (FD) 552 (Mϩ, 100%).
400 MHz) 1.09 (3 H, s, 4-Me), 2.21 and 3.14 (each 1 H, d, J 15,
5-H2), 2.48–2.52 and 2.56–2.65 (8 H, m, 2 × CH2CH2), 3.39 and
3.45 (each 1 H, d, J 16, CH2CO2), 3.43 and 3.48 (each 1 H, d,
J 16, CH2CO2), 3.64, 3.65, 3.67 and 3.73 (each 3 H, s, OMe),
7.94 (1 H, s, 2-H), 9.56 (1 H, s, CHO) and 10.44 (1 H, br s, NH);
m/z (FD) 504 (Mϩ, 100%).
9-Cyano-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-1(10H)-one 78
A solution of formyl lactam 74 (191 mg, 0.367 mmol) in
methanol (10 cm3) was treated with hydroxylamine hydro-
chloride (45 mg, 0.65 mmol), sodium acetate (54 mg, 0.66
mmol) and water (10 drops), heated at reflux under argon for 45
min and then evaporated under reduced pressure. The residue
was partitioned between dichloromethane (20 cm3) and water
(20 cm3) and the aqueous layer was extracted with dichloro-
methane (3 × 20 cm3). The combined organic layers were dried
and evaporated under reduced pressure to give crude oximes 76.
Without further purification, the oximes 76 were dissolved in
dry acetonitrile (3 cm3) and added to a mixture of dimethyl-
formamide (71 mg, 75 µl, 0.97 mmol) and freshly distilled
phosphorus oxychloride (120 mg, 0.80 mmol) in dry
acetonitrile (2 cm3) at Ϫ23 ЊC. The solution was stirred at
Ϫ23 ЊC for 20 min and then at room temperature for 1 h,
poured into 5% aqueous sodium hydrogen carbonate (25 cm3)
and extracted with dichloromethane (4 × 20 cm3). The com-
bined extracts were dried and evaporated under reduced pres-
sure. Purification by PLC, eluting with 10% ethanol in diethyl
ether, gave the nitrile 78 (142 mg, 74%) as a gum (Found: Mϩ,
517.2065. C25H31N3O9 requires M, 517.2060); νmax(CH2Cl2)/
cmϪ1 3300, 2960, 2210, 1725s, 1690, 1435, 1100 and 1065;
δH(CDCl3, 400 MHz) 1.29 (3 H, s, 4-Me), 2.50–2.66 and 2.81–
2.85 (8 H, m, 2 × CH2CH2), 2.77 and 3.02 (each 1 H, d, J 15,
5-H2), 3.33 and 3.47 (each 1 H, d, J 16, CH2CO2), 3.40 and 3.59
(each 1 H, d, J 17, CH2CO2), 3.64, 3.65, 3.70 and 3.77 (each
3 H, s, OMe), 7.53 (1 H, br s, lactam-NH) and 10.43 (1 H, br s,
pyrrole-NH); δC(CDCl3, 100 MHz) 23.15 (4-Me), 19.53, 20.12,
29.62, 30.59, 31.15, 33.36 and 34.27 (CH2), 51.55, 51.64, 52.24
Reaction of formyl lactam 74 (114 mg, 220 µmol) with
Lawesson’s reagent (91 mg, 220 µmol) as above gave thioformyl
thiolactam 79 (51%).
3-(2-Methoxycarbonylethyl)-4-methoxycarbonylmethyl-5-
methyl-2-thioformylpyrrole 60
A solution of aldehyde 5913 (260 mg, 0.97 mmol) in dry ben-
zene (10 ml) was heated at reflux with Lawesson’s reagent (215
mg, 0.53 mmol) under argon in the dark for 45 min and then
evaporated under reduced pressure. Purification by flash chrom-
atography (20 × 2 cm), eluting with dichloromethane, gave
thioaldehyde 60 (198 mg, 72%) as red blocks, mp 112–113 ЊC
(from diethyl ether–hexane) (Found: C, 55.0; H, 6.1; N, 4.85; S,
11.3%; Mϩ, 283.0874. C13H17NO4S requires C, 55.1; H, 6.05; N,
4.9; S, 11.3%; M, 283.0878); λmax(CH2Cl2)/nm 399 (strong) and
310; νmax(CH2Cl2)/cmϪ1 3300, 2940, 1740s, 1490, 1430 and 1160;
δH(CDCl3, 400 MHz) 2.24 (3 H, s, 5-Me), 2.48 and 3.00 (each
2 H, m, CH2CH2), 3.44 (2 H, s, CH2CO2), 3.68 and 3.71 (each
3 H, s, OMe), 9.35 (1 H, br s, NH) and 10.50 (1 H, s, CHS);
δC (CDCl3, 62.5 MHz) 12.23 (5-Me), 19.60, 29.66 and 35.49
(CH2), 51.67 and 52.06 (OMe), 117.60, 133.04, 140.10 and
142.10 (pyrrole-C), 171.24 and 172.54 (C᎐O) and 194.42
᎐
(CH=S); m/z 283 (Mϩ, 100%), 250, 224, 209, 164 and 150.
9-Formyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-1(10H)-thione
80
and 52.74 (OMe), 63.63 (C-4), 98.93, 113.95, 114.36, 130.29,
᎐
132.67, 135.39 and 151.55 (C᎐C and C᎐N) and 170.74, 171.89,
᎐
᎐
172.28, 172.81 and 173.70 (C᎐O); m/z (FD) 517 (Mϩ, 100%).
A solution of thioformyl thiolactam 79 (51 mg, 92 µmol) in
dimethylformamide (2 cm3) was stirred with morpholine (2
drops) and water (10 drops) under argon in the dark for 20 h,
then evaporated under reduced pressure. Purification by PLC,
eluting with 7% ethanol in diethyl ether, gave formyl thiolactam
80 (26 mg, 53%) as a gum (Found: Mϩ, 536.1835. C25H32N2O9S
requires M, 536.1829); νmax(CH2Cl2)/cmϪ1 3300, 2950, 1730s,
1695, 1440, 1175 and 1090; δH(CDCl3, 400 MHz) 1.36 (3 H, s,
4-Me), 2.54–2.74 (6 H, m) and 3.01 (2 H, t, J 7, 2 × CH2CH2),
2.81 and 3.07 (each 1 H, d, J 15, 5-H2), 3.42 and 3.52 (each 1 H,
d, J 16, CH2CO2), 3.46 and 3.62 (each 1 H, d, J 18, CH2CO2),
3.64, 3.65, 3.77 and 3.78 (each 3 H, s, OMe), 9.43 (1 H, br s,
thiolactam-NH), 9.47 (1 H, s, CHO) and 10.68 (1 H, br s,
pyrrole-NH); δC(CDCl3, 62.5 MHz) 22.05 (4-Me), 19.19, 20.90,
29.80, 31.08, 31.93, 33.13 and 35.97 (CH2), 51.54, 51.63, 52.64
and 52.86 (OMe), 71.08 (C-4), 115.88, 128.86, 133.43, 133.63,
᎐
9-Cyano-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin-1(10H)-thione 81
Lactam 78 was reacted with Lawesson’s reagent according to
the above general procedure. The residue was purified by flash
chromatography, eluting with diethyl ether, to give thiolactam
81 (88%) as a gum (Found: Mϩ, 533.1820. C25H31N3O8S
requires M, 533.1832); νmax(CH2Cl2)/cmϪ1 3300, 2960, 2220,
1730s, 1450 and 1000; δH(CDCl3, 400 MHz) 1.41 (3 H, s, 4-Me),
2.52–2.81 (6 H, m) and 2.84 (2 H, t, J 8, 2 × CH2CH2), 2.91 and
3.05 (each 1 H, d, J 15, 5-H2), 3.33 and 3.53 (each 1 H, d, J 16,
CH2CO2), 3.39 (1 H, d, J 17, CHAHBCO2), 3.64, 3.68, 3.78 and
3.80 (each 3 H, s, 4 × OMe), 3.64–3.80 (1 H, obscured, CHA-
HBCO2), 8.95 (1 H, br s, lactam-NH) and 10.18 (1 H, br s,
pyrrole-NH); δC(CDCl3, 100 MHz) 23.10 (C-4), 20.16, 21.14,
29.77, 30.84, 31.45, 32.72 and 34.53 (CH2), 51.79, 51.94, 52.93
141.43 and 149.79 (C᎐C), 170.56, 172.80, 172.91 and 173.73
᎐
(C᎐O), 177.31 (CHO) and 196.44 (C᎐S); m/z (FD) 536 (Mϩ,
᎐
᎐
and 53.16 (OMe), 70.96 (C-4), 98.81, 113.79, 129.97, 132.92,
100%).
᎐
142.2 and 148.97 (C᎐C and C᎐N), 171.67, 172.94, 173.42 and
᎐
᎐
174.52 (C᎐O) and 196.19 (C᎐S); m/z (FD) 533 (Mϩ, 100%).
᎐
᎐
9-Formyl-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin 82
A solution of thiolactam 80 (45 mg, 84 µmol) in methanol
(3 cm3) was heated at reflux with freshly prepared Raney nickel
(one small spatula) for 20 min, then filtered, washing with
methanol, and evaporated under reduced pressure. The residue
was purified by PLC to give the pyrrolenine 82 (15 mg, 52%
based on unrecovered 80) as a gum (Found: Mϩ, 504.2110.
C25H32N2O9 requires M, 504.2108); νmax(CH2Cl2)/cmϪ1 3300,
2950, 1730s, 1640, 1570, 1435, 1260, 1200 and 1170; δH(CDCl3,
9-Cyano-2,8-bis(2-methoxycarbonylethyl)-3,7-bis(methoxy-
carbonylmethyl)-4-methyl-4,5-dihydrodipyrrin 83
Thiolactam 81 was reduced with nickel boride according to the
general procedure above. Purification by PLC, eluting with
ethanol–diethyl ether (1:9), gave pyrrolenine 83 (40% based on
unrecovered 81) as a gum (Found: Mϩ, 501.2108. C25H31N3O8
requires M, 501.2111); νmax(CH2Cl2)/cmϪ1 3350, 2960, 2220,
1725s, 1690, 1440 and 1150; δH(CDCl3, 400 MHz) 1.07 (3 H, s,
1506
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
4-Me), 2.14 and 3.10 (each 1 H, d, J 15, 5-H2), 2.51 and 2.66
(6 H, m) and 2.86 (2 H, t, J 8, 2 × CH2CH2), 3.40–3.43 (4 H, m,
2 × CH2CO2), 3.66, 3.67 and 3.73 (12 H, each s, 4 × OMe), 7.95
(1 H, s, 2-H) and 10.45 (1 H, br s, NH); δC(CDCl3, 100 MHz)
19.39 (4-Me), 20.28, 20.51, 29.71, 31.21, 32.24, 32.66 and 34.47
(CH2), 51.50, 51.70, 51.87 and 52.35 (OMe), 83.3 (C-4), 97.88,
2950, 2220, 1730s, 1440, 1270 and 1000; δH(CDCl3, 400 MHz)
2.49–2.82 (13 H, m, 3 × CH2CH2 and 4-CHAHB), 2.89 and 3.10
(each 1 H, d, J 15, 4-CH2), 3.22 and 3.50 (each 1 H, d, J 16,
CH2CO2), 3.29 (1 H, d, J 15, 4-CHAHB), 3.56 (2 H, s, CH2CO2),
3.64, 3.67, 3.70, 3.73, 3.75 and 3.86 (each 3 H, s, 6 × OMe),
3.64–3.86 (2 H, obscured, CH2CO2), 9.31, 9.61 and 10.07 (each
1 H, br s, NH); δC(CDCl3, 100 MHz) 19.17, 20.17, 21.25, 29.28,
30.34, 30.72, 30.85, 31.11, 31.74, 34.15 and 34.47 (CH2), 51.79,
52.25, 52.32, 52.87 and 53.49 (OMe), 73.48 (C-4), 99.15, 100.90,
114.04, 114.7, 132.62, 132.92, 137.6 and 158.0 (C᎐C and
᎐
᎐
C᎐N), 164.9 (C-2), 170.08, 171.65, 171.71 and 172.71 (C᎐O),
᎐
᎐
m/z (FD) 501 (Mϩ, 100%).
113.58, 113.82, 114.31, 121.33, 126.03, 128.46, 129.26, 133.01,
᎐
9-Formyl-4-[5-formyl-3-(2-methoxycarbonylethyl)-4-(methoxy-
carbonylmethyl)pyrrol-2-ylmethyl]-2,8-bis(2-methoxycarbonyl-
ethyl)-3,7-bis(methoxycarbonylmethyl)-4,5-dihydrodipyrrin-
1(10H)-one 86
143.81 and 147.91 (C᎐C and C᎐N), 170.84, 172.06, 172.86,
᎐
᎐
173.36, 173.93 and 174.85 (C᎐O) and 197.20 (C᎐S); m/z (FD)
᎐
᎐
781 (Mϩ, 100%).
Hydrogenation of dibenzyl ester 29 and decarboxylation–
formylation of the resulting diacid 85 was carried out using
similar procedures to those used for 21→73→74 except that the
hydrogenation required 3 h and decarboxylation required 6.5 h.
Purification by flash chromatography, eluting with 0–5%
ethanol in diethyl ether, gave the dialdehyde 86 (72% over both
steps) as a gum (Found: Mϩ, 771.2862. C37H45N3O15 requires
M, 771.2851); νmax(CH2Cl2)/cmϪ1 3280, 2950, 1730, 1640, 1460,
1250 and 1070; δH(CDCl3, 400 MHz) 2.41–2.55 (6 H, m), 2.72
(2 H, t, J 7) and 2.91–2.98 (4 H, m, 3 × CH2CH2), 2.52 and 3.18
(each 1 H, d, J 15, 4-CH2), 2.85 and 3.08 (each 1 H, d, J 15,
4-CH2), 3.25 and 3.47 (each 1 H, d, J 16, CH2CO2), 3.62, 3.63,
3.64, 3.67, 3.68 and 3.83 (each 3 H, s, 6 × OMe), 3.62–3.83 (4 H,
obscured, 2 × CH2CO2), 7.63 (1 H, br s, lactam-NH), 9.50 (2 H,
s, 2 × CHO) and 10.14 and 10.46 (each 1 H, br s, pyrrole-NH);
δC(CDCl3, 62.5 MHz) 19.10, 19.26, 19.68, 29.60, 30.93, 31.03,
31.73, 31.96, 32.10 and 34.64 (CH2), 51.56, 51.68, 52.19, 52.29
and 53.01 (OMe), 66.66 (C-4), 116.30, 122.96, 129.05, 129.75,
9-Cyano-4-[5-cyano-3-(2-methoxycarbonylethyl)-4-(methoxy-
carbonylmethyl)pyrrol-2-ylmethyl]-2,8-bis(2-methoxycarbonyl-
ethyl)-3,7-bis(methoxycarbonylmethyl)-4,5-dihydrodipyrrin 89
Thiolactam 88 was reduced with nickel boride following the
general procedure described above, except that the reaction
time was increased to 2.5 h. Purification by normal phase
HPLC on a Kontron S5W column, eluting with hexane–ethyl
acetate (1:1), gave the pyrrolenine 89 (14%) as a gum (Found:
Mϩ, 749.2908. C37H43N5O12 requires M, 749.2908); νmax(CH2-
Cl2)/cmϪ1 3300, 2950, 2220, 1730s, 1695, 1440, 1200 and
1175; δH(CDCl3, 400 MHz) 2.29 and 3.19 (each 1 H, d, J 15,
4-CHAHB), 2.41–2.50, 2.55–2.65 and 2.86 (13 H, m, 3 ×
CH2CH2 and 4-CHAHB), 3.07 (1 H, d, J 15, 4-CHAHB), 3.29
and 3.40 (each 1 H, d, J 16, CH2CO2), 3.49 and 3.58 (each 1 H,
d, J 17, CH2CO2), 3.59 (2 H, s, CH2CO2), 3.63, 3.65, 3.67, 3.70,
3.74 and 3.83 (each 3 H, s, OMe), 7.81 (1 H, s, N᎐C᎐H) and
᎐
10.16 and 10.35 (each 1 H, br s, NH); m/z (FD) 749 (Mϩ,
100%).
132.03, 132.73, 137.40 and 149.83 (C᎐C), 170.46, 171.11,
᎐
172.29, 172.87, 173.31 and 173.38 (C᎐O) and 177.60 and 177.79
᎐
Hydrolysis of the ester groups of pyrrolenines 83 and 89
(CHO); m/z (FD) 771 (Mϩ, 100%).
A solution of pyrrolenine 83 (44 mg, 88 µmol) in dry degassed
methanol (1 cm3) was treated with degassed aqueous potassium
hydroxide (4 mol dmϪ3; 1 cm3) and then shaken under argon in
the dark at room temperature for 15 h. A sample was then
removed and prepared for NMR analysis by four times evapor-
ating in vacuo and redissolving the residue in D2O (1 cm3);
δH(D2O, 400 MHz, relative to HOD signal at 4.77 ppm) 1.14
(3 H, s, 4-Me), 2.12, 2.25, 2.43, 2.62 (each 2 H, t, J 8, 2 ×
CH2CH2), 2.60 and 3.01 (each 1 H, d, J 15, 5-H2), 3.18 and 3.27
(each 2 H, d, J 16, 2 × CH2CO2) and 7.79 (1 H, s, 2-H).
The remainder of the solution was then washed with diethyl
ether (2 × 2 cm3) and evaporated in vacuo. The residue was
dissolved in acetic acid (400 µl), and methanol (4 cm3) and
diethyl ether (10 cm3) were added. The mixture was treated with
diazomethane at room temperature until the yellow colour per-
sisted, stirred for a further hour and then evaporated under
reduced pressure. Purification by PLC gave the starting
pyrrolenine 83 as the major product (20 mg, 46% recovery).
For enzymatic studies, the pyrrolenine 89 was hydrolysed
under exactly the same conditions.
9-Cyano-4-[5-cyano-3-(2-methoxycarbonylethyl)-4-(methoxy-
carbonylmethyl)pyrrol-2-ylmethyl]-2,8-bis(2-methoxycarbonyl-
ethyl)-3,7-bis(methoxycarbonylmethyl)-4,5-dihydrodipyrrin-
1(10H)-one 87
Dialdehyde 86 was reacted with hydroxylamine hydrochloride
and then phosphorus oxychloride following an analogous pro-
cedure to that employed for 74→76→78. Purification by flash
chromatography, eluting with 2% ethanol in diethyl ether,
gave the dinitrile 87 (50%) as a gum (Found: Mϩ, 765.2845.
C37H43N5O13 requires M, 765.2857); νmax(CH2Cl2)/cmϪ1 3300,
2960, 2220, 1725s, 1695, 1435, 1200 and 1170; δH(CDCl3, 400
MHz) 2.39–2.60 (8 H, m), 2.67 (2 H, t, J 7) and 2.78 (2 H, t, J 8,
3 × CH2CH2), 2.71 and 3.15 (each 1 H, d, J 15, 4-CH2), 2.82
and 3.00 (each 1 H, d, J 15, 4-CH2), 3.18 and 3.43 (each 1 H, d,
J 16, CH2CO2), 3.55 (2 H, s, CH2CO2), 3.64, 3.64, 3.68, 3.69,
3.69 and 3.83 (each 3 H, s, 6 × OMe), 3.64–3.83 (2 H, obscured,
CH2CO2) and 7.74, 9.97 and 10.21 (each 1 H, br s, NH);
δC(CDCl3, 100 MHz) 19.25, 19.90, 20.20, 29.30, 30.63,
30.68, 30.87, 32.24 and 34.33 (CH2), 51.69, 51.83, 52.06, 52.22,
52.55 and 53.31 (OMe), 66.38 (C-4), 99.17, 100.72, 113.66,
Crystal data for 60§
113.91, 114.65, 121.25, 125.89, 128.29, 128.92, 129.68, 132.87,
C13H17NO4S, M = 283.34. Monoclinic, a = 8.367(4), b =
19.764(8), c = 18.672(4) Å, β = 95.16(3)Њ, V = 1428.2(11) Å3
[from centring angles for 25 reflections (40 р 2θ р 50Њ,
λ = 1.541 84 Å, T = 290 K)], space group P21/a (Alt. P21/c, No.
14), Z = 4, Dx = 1.318 g cmϪ3, red block, 0.38 × 0.35 × 0.19 mm,
᎐
137.76 and 149.90 (C᎐C and C᎐N), 170.83, 171.70, 172.15,
᎐
᎐
172.87, 172.89, 173.59 and 174.21 (C᎐O); m/z (FD) 765 (Mϩ,
᎐
100%).
µ(Cu-Kα) = 2.111 mmϪ1
.
9-Cyano-4-[5-cyano-3-(2-methoxycarbonylethyl)-4-(methoxy-
carbonylmethyl)pyrrol-2-ylmethyl]-2,8-bis(2-methoxycarbonyl-
ethyl)-3,7-bis(methoxycarbonylmethyl)-4,5-dihydrodipyrrin-
1(10H)-thione 88
Lactam 87 was reacted with Lawesson’s reagent following
the general procedure described above. Purification by flash
chromatography, eluting with 2% ethanol in diethyl ether, gave
the thiolactam 88 (67%) as a gum (Found: Mϩ, 781.2632.
C37H43N5O12S requires M, 781.2629); νmax(CH2Cl2)/cmϪ1 3300,
§ Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details of the deposition scheme, see ‘Instructions for
Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC Web
page (http://www.rsc.org/authors). Any request to the CCDC for this
material should quote the full literature citation and the reference
number 207/200.
J. Chem. Soc., Perkin Trans. 1, 1998
1507

View Article Online
2 Preliminary account of part of this work: C. J. Hawker, W. M. Stark
Data collection and processing
and A. R. Battersby, J. Chem. Soc., Chem. Commun., 1987, 1313.
3 F. J. Leeper and A. R. Battersby, Chem. Rev., 1990, 90, 1261;
F. J. Leeper, Nat. Prod. Rep., 1989, 6, 171.
Siemens P3 diffractometer, ω/2θ scans, graphite-mono-
chromated Cu-Kα X-radiation; 2255 reflections measured
(9 р 2θ р 115Њ), 1959 unique [merging R = 0.018], giving 1809
with F у 4σ(F) and 1959 which were retained in all calcu-
lations. No crystal decay was observed and no corrections
were applied for absorption.
4 A. R. Battersby, G. L. Hodgson, E. Hunt, E. McDonald and
J. Saunders, J. Chem. Soc., Perkin Trans. 1, 1976, 273.
5 A. R. Battersby, C. J. R. Fookes, M. J. Meegan, E. McDonald and
H. K. W. Wurziger, J. Chem. Soc., Perkin Trans. 1, 1982, 2786.
6 A. R. Battersby, M. G. Baker, H. A. Broadbent, C. J. R. Fookes and
F. J. Leeper, J. Chem. Soc., Perkin Trans. 1, 1987, 2027.
7 J. H. Mathewson and A. H. Corwin, J. Am. Chem. Soc., 1961, 83,
135.
8 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.
9 M. A. Cassidy, N. Crockett, F. J. Leeper and A. R. Battersby,
J. Chem. Soc., Perkin Trans. 1, 1996, 2079.
10 A. C. Spivey, A. Capretta, C. S. Frampton, F. J. Leeper and A. R.
Battersby, J. Chem. Soc., Perkin Trans. 1, 1996, 2091.
11 C. J. Hawker, A. C. Spivey, F. J. Leeper and A. R. Battersby,
J. Chem. Soc., Perkin Trans. 1, 1998, 1509.
Structure solution and refinement
Automatic direct methods35 (all non-H atoms). Full-matrix
least-squares refinement35 with all non-H atoms anisotropic; H
atoms were included at geometrically calculated positions and
thereafter allowed to ride on their respective parent atoms at a
distance of 0.98 Å. The weighting scheme selected gave satisfac-
tory agreement analyses. Final Rf [F у 4σ(F)] = 0.0459, wR2
[all data] = 0.1310, S[F2] = 1.03 for 187 refined parameters. An
extinction correction35 refined to 0.0065(10) and the final ∆F
synthesis showed no peaks above 0.33 e ÅϪ3
.
12 A. R. Battersby, C. J. R. Fookes, K. E. Gustafson-Potter,
E. McDonald and G. W. J. Matcham, J. Chem. Soc., Perkin Trans. 1,
1982, 2427.
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 D. Liotta, Organoselenium Chemistry, Wiley, Chichester, 1987,
p. 325.
Crystal data for 77§
C27H35N3O11, M = 577.58. Monoclinic, a = 7.517(3), b =
18.551(5), c = 20.760(8) Å, β = 94.30(3)Њ, V = 2887(2) Å3 [from
centring angles for 25 reflections (40 р 2θ р 50Њ, λ = 1.541 84
Å, T = 290 K)], space group P21/c (No. 14), Z = 4, Dx = 1.329 g
cmϪ3, colourless block, 0.41 × 0.38 × 0.25 mm, µ(Cu-Kα) =
0.875 mmϪ1
.
15 S. Karady, J. S. Amato, L. M. Weinstock and M. Sletzinger,
Tetrahedron Lett., 1978, 407.
16 H. J. Reich and M. L. Cohen, J. Org. Chem., 1979, 44, 3148.
17 C. J. Hawker, A. Philippides and A. R. Battersby, J. Chem. Soc.,
Perkin Trans. 1, 1991, 1833.
18 G. R. Pettit and E. E. Van Tamelen, Org. React., 1962, 12, 356;
J. S. Pizey, Synthetic Reagents, Ellis Horwood, Chichester, 1974,
vol. 2, p. 175.
19 B. S. Petersen and S.-O. Lawesson, Tetrahedron, 1979, 35, 2433.
20 H. Davy, J. Chem. Soc., Chem. Commun., 1982, 457.
21 R. Paul, P. Buisson and N. Joseph, Ind. Eng. Chem., 1952, 44, 1006.
22 I. Ojima, S. Inaba and K. Nakatsugawa, Synthesis, 1976, 207.
23 A. R. Battersby, S. Kishimoto, E. McDonald, F. Satoh and H. K. W.
Wurziger, J. Chem. Soc., Perkin Trans. 1, 1979, 1927.
24 R. L. N. Harris, Aust. J. Chem., 1970, 23, 1199; 1972, 25, 985.
25 A. R. Battersby, E. Hunt, E. McDonald, J. B. Paine III and
J. Saunders, J. Chem. Soc., Perkin Trans. 1, 1976, 1008.
26 D. Mauzerall, J. Am. Chem. Soc., 1960, 82, 2601, 2605.
27 P. Wipf, C. Jenny and H. Heinzgartner, Helv. Chim. Acta, 1987, 70,
1001.
Data collection and processing
Siemens P3 diffractometer, ω/2θ scans, graphite-mono-
chromated Cu-Kα X-radiation; 4195 reflections measured
(6 р 2θ р 115Њ), 3938 unique [merging R = 0.013], giving 3441
with F у 4σ(F) and 3938 which were retained in all calcu-
lations. No crystal decay was observed and no corrections
were applied for absorption.
Structure solution and refinement
Automatic direct methods35 (all non-H atoms). Full-matrix
least-squares refinement35 with all non-H atoms anisotropic; H
atoms were included at geometrically calculated positions and
thereafter allowed to ride on their respective parent atoms at a
distance of 0.98 Å. The weighting scheme selected gave satisfac-
tory agreement analyses. Final R [F у 4σ(F)] = 0.0437, wR2
[all data] = 0.1284, S[F2] = 1.03 for 391 refined parameters. The
28 R. Mayer, J. Morgensten and J. Fabian, Angew. Chem., Int. Ed.
Engl., 1964, 3, 277.
29 M. G. Baker, PhD Thesis, Cambridge, 1985.
final ∆F synthesis showed no peaks above 0.38 e ÅϪ3
.
30 G. P. Arsenault and S. F. MacDonald, Can. J. Chem., 1961, 39, 2043.
31 G. J. Hart and A. R. Battersby, Biochem. J., 1985, 232, 151.
32 A. D. Miller, F. J. Leeper and A. R. Battersby, J. Chem. Soc., Perkin
Trans. 1, 1989, 1943.
33 A. R. Battersby, M. Ihara, E. McDonald, J. Saunders and R. J.
Wells, J. Chem. Soc., Perkin Trans. 1, 1976, 283.
34 W. J. Gensler, F. A. Johnson and D. B. Sloan, J. Am. Chem. Soc.,
1960, 82, 6074.
35 SHELXTL-Plus Release 5.0. Siemens Analytical X-ray Instruments,
Inc., Madison, WI, USA, 1993.
Acknowledgements
Grateful acknowledgement is made to the Commissioners
for the Exhibition of 1851 for an Overseas Scholarship (to
C. J. H.), to Dr G. J. Hart for the enzymic measurements and
to Dr A. Philippides for a sample of the spirolactam ester 5
and for the indicated experiments. We also thank the EPSRC,
Zeneca, Roche Products and F. Hoffmann-La Roche for
financial support.
References
Paper 7/08132D
Received 11th November 1997
Accepted 24th February 1998
1 The following paper is regarded as Part 46: N. P. J. Stamford,
J. Crouzet, B. Cameron, A. I. D. Alanine, A. R. Pitt, A. A. Yeliseev
and A. R. Battersby, Biochem. J., 1996, 313, 335.
1508
J. Chem. Soc., Perkin Trans. 1, 1998