Haem d1: Stereoselective synthesis of the macrocycle to establish its absolute configuration as 2R,7R

Article abstract of DOI:10.1039/a700655a

Although the gross structure of haem d₁ 1 has been established, the absolute stereochemistry at C-2 and C-7 is unknown. An unambiguous stereoselective synthesis of the ester of the metal-free macrocycle corresponding to haem d₁ has b

Full text of DOI:10.1039/a700655a

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Haem d1: stereoselective synthesis of the macrocycle to establish its
absolute configuration as 2R,7R 1
Jason Micklefield,a Marion Beckmann,a Richard L. Mackman,a
Michael H. Block,b Finian J. Leeper a and Alan R. Battersby*,a
a
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
b Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK SK10 4TG
Although the gross structure of haem d1 1 has been established, the absolute stereochemistry at C-2 and
C-7 is unknown. An unambiguous stereoselective synthesis of the ester of the metal-free macrocycle
corresponding to haem d1 has been completed which establishes the absolute configuration of the natural
cofactor as 2R,7R. H aem d1 is thus shown to match stereochemically other biologically important
macrocycles, e.g. those involved in the biosynthesis of vitamin B12, which are related to isobacteriochlorins
and also display 2R,7R configurations. The synthetic sequence used is based on a new procedure for
assembly of the western and eastern building blocks and it serves as an efficient general route for
construction of isobacteriochlorins.
as illustrated. The topic of biosynthesis will be revisited at the
end of this paper.
Introduction
Haem d1 is one of two different haem residues present in the
bacterial enzyme cytochrome cd1. The first 2 of this set of three
papers reviewed the isolation of haem d1 and previous work on
its structure together with complete references to the literature.
The outcome of all these studies was that haem d1 was shown to
have the gross structure 1 (Scheme 1), although the absolute
configuration of the quaternary centres at C-2 and C-7 was
unknown. Our interest in solving this stereochemical problem
arose because of the work in Cambridge on precorrin-2, which
The importance of establishing the absolute configuration
of haem d1 was thus clear, yet any direct approach using the
natural material, e.g. X-ray analysis, was not possible since only
microgram quantities were available. Here we describe how the
problem was solved by an unambiguous stereoselective syn-
thesis of the ester of the metal-free macrocycle of haem d1 2.
Although the 2R,7R-configurations were selected for the initial
target molecule 2, the synthesis was designed to allow any of
the four stereoisomers of structure 2 to be constructed.
It was envisaged that the macrocycle 2 could be derived from
the isobacteriochlorin 62 (Scheme 7) by introduction of the C-3
and C-8 oxo functions and the double bond in the ring D side-
chain at the end of the synthesis. This substance 62 had already
been synthesised in small quantities by an experimentally
demanding route (see first paper2). It was the difficulty of scal-
3
is an intermediate for the biosynthesis of vitamin B12 and a
dihydro form of sirohydrochlorin, the latter having the estab-
lished structure and absolute configuration 4 3. We felt that
haem d1 and sirohydrochlorin are probably related biosyn-
thetically and hence that the absolute configuration at C-2
and C-7 is likely to be the same in both substances, i.e. 2R,7R
HO2C
O
Me
Me
CO2R
CO2H
3
7
RO2C
Me
HO2C
Me
O
A
B
8
2
CO2H
N
N
N
N
HN
N
M
HO2C
N
NH
D
C
MeO2C
Me
HO2C
Me
Me
O
CO2H
O
8
1 M = FeII, R = H
RO2C
CO2R
HO2C
CO2H
3
+
2 M = H,H, R = Me
Me
CO2Me
O
Me
Me
CO2Me
CO2Me
MeO2C
Me
MeO2C
Me
O
O
O
O
O
HN
O
NH
NH
9
O
CO2H
+
O
O
HN
ButO2C
NH
HN
ButO2C
HN
Me
Me
Me
Me
Me
Me
CO2But
CO2But
CO2Me
MeO2C
10
MeO2C
CO2Me
CO2Me
6
7
4
5
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 1997
2123

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ing up this synthesis that prompted the development of a new
synthetic approach for assembly of the western 4 and eastern 5
units for construction of the required macrocycle 62 (Scheme
1). This new approach was described in the preceding paper.5
For the present synthesis, the new route required construction
of the ketones 6 and 7 as precursors of the lactams 4 and 5.
These ketones 6 and 7 were to be generated by acylation of the
same α-free pyrrole 10 with activated forms of the lactonic
acids 8 and 9 (Scheme 1).
O
O
O
Me
R
Me
O
O
O
OCPh3
OCPh3
OR
i
18
16 R = H
17 R = Me
19 R = CPh3
20 R = H
ii
iii
R
O
MeO2C
Me
O
O
O
Results and discussion
v
vii
Me
Me
Synthesis of the lactonic acids 8 and 9
O
O
O
The lactone 11 (Scheme 2), readily available from -glutamic
CO2H
CO2Bn
CO2R
23 R = H
24 R = OH
25 R = OMe
21 R = H
22 R = Bn
8
R
iii
vi
iv
O
CO2Me
Me
O
Me
O
Me
O
O
O
O
ii
v
R
17
M
M
viii
CO2R
CO2Bn
CO2H
O
Me
11 R = H
12 R = Bn
13 R = H
14 R = OH
15 R = OMe
R'
9
Me
Me
26
i
iii
iv
Me
O
O
R
Me
Me
Scheme 2 Reagents: i, BnBr, K2CO3; ii, RuO4, NaIO4; iii, CrO3,
H2SO4; iv, CH2N2; v, H2, Pd/C
O
O
Me
O
R'
Me
OCPh3
OCPh3
27
28
29
acid, was in hand.5 Oxidative cleavage of the double bond of
the allyl residue in the corresponding benzyl ester 12 was
achieved with ruthenium tetroxide generated in situ, to give a
mixture of the aldehyde 13 and acid 14. Chromic acid converted
the former into the latter, which with diazomethane afforded
the ester 15 in 68% yield overall. Hydrogenolysis of the benzyl
group then gave the lactonic acid 9 required for ring B of the
macrocycle 2.
Scheme 3 Reagents: i, (allyl)2CuCNLi2; ii, Amberlyst 15(Hϩ); iii,
CrO3, H2SO4; iv, BnBr, K2CO3; v, RuO4, NaIO4; vi, CH2N2; vii, H2,
Pd/C; viii, (prenyl)2CuCNLi2
groups of the two enantiomers. Under the same conditions,
the sample of 19 formed above directly from the homo-
chiral butenolide 17 showed just one of these singlets, so
proving its enantiomeric purity.
-Glutamic acid was also the chosen starting material for the
lactonic acid 8, which was to provide ring A of the target
molecule 2. Ireland et al.6 and Hanessian et al.7 had shown
that chiral butenolides such as 16 (Scheme 3) act as Michael
acceptors for the addition of anions from lithium dialkyl-
cuprates to yield trans-substituted lactones, e.g. 18. We there-
fore planned to add an allyl group from a suitable allylic cuprate
to the known 8 substituted butenolide 17, derived from
-glutamic acid. However, a literature survey uncovered few
successful reactions involving lower-order allylic cuprates,
especially for building quaternary centres by additions to
butenolides or α,β-unsaturated esters. Accordingly, the chosen
reagent was the more stable and reactive higher-order cuprate,
(allyl)2CuCNLi2 developed by Lipshutz et al.9 This reacted with
the butenolide 17 to afford the desired lactone 19 in 25% yield
with complete stereocontrol (see below). The trans-orientation
of the allyl group and the cis-arrangement for the methyl group
relative to the trityloxymethyl group were confirmed by NOE
experiments.
Cleavage of the trityl group from 19 afforded the alcohol
20, which was oxidised to the acid 21 by chromic acid. The
remaining steps for cleavage of the allyl group, 21 → 25 and
forward to 8 (Scheme 3), were analogous to those used in
Scheme 2.
Many experiments were carried out under different condi-
tions and with other allylic copper reagents, aiming to improve
the foregoing yield of lactone 19, but without success. However,
one approach gave an interesting result. The current view10 is
that allylic organometallic reagents react with carbonyl groups
via a cyclic chair transition state 26. On that basis, it seemed
that replacement of allyl by 3,3-dimethylallyl9 should destab-
ilise the system 27 by steric factors, so disfavouring 1,2-attack
and thereby increasing the yield from 1,4-addition. In the event,
the 1,4-product from this approach was the lactone 28 formed
by allylic rearrangement, which was of no further value for
the synthesis, rather than the unrearranged system 29. These
experiences, coupled with the easy availability of the butenolide
17 on a large scale and the complete stereocontrol in generating
the quaternary centre of 19, led to the view that the route to 8 in
Scheme 3 was the best available.
The main competing reaction in the foregoing process was
attack at the lactonic carbonyl group to form the diallyl tertiary
alcohol but, interestingly, 20% of starting material was
recovered even when a large excess of allyl cuprate was used.
The reason became clear when this recovered lactone was found
to be fully racemised. Evidently, deprotonation at the chiral
centre of the butenolide 17 was a further competing process.
This last finding raised concern as to whether the desired prod-
uct 19 could have been formed partly or wholly from racemised
butenolide (as 17). Accordingly, the allylation step was repeated
on the recovered racemic butenolide (as 17) to give a racemic
Construction of the western and eastern lactams 4 and 5 and their
conversion into the building blocks 61 and 53 for synthesis of
macrocycle 62
The synthetic steps used for construction of the eastern lactam
5 are shown in Scheme 4; they followed the general methods
developed in the preceding paper,5 so the description here will
be brief. The acid 9 (Scheme 2) reacted with 2,2Ј-dipyridyl
disulfide and triphenylphosphine to yield the thioester 30,
which without isolation was added to the magnesium chloride
salt 31 of pyrrole 10. A virtually quantitative yield of the ketone
32 was obtained and its pyrrolic α-methyl group was converted
1
sample of the methyl allyl system (as 19). The H NMR spec-
trum of this material in the presence of the chiral shift reagent,
tris[3-(heptafluoropropylhydroxymethylene)-(ϩ)-camphorato]-
europium(), showed two discrete singlets, from the methyl
2124
J. Chem. Soc., Perkin Trans. 1, 1997

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MeO2C
Me
O
8
i
9
O
MeO2C
Me
Me
i
CO2Me
O
O
O
O
MeO2C
Me
Me
O
RO
CO2Me
CO2Me
Me
O
O
S
O
O
NH
v
N
O
39
O
Me
CO2But
O
O
S
v
NH
R
N
O
OR
Me
NMgCl
Me
30
Me
Me
HN
R
HN
ButO2C
MeO2C
vi
Me
ClMgN
Me
43 R = H
44 R = Ac
Me
MeO2C
40 R = Me
MeO2C
31
ii
iii
iv
CO2Me
CO2Me
35 R = H
36 R = Ac
41 R = CHO
42 R = CO2H
vii
32 R = Me
CO2Me
31
ii
iii
iv
vi
33 R = CHO
34 R = CO2H
6
R = CO2But
O
O
MeO2C
MeO2C
Me
HO
R = CO2But
viii
7
vii
Me
O
NH
O
MeO2C
Me
HO
Me
Me
Me
CO2Me
CO2Me
CO2Me
O
O
O
NH
ix
46a
45
HN
HN
O
OH
Me
ix
viii
46b
O
O
Me
MeO2C
Me
HN
ButO2C
HN
ButO2C
HN
ButO2C
Me
Me
x
NH
NH
O
O
OMe
MeO2C
Me
NH
CO2But
CO2Me
5
38
CO2Me
37 CO2Me
47
Me
N
xi
Scheme 4 Reagents: i, Ph3P, dipyridyl disulfide; ii, SO2Cl2 then H2O;
iii, KMnO4; iv, isobutene, H2SO4; v, NaBH4; vi, Ac2O, DMAP; vii, heat;
viii, NH3; ix, TsOH
48
MeO2C
4
Scheme 5 Reagents: i, Ph3P, dipyridyl disulfide; ii, SO2Cl2 then H2O;
iii, KMnO4; iv, isobutene, H2SO4; v, NaBH4; vi, Ac2O, DMAP; vii, heat;
viii, NH3; ix, TsOH; x, CH2N2, NaOMe; xi, H3Oϩ
into a carboxyl residue by the steps 32 → 33 → 34 (76%
overall); acid-catalysed esterification then afforded ketone 7
(80%).
Borohydride reduction of the ketone 7 gave a 1:1 mixture of
the diastereoisomeric alcohols 35 in essentially quantitative
yield. The corresponding acetates 36 then underwent thermal
elimination of acetic acid to form the enol lactones 37 as a
1:1.2 mixture of the (E)- and (Z)-isomers in 84% yield.
Aqueous ammonia converted the enol lactones smoothly into
the lactam 38 as a mixture of diastereoisomers which were
dehydrated under acidic catalysis to form the (E)- and (Z)-
isomers of the eastern lactam 5 as a 1:1 mixture (91% yield).
All the foregoing diastereoisomers and (E)- and (Z)-isomers
were separated for full characterisation but could be used in
admixture for preparative runs. As earlier,2,5 the (E)- and (Z)-
isomers of the lactam 5 were distinguished by the strong
bathochromic shift in the UV spectrum of the illustrated
(Z)-isomer 5 upon chelation of zinc() ions. Further, the two
isomers of 5 were shown to be spectroscopically identical to
the samples of the same materials synthesised by the original
coupling strategy.2
All the chemistry illustrated in Scheme 4 was first explored
starting from the benzyl ester of 34 rather than the tert-butyl
ester 7. The benzyl esters of the entire series (analogues of 7,
35–38 and 5) were prepared and characterised; they are
included in the Experimental section.
Attention then turned to the synthesis of the western lactam
4 (Scheme 1). The enol lactone 45 (Scheme 5) was constructed
by steps analogous to those used in Scheme 4; these were
31 ϩ 39 → 40 and then through the illustrated series 41–44 to
afford the single (Z)-isomer 45 in 42% overall yield from the
acid 8. Ammonolysis of the enol lactone 45 followed by the
acid-catalysed dehydration step gave the western lactam as
the single (Z)-isomer 4 (34% yield). The major product was the
lactone lactam 47 (50%), formed from the diastereoisomer 46a
of the intermediate hydroxy lactam; the other isomer 46b was
the main source of the (Z)-lactam 4. A lactone lactam similar to
47 had been encountered in the work on the total synthesis of
vitamin B12 by Eschenmoser and Woodward.11 Following their
lead, 47 was treated with diazomethane and a catalytic quantity
of sodium methoxide to generate more of lactam 4 together
with its imino ether 48. Mild acidic hydrolysis converted 48 into
4, so that the total overall yield of 4 from the enol lactone 45 by
these steps was a very satisfactory 73%. This product also was
shown to be identical to that prepared earlier 2 by a different
route.
The foregoing studies established practical routes for syn-
thesis of the lactams 4 and 5 on a substantial scale. These were
then converted into the building blocks 61 and 53 (Scheme 7) by
the methods described in the first paper of this set.2 Every atom
required for the synthesis of the macrocycle 62 was now present
in 61 and 53; they were ready for condensation to yield the
open-chain 18π-electron system followed by photochemical
cyclisation to the isobacteriochlorin 62 (Scheme 7). However,
we first wished to select the best conditions for these two reac-
tions using related model compounds.
Study of the condensation and photochemical steps for synthesis
of isobacteriochlorins
The first experiments were aimed at the synthesis of the isobac-
teriochlorin 59 (Scheme 6). The known tert-butyl ester 12 49 was
treated with trifluoroacetic acid (TFA) to yield 50, one of the
required halves. The other half 52 was prepared from the
lactam 5 54 via the thiolactam 55 (Scheme 6). Both compounds
50 and 52 were rather labile but they were quickly purified
under argon with protection against light and then used dir-
ectly. The best conditions found for condensation of 50 with 52
involved catalysis by TFA in methanol to yield the 18π-electron
J. Chem. Soc., Perkin Trans. 1, 1997
2125

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R2
4
Me
ref. 2
R3
CO2Me
MeS
Me
MeO2C
Me
MeS
Me
R1
R1
Me
Me
N
N
N
N
HN
NH
HN
OHC
NH
R2
Me
Me
Me
R1
OHC
i
CO2Me
53
MeO2C
CO2Me
MeO2C
X
Me
CO2Me
Y
49 R1 = CO2But, R2 = CH2CO2Me
50 R1 = H, R2 = CH2CO2Me
51 R1 = H, R2 = Me
52 R1 = Me, R2 = R3 = H
53 R1 = H, R2 = Me,
R3 = CH2CO2Me
61
MeO2C
Me
i
3
8
N
HN
iii
iv
NH
N
R2
R3
D
C
R2
Me
MeS
Me
Me
R3
R1
R1
Me
Me
X
R1
R1
N
N
HN
HN
MeO2C
ii
ii
CO2Me
62 X = Y = H,H
63 X = O, Y = H,H
64 X = Y = O
NH
N
R4
Me
Me
ButO2C
iii
OH
Me
N
C
MeO2C
CO2Me
CO2Me
O
Me
HO
CO2Me
O
57 R1 = Me, R2 = R3 = H,
R4 = CH2CO2Me
58 R1 = H, R2 = R4 = Me,
R3 = CH2CO2Me
54 R1 = Me, R2 = R3 = H, X = O
55 R1 = Me, R2 = R3 = H, X = S
MeO2C
65
ii
ii
+
CO2Me
Me
5
R1 = H, R2 = Me,
N
HN
R3 = CH2CO2Me, X = O
56 R1 = H, R2 = Me,
R3 = CH2CO2Me, X = S
iv
v
HO
N
NH
N
R2
R3
D
D
C
Me
Me
Me
R1
R1
Me
Me
OH
66
N
HN
N
59 R1 = Me, R2 = R3 = H,
R4 = CH2CO2Me
60 R1 = H, R2 = R4 = Me,
R3 = CH2CO2Me
2
MeO2C
MeO2C
CO2Me
Scheme 7 Reagents: i, TFA, MeOH then hν; ii, SeO2; iii, OsO4; iv, HCl
NH
R4
Me
thesised in this way. Heating the macrocycle 62 for 30 min with
selenium dioxide in 1,4-dioxane (an important choice of sol-
vent) yielded a mixture of the dioxo system 64 and mono-
oxidised material 63 (or with X and Y exchanged). The latter
gave the dioxo product 64 by further treatment in the same way
and when 62 was oxidised for 2 h, only dioxo system 64 was
isolated (42%).
MeO2C
CO2Me
Scheme 6 Reagents: i, TFA; ii, Lawesson’s reagent, Pri2NEt; iii, TFA,
(MeO)3CH; iv, TFA, MeOH; v, hν
open-chain system 57, probably as a mixture of double bond
isomers. Irradiation of this product for 4 days afforded the iso-
bacteriochlorin 59 in 47% overall yield for the two steps, a very
satisfactory outcome for such a macrocyclisation process.
The macrocycle 60 is still more closely related to the target 62
(Scheme 7) for the work on haem d1. The eastern unit 53 was
prepared from lactam 5 via thiolactam 56 (Scheme 6). The start-
ing material for the western unit 51 was the lactam 5 54 and the
additional carbon atom to form 51 was added to the corre-
sponding thiolactam 55 by a sulfur-extrusion step as usual.2
These rapidly purified materials 51 and 53 were immediately
condensed together to yield 58, followed by photochemical
cyclisation under the foregoing best conditions to yield the
isobacteriochlorin 60 in 55% yield. The foundation was thus
well laid for synthesis of the macrocycle 62.
The double bond was introduced into the ring D propionate
side-chain by following the procedure of Chang and Wu.13 This
involved treatment of the dioxo compound 64 with osmium
tetroxide to generate the two diols 65 and 66, which underwent
acid-catalysed dehydration and allylic rearrangement to yield
the metal-free macrocycle of haem d1 as its ester 2. A smaller
amount of the separable isomer having the acrylic side-chain on
ring C was also isolated. That the stereoselective synthesis of
the metal-free macrocycle of haem d1 had been accomplished
was shown by the identity of ester 2 with the corresponding
ester derived from natural haem d1, kindly provided by Profes-
sor R. Timkovich (Alabama). The comparisons were by UV–
visible and 1H NMR spectroscopy, mass spectrometry and
chromatography. Importantly, the circular dichroism spectrum
of the synthetic sample was virtually identical to that of the
sample derived from natural sources (Fig. 1). This unambigu-
ous synthesis firmly establishes that haem d1 has the 2R,7R
configuration also displayed by sirohydrochlorin 4 3, pre-
Synthesis of the ester 2 of the metal-free macrocycle
corresponding to haem d1
3
The best conditions established by the foregoing experiments
were now applied to the intermediates 61 and 53 (Scheme 7),
with the latter, more readily available material used in excess.
The condensation and photochemical reactions proceeded
smoothly to afford the isobacteriochlorin 62 in 53% yield over
the two steps; more than 100 mg of this material was syn-
corrin-23 67, vitamin B12 and the nickel-containing cofactor
F-430.14 It thus appears highly probable that all these materials
are members of a biosynthetically related family. Following our
brief account of the above synthesis,1 Kusch et al. outlined a
different synthesis of the macrocycle 62 enriched in the oppos-
ite 2S,7S enantiomer.15
2126
J. Chem. Soc., Perkin Trans. 1, 1997

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HO2C
Me
CO2H
HO2C
Me
CO2H
N
HN
HO2C
NH
HN
CO2H
H
H
HO2C
CO2H
HO2C
67
Me
CO2H
CO2H
HO2C
Me
A
B
N
HN
HO2C
NH
N
CO2H
CO2H
HO2C
HO2C
3
HO
Me
CO2H
OH
HO2C
Me
Fig. 1 Circular dichroism spectra determined in CH2Cl2 of (a) macro-
cycle 2 derived from natural haem d1, measured by Timkovich’s group,
and (b) the synthetic sample of 2, determined in Cambridge. The scales
for (a) and (b) differ slightly because the instruments used were not
identical.
A
B
CO2H
N
HN
H+
68
O
Me
CO2H
O
The foregoing stereochemical relationships strengthen the
view that positions C-3 and C-8, which are unsubstituted in
haem d1 1, still carry propionate residues in the earlier bio-
synthetic intermediates. Knowledge of the enzymic reactions by
which the propionates are removed and their sequence will only
come by pinpointing the enzymes involved. It may be helpful
for this phase of research to suggest that the pathway to haem
d1 probably follows that for the biosynthesis3 of vitamin B12 as
far as precorrin-2 67 (Scheme 8), and then goes forward to
sirohydrochlorin 3. Several reasonable mechanisms can be
envisaged for removal of the propionate side-chains, one possi-
bility being hydroxylation to 68, as illustrated, followed by a
reverse aldol reaction. Decarboxylation of the C-12 and C-18
acetate groups is shown in Scheme 8 as following the intro-
duction of the C-3 and C-8 oxo-functions (see 69) but
acid-catalysed decarboxylation at the precorrin-2 stage 67 is
mechanistically equally plausible. Research on the enzymes of
this pathway is awaited with interest. The availability of the
metal-free macrocycle of haem d1 2 together with the iso-
bacteriochlorin 62 and its mono-oxo 63 and dioxo 64 deriv-
atives from the synthesis described herein could be helpful in
this endeavour.
HO2C
Me
NH
N
HO2C
N
HN
O
O
H
HO2C
CO2H
69
Scheme 8
cm3), dried and evaporated under reduced pressure. Purification
by column chromatogaphy, eluting with ethyl acetate–hexane
(1:7), gave the benzyl ester 12 (18.3 g, 68%) as an oil (Found: C,
70.1; H, 6.6%; Mϩ, 274.1214. C16H18O4 requires C, 70.1; H,
6.6%; M, 274.1205); νmax(CHCl3)/cmϪ1 1780 and 1760 (C᎐O);
᎐
δH (400 MHz, CDCl3) 1.25 (3 H, s, Me), 2.21–2.35 (4 H, m,
CH2CCH2), 4.86 (1 H, t, J 8, CH᎐O), 5.00–5.10 (2 H, m,
CH᎐CH ), 5.21 (2 H, br s, CH Ph), 5.59–5.70 (1 H, m,
CH᎐CH ) and 7.26–7.39 (5 H, m, Ph); δ (100 MHz, CDCl )
22.9 (Me), 36.9, 41.6 and 42.6 (CH2CCH2), 67.5 (CH2Ph), 72.8
᎐
᎐
2
2
2
C
3
(CH᎐O), 119.9 (CH᎐CH ), 128.7, 128.6 and 134.8 (Ph), 132.2
᎐
2
(CH᎐CH ) and 169.8 and 179.8 (C᎐O); m/z (FD) 274 (Mϩ,
Experimental
᎐
᎐
2
100%).
General
General directions are as given in the first of this set of three
papers.2
(3R,5S)-5-Benzyloxycarbonyl-3-methoxycarbonylmethyl-3-
methyltetrahydrofuran-2-one 15
(3S,5S)-3-Allyl-5-benzyloxycarbonyl-3-methyltetrahydrofuran-
2-one 12
A solution of benzyl ester 12 (18.0 g, 65.7 mmol) in carbon
tetrachloride (100 cm3), acetonitrile (100 cm3) and glacial acetic
acid (50 cm3) was added dropwise over 2 h to a vigorously
stirred mixture of ruthenium() oxide monohydrate (88 mg,
0.01 equiv.) and sodium periodate (56.2 g, 263 mmol) in water
(300 cm3) at 0 ЊC. The mixture was allowed to warm to room
temperature, then diluted with dichloromethane (100 cm3) and
A mixture of acid 11 (18.0 g, 97.8 mmol), anhydrous potassium
carbonate (14.9 g, 108 mmol), benzyl bromide (17.4 cm3, 147
mmol) and dry N,N-dimethylformamide (270 cm3) was stirred
for 6 h at room temperature. tert-Butyl methyl ether (600 cm3)
was added and the mixture was washed with water (4 × 500
J. Chem. Soc., Perkin Trans. 1, 1997
2127

View Article Online
filtered through Celite. Dichloromethane (100 cm3) and water
(100 cm3) were added and the organic phase was separated. The
aqueous phase was acidified to pH 1 with concentrated hydro-
chloric acid and extracted with ethyl acetate (3 × 100 cm3). The
combined organic layers were dried and evaporated under
reduced pressure. A solution of the resulting oil in acetone (400
cm3) was treated with Jones’ reagent (2.58 mol dmϪ3; 51 cm3,
0.131 mol) over 30 min and stirred for 2 h at room temperature.
Propan-2-ol (10 cm3) was added and the acetone was evapor-
ated under reduced pressure. Water (300 cm3) was added and
the solution was extracted with diethyl ether (5 × 100 cm3). The
combined extracts were concentrated to 100 cm3 under reduced
pressure and extracted with saturated aqueous sodium hydro-
gen carbonate (3 × 100 cm3). The combined aqueous extracts
were acidified to pH 1 with concentrated hydrochloric acid,
saturated with sodium chloride and extracted with diethyl ether
(2 × 100 cm3), ethyl acetate (2 × 100 cm3) and dichloromethane
(100 cm3). The combined organic extracts were dried and evap-
orated under reduced pressure. A solution of the resulting oil in
tetrahydrofuran (300 cm3) was stirred with an ethereal solution
of diazomethane (2 equiv.) for 15 min and then the excess
diazomethane was destroyed by the dropwise addition of
glacial acetic acid. The solvent was evaporated under reduced
pressure. Purification by column chromatography, eluting with
hexane–ethyl acetate (5:2), gave the methyl ester 15 (13.6 g,
68%) as an oil (Found: C, 62.5; H, 6.1. C16H18O6 requires C,
62.7; H, 5.9%); νmax(CHCl3)/cmϪ1 1780, 1760 and 1737; δH (400
MHz, CDCl3) 1.32 (3 H, s, Me), 2.46 (1 H, dd, J 13 and 9) and
2.50 (1 H, dd, J 13 and 8, CH2CH᎐O), 2.62 and 2.72 (each 1 H,
d, J 17, CH2CO), 3.63 (3 H, s, OMe), 4.91 (1 H, t, J 8, CH᎐O),
5.22 and 5.25 (each 1 H, d, J 12, CH2Ph) and 7.33–7.37 (5 H, m,
Ph); δC(100 MHz, CDCl3) 23.1 (Me), 37.3, 40.9 and 41.1
(CH2CCH2), 51.9 (OMe), 67.5 (CH2Ph), 73.0 (CH᎐O), 128.5,
solid, mp 105–107 ЊC (Found: Mϩ, 412.2047. C28H28O3 requires
M, 412.2038); [α]D ϩ43.3 (c 1.12, CHCl3); νmax(CHCl3)/cmϪ1
1775; δH (400 MHz, CDCl3) 0.91 (3 H, s, Me), 2.15 (2 H, d, J 8,
CH C᎐C), 2.43 and 2.56 (each 1 H, d, J 17, CH CO), 3.14 and
᎐
2
2
3.43 (each 1 H, dd, J 10.5 and 4, CH2O), 4.28 (1 H, t, J 4,
CH᎐O), 5.06–5.12 (2 H, m, CH᎐CH ), 5.63–5.72 (1 H, m,
᎐
2
CH᎐CH ) and 7.22–7.46 (15 H, m, Ph); δ (100 MHz, CDCl )
᎐
2
C
3
19.4 (Me), 41.3, 41.8 and 44.6 (CH2CCH2), 63.6 (CH2O), 84.9
(CH᎐O), 87.4 (CPh ), 119.6 (CH᎐CH ), 127.1, 127.9, 128.6 and
᎐
3
2
143.3 (Ph), 132.6 (CH᎐CH ) and 176.4 (C᎐O); m/z (FD) 412
᎐
᎐
2
(Mϩ, 100%).
(4S,5S)-4-Allyl-5-hydroxymethyl-4-methyltetrahydrofuran-2-
one 20
A solution of lactone 19 (6.9 g, 16.7 mmol) in dry methanol
(150 cm3) was heated under reflux with Amberlyst 15(Hϩ) resin
(1.5 g) for 1.5 h, then filtered through a short column of basic
alumina and evaporated under reduced pressure. Purification
by column chromatography, eluting with hexane–ethyl acetate
(1:1), gave the alcohol 20 (2.64 g, 93%) as an oil (Found: Mϩ Ϫ
CH2OH, 139.0763. C9H14O3 requires M Ϫ CH2OH, 139.0759);
νmax(CHCl3)/cmϪ1 3400 and 1775; δH (400 MHz, CDCl3) 1.08 (3
H, s, Me), 2.15 (2 H, d, J 7, CH C᎐C), 2.37 (2 H, s, CH CO),
᎐
2
2
3.27 (1 H, t, J 6, OH), 3.69–3.81 (2 H, m, CH2OH) 4.20 (1 H,
dd, J 5 and 3, CH᎐O), 5.05–5.12 (2 H, m, CH᎐CH ) and 5.65–
᎐
2
5.76 (1 H, m, CH᎐CH ); δ (100 MHz, CDCl ) 19.5 (Me), 41.1,
᎐
2
C
3
41.8 and 44.4 (CH2CCH2), 61.4 (CH2OH), 86.9 (CH᎐O), 119.6
(CH᎐CH ), 132.6 (CH᎐CH ) and 176.8 (C᎐O); m/z (FD) 170
᎐
᎐
᎐
2
2
(Mϩ, 100%).
(4S,5S)-4-Allyl-5-carboxy-4-methyltetrahydrofuran-2-one 21
A solution of alcohol 20 (2.54 g, 15 mmol) in acetone (150 cm3)
was treated with Jones’ reagent (2.58 mol dmϪ3; 11.6 cm3, 29.9
mmol) over 30 min and then stirred for 12 h at room temp-
erature. Propan-2-ol (10 cm3) was added and the acetone was
evaporated under reduced pressure. Water (300 cm3) was added
and the solution was extracted with diethyl ether (5 × 100 cm3).
The combined extracts were concentrated under reduced pres-
sure to 100 cm3 and extracted with saturated aqueous sodium
hydrogen carbonate (3 × 100 cm3). The combined aqueous
extracts were acidified to pH 1 with concentrated hydrochloric
acid, then saturated with sodium chloride and extracted with
diethyl ether (2 × 100 cm3), ethyl acetate (2 × 100 cm3) and
dichloromethane (100 cm3). The combined organic extracts
were dried and evaporated under reduced pressure to give the
carboxylic acid 21 (2.75 g, 100%) as an oil (Found: Mϩ,
184.0722. C9H12O4 requires M, 184.0736); νmax(CHCl3)/cmϪ1
1785 and 1735; δH (400 MHz, CDCl3) 1.13 (3 H, s, Me), 2.30 (2
128.7 and 134.9 (Ph) and 169.3, 170.6 and 179.1 (C᎐O); m/z
᎐
(FD) 306 (Mϩ, 100%).
(3R,5S)-5-Carboxy-3-methoxycarbonylmethyl-3-methyltetra-
hydrofuran-2-one 9
A solution of benzyl ester 15 (13.62 g, 44.5 mmol) in methanol
(400 cm3) was stirred under an atmosphere of hydrogen with
10% palladium-on-carbon (750 mg) for 3 h and then filtered
through Celite. The methanol was evaporated under reduced
pressure to give the carboxylic acid 9 (9.53 g, 99%) as a crystal-
line solid, mp 118–124 ЊC (Found: C, 49.9; H, 5.5. C9H12O6
requires C, 50.0; H, 5.6%); νmax(CHCl3)/cmϪ1 1762, 1736 and
1724; δH (400 MHz, CDCl3) 1.35 (3 H, s, Me), 2.49 (1 H, dd, J 13
and 8.5) and 2.55 (1 H, dd, J 13 and 9, CH2CH᎐O), 2.66 and
2.81 (each 1 H, d, J 17, CH2CO), 3.69 (3 H, s, OMe), 4.95 (1 H,
t, J 8.5, CH᎐O) and 5.30 (1 H, br s, CO2H); δC(100 MHz,
CDCl3) 23.1 (Me), 37.7, 41.1 and 41.9 (CH2CCH2), 51.8 (OMe),
H, d, J 7, CH C᎐C), 2.40 and 2.48 (each 1 H, d, J 17, CH CO),
᎐
2
2
4.64 (1 H, s, CH᎐O), 5.12–5.20 (2 H, m, CH᎐CH ), 5.70–5.77 (1
᎐
2
73.3 (CH᎐O) and 171.1, 171.4 and 179.8 (C᎐O).
H, m, CH᎐CH ) and 10.45 (1 H, br s, CO H); δ (100 MHz,
᎐
2 2 C
᎐
CDCl3) 20.7 (Me), 39.7, 42.6 and 43.5 (CH2CCH2), 82.47
(4S,5S)-4-Allyl-4-methyl-5-triphenylmethoxymethyltetra-
hydrofuran-2-one 19
(CH᎐O), 120.57 (CH᎐CH ), 131.72 (CH᎐CH ) and 172.54 and
᎐
᎐
2
2
175.50 (C᎐O); m/z (FD) 184 (Mϩ, 100%).
᎐
A suspension of copper() cyanide (2.42 g, 27 mmol) in dry
tetrahydrofuran at Ϫ78 ЊC under argon was stirred with a solu-
tion of methyllithium in diethyl ether (1.4 mol dmϪ3; 38.6 cm3,
54 mmol). The resultant solution was allowed to warm to 0 ЊC
over 30 min, then cooled to Ϫ78 ЊC again, treated with allyl-
tri-n-butylstannane (16.8 cm3, 54 mmol), allowed to warm to
0 ЊC over 30 min and then cooled again to Ϫ78 ЊC. A solution
of butenolide 178 (5 g, 13.5 mmol) in dry tetrahydrofuran (30
cm3) at Ϫ78 ЊC was added over 1 min. After 30 min at Ϫ78 ЊC
saturated aqueous ammonium chloride (200 cm3) was added,
followed by concentrated aqueous ammonia (200 cm3) and
ethyl acetate (300 cm3). The organic phase was separated,
washed with brine and evaporated under reduced pressure.
Purification by column chromatography, eluting with hexane–
diethyl ether, gave recovered butenolide 17 (1 g) and allyl lac-
tone 19 (1.11 g, 25% based on unrecovered 17) as a crystalline
(4S,5S)-4-Allyl-5-benzyloxycarbonyl-4-methyltetrahydrofuran-
2-one 22
A mixture of acid 21 (2.70 g, 14.7 mmol), potassium carbonate
(2.43 g, 17.6 mmol) and benzyl bromide (8.73 cm3) in dry N,N-
dimethylformamide (150 cm3) was stirred for 6 h at room temp-
erature, then evaporated under high vacuum. Water (50 cm3)
was added and the mixture was extracted with ethyl acetate (100
cm3 then 3 × 50 cm3). The combined organic extracts were dried
and evaporated under reduced pressure. Purification by column
chromatogaphy, eluting with ethyl acetate–hexane, gave the
benzyl ester 22 (3.07 g, 76%) as an oil (Found: Mϩ, 274.1193.
C16H18O4 requires M, 274.1205); νmax(CHCl3)/cmϪ1 1795 and
1750; δH (400 MHz, CDCl3) 0.98 (3 H, s, Me), 2.25 (2 H, d, J 7,
CH C᎐C), 2.40 (2 H, m, CH CO), 4.63 (1 H, s, CH᎐O), 5.11–
᎐
2
2
5.28 (4 H, m, CH᎐CH and CH2Ph), 5.67–5.78 (1 H, m,
᎐
2
2128
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
CH᎐CH ) and 7.33–7.41 (5 H, m, Ph); δ (100 MHz, CDCl )
20.6 (Me), 39.6, 42.8 and 43.9 (CH2CCH2), 67.3 (CH2Ph), 82.6
lactone 19. The prenyl cuprate was prepared from a solution of
᎐
2
C
3
methyllithium (1.28 cm3, 1.79 mmol), copper() cyanide (80 mg,
0.893 mmol) and prenyltri-n-butylstannane (619 µl, 1.79 mmol)
in dry tetrahydrofuran (1 cm3) and a solution of butenolide 17
in tetrahydrofuran (0.7 cm3) was added. Work up and purifi-
cation by PLC gave the lactone 28 (104 mg, 79%) as a crystalline
solid, mp 108–110 ЊC (Found: Mϩ, 440.2321. C30H32O3 requires
M, 440.2351); νmax(CHCl3)/cmϪ1 1765; δH (400 MHz, CDCl3)
0.93, 0.95, 0.97 (each 3 H, s, Me), 2.40 and 2.70 (each 1 H, d, J
18, CH2CO), 3.07 (1 H, dd, J 10.5 and 4) and 3.47 (1 H, dd, J
10.5 and 3, CH2O), 4.56 (1 H, t, J 3.5, CH᎐O), 4.98–5.05 (2 H,
(CH᎐O), 120.5 (CH᎐CH ), 128.6, 128.7 and 134.6 (Ph), 131.8
᎐
2
(CH᎐CH ) and 168.4 and 175.0 (C᎐O); m/z (FD) 274 (Mϩ,
᎐
᎐
2
100%).
(4S,5S)-5-Benzyloxycarbonyl-4-methoxycarbonylmethyl-4-
methyltetrahydrofuran-2-one 25
A solution of benzyl ester 22 (2.43 g, 8.87 mmol) in carbon
tetrachloride (23 cm3), acetonitrile (23 cm3) and glacial acetic
acid (12 cm3) was added dropwise over 2 h to a vigorously
stirred mixture of ruthenium() oxide monohydrate (30 mg)
and sodium periodate (7.59 g, 35.5 mmol) in water (70 cm3) at
0 ЊC. The solution was allowed to warm to room temperature,
diluted with dichloromethane (50 cm3) and filtered through
Celite. Dichloromethane (50 cm3) and water (50 cm3) were
added and the organic phase was separated. The aqueous phase
was acidified to pH 1 with concentrated hydrochloric acid and
extracted with ethyl acetate (3 × 50 cm3). The combined organic
layers were dried and evaporated under reduced pressure. A
solution of the resulting oil in acetone (100 cm3) was treated
with Jones’ reagent (2.58 mol dmϪ3; 3.5 cm3, 9.01 mmol) over 30
min and stirred for 2 h at room temperature. Propan-2-ol (5
cm3) was added and the acetone was evaporated under reduced
pressure. Water (100 cm3) was added and the solution was
extracted with diethyl ether (5 × 50 cm3). The combined
extracts were concentrated to 50 cm3 under reduced pressure
and extracted with saturated aqueous sodium hydrogen car-
bonate (3 × 50 cm3). The combined aqueous extracts were acid-
ified to pH 1 with concentrated hydrochloric acid, saturated
with sodium chloride and extracted with diethyl ether (2 × 50
cm3), ethyl acetate (2 × 50 cm3) and dichloromethane (50 cm3).
The combined organic extracts were dried and evaporated
under reduced pressure. A solution of the resulting oil in tetra-
hydrofuran (75 cm3) was treated with an ethereal solution of
diazomethane (2 equiv.) and stirred for 15 min. The diazo-
methane was then destroyed by the dropwise addition of glacial
acetic acid and the solvent was evaporated under reduced pres-
sure. Purification by column chromatography, eluting with
hexane–ethyl acetate (3:1), gave the methyl ester 25 (2.32 g,
86%) as an oil (Found: Mϩ, 306.1102. C16H18O6 requires M,
306.1103); νmax(CHCl3)/cmϪ1 1800 and 1740; δH (400 MHz,
CDCl3) 1.03 (3 H, s, Me), 2.51 and 2.70 (each 1 H, d, J 17.5,
3-H2), 2.54 and 2.59 (each 1 H, d, J 15.5, CH2CO2Me), 3.65 (3
H, s, OMe), 4.86 (1 H, s, CH᎐O), 5.17–5.24 (2 H, m, CH2Ph)
and 7.33–7.35 (5 H, s, Ph); δC(100 MHz, CDCl3) 20.7 (Me),
40.2, 41.4 and 42.2 (CH2CCH2), 51.8 (OMe), 67.4 (CH2Ph),
82.1 (CH᎐O), 128.6, 128.7 and 134.5 (Ph) and 167.7, 170.5 and
m, CH᎐CH ), 5.75 (1 H, dd, J 17 and 11, CH᎐CH ) and 7.21–
᎐
᎐
2
2
7.50 (15 H, m, Ph); δC(100 MHz, CDCl3) 17.1, 22.1 and 22.5
(3 × Me), 39.5 (CH2CO), 41.3 and 46.4 (MeC᎐CMe2), 63.6
(CH O), 82.9 (CH᎐O), 87.3 (CPh ), 114.2 (CH᎐CH ), 127.0,
᎐
2
3
2
127.8, 128.5 and 143.4 (Ph), 143.3 (CH᎐CH ) and 176.7 (C᎐O);
᎐
᎐
2
m/z (FD) 440 (Mϩ, 100%).
4-(2-Methoxycarbonylethyl)-2-[(2S,4R)-4-methoxycarbonyl-
methyl-4-methyl-5-oxotetrahydrofuran-2-yl]formyl-3,5-
dimethylpyrrole 32
A solution of acid 9 (5 g, 23 mmol), 2,2Ј-dipyridyl disulfide
(7.64 g, 34.7 mmol) and triphenylphosphine (9.1 g, 34.7 mmol)
in dry toluene (150 cm3) was kept under argon at room temper-
ature for 22 h to give a solution containing thioester 30. A
solution of methylmagnesium chloride in diethyl ether (3 mol
dmϪ3; 31 cm3, 93 mmol) was added to a stirred solution of α-
free pyrrole 105 (16.8 g, 92.3 mmol) in dry toluene (400 cm3)
and dry tetrahydrofuran (5 cm3) at Ϫ78 ЊC under argon. This
solution was allowed to warm for 10 min with vigorous stirring
and then cooled to Ϫ78 ЊC and the above thioester solution was
then added via double-ended needle under a positive pressure
of argon over a period of 30 min. The solution was stirred at
Ϫ78 ЊC for a further 1.5 h, then treated with saturated aqueous
ammonium chloride (10 cm3) and allowed to warm to room
temperature. Diethyl ether (300 cm3), saturated aqueous
ammonium chloride (200 cm3) and water (200 cm3) were then
added. The organic phase was separated, washed with 10%
aqueous potassium carbonate (200 cm3) and then water (200
cm3), dried and evaporated under reduced pressure. Column
chromatography, eluting with hexane–ethyl acetate, gave
recovered α-free pyrrole 10 (8.40 g, 50%) and ketone 32 (8.28 g,
94%) as a gum (Found: Mϩ, 379.1612. C19H25NO7 requires M,
379.1631); λmax(MeOH)/nm 314; νmax(CHCl3)/cmϪ1 3445, 1781,
1731 and 1620; δH (400 MHz, CDCl3) 1.37, 2.27 and 2.33 (each 3
H, s, Me), 2.36–2.44 (3 H, m, CH2CH2CO and CHAHBCH᎐O),
2.61–2.73 (4 H, m, CH2CH2CO, CHAHBCH᎐O and CHAHB-
CO), 2.88 (1 H, d, J 17.5, CHAHBCO), 3.65 and 3.66 (each 3 H,
s, OMe), 5.09 (1 H, t, J 8, CH᎐O) and 9.63 (1 H, br s, NH);
δC(100 MHz, CDCl3) 11.5 and 11.6 (Ar–Me), 19.1 (CH2CH2-
CO), 22.8 (CMe), 34.6 (CH2CH2CO), 37.2, 40.8 and 41.1
(CH2CCH2), 51.5 and 52.0 (OMe), 79.0 (CH᎐O), 121.4, 124.1,
131.4 and 134.1 (pyrrole-C) and 171.5, 173.3, 179.5 and 182.4
174.2 (C᎐O); m/z (FD) 306 (Mϩ, 100%).
᎐
(4S,5S)-5-Carboxy-4-methoxycarbonylmethyl-4-methyltetra-
hydrofuran-2-one 8
A solution of benzyl ester 25 (2.80 g, 9.15 mmol) in methanol
(100 cm3) was stirred under an atmosphere of hydrogen with
10% palladium-on-carbon (250 mg) for 3 h at room temper-
ature then filtered through Celite. The methanol was evaporated
under reduced pressure to give the carboxylic acid 8 (1.97 g,
100%) as an oil (Found: Mϩ Ϫ CO2H, 171.0669. C9H12O6
requires M Ϫ CO2H, 171.0657); νmax(CHCl3)/cmϪ1 1795 and
1735; δH (400 MHz, CDCl3) 1.19 (3 H, s, Me), 2.54 and 2.78
(each 1 H, d, J 17.5, 3-H2), 2.60 and 2.68 (1 H, d, J 16,
CH2CO2Me), 3.67 (3 H, s, OMe), 4.91 (1 H, s, CH᎐O) and 9.24
(1 H, br s, CO2H); δC(100 MHz, CDCl3) 20.8 (Me), 40.5, 41.1
and 41.9 (CH2CCH2), 52.0 (OMe), 82.1 (CH᎐O), 170.9, 171.3
(C᎐O); m/z (FD) 379 (Mϩ, 100%); m/z (EI) 379 (Mϩ), 348
᎐
(M Ϫ OMe) and 306 (M Ϫ CH2CO2Me).
5-Formyl-4-(2-methoxycarbonylethyl)-2-[(2S,4R)-4-methoxy-
carbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-yl]formyl-3-
methylpyrrole 33
Freshly distilled sulfuryl chloride (3.6 cm3, 45 mmol) in dry
dichloromethane (170 cm3) was added over 4 min to a stirred
solution of ketone 32 (8.5 g, 22.4 mmol) in dry dichloro-
methane (255 cm3) at Ϫ5 ЊC under argon. The solution was
stirred for 10 min and then evaporated under reduced pressure.
Acetone (150 cm3) and water (300 cm3) were added and the
solution was stirred for 15 min. More water (200 cm3) was
added and the mixture was extracted with dichloromethane
(500 cm3 then 2 × 200 cm3). The combined extracts were dried
and evaporated under reduced pressure to give crude aldehyde
33 (9.00 g) as a foam, which was used in the next step without
and 175.1 (C᎐O); m/z (FD) 216 (Mϩ, 100%).
᎐
(4R,5S)-4-Methyl-4-(1,1-dimethylprop-2-enyl)-5-triphenyl-
methoxymethyltetrahydrofuran-2-one 28
Butenolide 178 (110 mg, 0.298 mmol) was reacted with (pre-
nyl)2CuCNLi2 as described above for the preparation of allyl
J. Chem. Soc., Perkin Trans. 1, 1997
2129

View Article Online
further purification (Found: Mϩ, 393.1421. C19H23NO8 requires
M, 393.1424); λmax(MeOH)/nm 246 and 315; νmax(CHCl3)/cmϪ1
3940, 3000, 1800, 1740 and 1660; δH (400 MHz, CDCl3) 1.38 and
2.33 (each 3 H, s, Me), 2.39 (1 H, dd, J 13 and 7.5) and 2.71 (1
H, dd, J 13 and 10, CH2CH᎐O), 2.56 (2 H, t, J 8, CH2CH2CO),
2.66 and 2.86 (each 1 H, d, J 18, CH2CO), 3.06 (2 H, t, J 8,
CH2CH2CO), 3.63 and 3.64 (each 3 H, s, OMe), 5.17 (1 H, dd, J
10 and 7.5, CH᎐O), 9.89 (1 H, s, CHO) and 10.48 (1 H, br s,
NH); δC(100 MHz, CDCl3) 10.3 (3-Me), 18.5 (CH2CH2CO),
23.1 (CMe), 34.5 (CH2CH2CO), 36.1, 40.8 and 41.9 (CH2-
CCH2), 51.5 and 51.9 (OMe), 78.1 (CH᎐O), 128.9, 129.6 and
130.9 (pyrrole-C) and 171.2, 172.6, 178.9, 180.6 and 186.2
305; νmax(CHCl3)/cmϪ1 3435, 2955, 1790, 1735 and 1645; δH (400
MHz, CDCl3) 1.37 (3 H, s, CMe), 1.55 (9 H, s, But), 2.32 (3 H, s,
4-Me), 2.39 (1 H, dd, J 13 and 8) and 2.65 (1 H, dd, J 13 and 9,
CH2CH᎐O), 2.50 (2 H, t, J 8, CH2CH2CO), 2.63 and 2.80 (each
1 H, d, J 17, CH2CO), 3.01 (2 H, t, J 8, CH2CH2CO) 3.60 and
3.65 (each 3 H, s, OMe), 5.18 (1 H, dd, J 8 and 9, CH᎐O) and
10.11 (1 H, br s, NH); δC(100 MHz, CDCl3) 10.7 (4-Me), 19.7
(CH2CH2CO), 23.4 (CMe), 28.2 (CMe3), 34.6, 36.6, 40.6 and
41.0 (CH2CH2CO and CH2CCH2), 51.5 and 51.9 (OMe), 78.3
(CH᎐O), 82.3 (CMe3), 124.9, 126.7, 128.6 and 130.0 (pyrrole-C)
and 159.5, 170.7, 173.2, 178.7 and 185.3 (C᎐O); m/z (FD) 465
᎐
(Mϩ, 100%).
(C᎐O); m/z (FD) 393 (Mϩ, 100%).
᎐
Benzyl 3-(2-methoxycarbonylethyl)-5-[(2S,4R)-4-methoxy-
carbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-yl]formyl-4-
methylpyrrole-2-carboxylate
3-(2-Methoxycarbonylethyl)-5-[(2S,4R)-4-methoxycarbonyl-
methyl-4-methyl-5-oxotetrahydrofuran-2-yl]formyl-4-
methylpyrrole-2-carboxylic acid 34
A mixture of acid 34 (1 g, 2.44 mmol), anhydrous potassium
carbonate (610 mg, 6.22 mmol) and freshly distilled benzyl
bromide (875 cm3, 7.36 mmol) in dry N,N-dimethylformamide
(40 cm3) was stirred for 12 h at room temperature under argon.
tert-Butyl methyl ether (200 cm3) was then added and the mix-
ture was washed with water (3 × 75 cm3), dried and evaporated
under reduced pressure. Purification by column chroma-
tography, eluting with dichloromethane–ethyl acetate (12:1),
gave the benzyl ester (corresponding to tert-butyl ester 7) (920
mg, 75%) as a solid, mp 89–90 ЊC (Found: C, 62.6; H, 5.7; N,
2.9%; Mϩ, 499.1829. C26H29NO9 requires C, 62.5; H, 5.85; N,
2.8%; M, 499.1842); λmax(MeOH)/nm 233 and 304; νmax
(CHCl3)/cmϪ1 3440, 2950, 1800, 1735 and 1650; δH (400 MHz,
CDCl3) 1.37 (3 H, s, CMe), 2.33 (3 H, s, 4-Me), 2.39 (1 H, dd, J
13 and 8) and 2.68 (1 H, dd, J 13 and 9, CH2CH᎐O), 2.49 (2 H,
t, J 8, CH2CH2CO), 2.63 and 2.80 (each 1 H, d, J 17, CH2CO),
3.03–3.07 (2 H, m, CH2CH2CO), 3.53 and 3.62 (each 3 H, s,
OMe), 5.20 (1 H, dd, J 9 and 8, CH᎐O), 5.33 (2 H, s, CH2Ph),
7.32–7.43 (5 H, m, Ph) and 10.22 (1 H, br s, NH); δC(67.7 MHz,
CDCl3) 10.8 (4-Me), 19.8 (CH2CH2CO), 23.4 (CMe), 34.4
(CH2CH2CO), 36.4, 40.7 and 41.1 (CH2CCH2), 51.7 and 52.0
(OMe), 60.7 (CH2Ph), 78.3 (CH᎐O), 123.2, 127.3, 128.1, 128.3,
128.7, 129.9 and 135.3 (pyrrole-C and Ph) and 160.0, 170.8,
A solution of potassium permanganate (6.11 g, 38.7 mmol) in
water (167 cm3) and acetone (122 cm3) was added over 2 h at
room temperature to a solution of formylpyrrole 33 (9 g) in
acetone (200 cm3). The mixture was stirred for a further 3 h and
then the acetone was evaporated under reduced pressure.
Dichloromethane (150 cm3), water (100 cm3) and sodium
metabisulfite (25 g) were added. Concentrated hydrochloric
acid was added dropwise until the pH of the aqueous layer
was 1. The organic phase was then separated and the aqueous
phase was saturated with sodium chloride and extracted with
dichloromethane (2 × 100 cm3). The combined organic extracts
were evaporated under reduced pressure. Saturated aqueous
sodium hydrogen carbonate (400 cm3) was added and the mix-
ture was extracted with dichloromethane (100 cm3). The
organic extract was evaporated under reduced pressure to give
recovered formylpyrrole 33 (1.43 g). The aqueous phase was
acidified to pH 1 with concentrated hydrochloric acid, extracted
with dichloromethane (4 × 200 cm3), then saturated with
sodium chloride and further extracted with dichloromethane
(2 × 100 cm3). The combined organic extracts were dried and
evaporated under reduced pressure to give the carboxylic acid
34 (6.32 g) as a foam. The recovered formyl pyrrole 33 (1.43 g)
was oxidised as described above to give further acid 34 (678 mg;
total yield 7.00 g, 76% from ketone 32) (Found: Mϩ, 409.1371.
C19H23NO9 requires M, 409.1373); λmax(MeOH)/nm 230 and
305; νmax(CHCl3)/cmϪ1 3450, 2980, 1800, 1740 and 1660; δH (400
MHz, CDCl3) 1.38 (3 H, s, CMe), 2.33 (3 H, s, 4-Me), 2.41 (1 H,
dd, J 13 and 8) and 2.70 (1 H, dd, J 13 and 9, CH2CH᎐O), 2.54
(2 H, t, J 8, CH2CH2CO), 2.65 and 2.83 (each 1 H, d, J 17,
CH2CO), 3.06 (3 H, t, J 8, CH2CH2CO), 3.63 and 3.66 (each 3
H, s, OMe), 5.24 (1 H, dd, J 9 and 8, CH᎐O) and 10.34 (1 H, br
s, NH); δC(100 MHz, CDCl3) 10.7 (4-Me), 19.6 (CH2CH2CO),
23.3 (CMe), 34.3 (CH2CH2CO), 36.3, 40.8 and 41.0 (CH2-
CCH2), 51.6 and 52.0 (OMe), 78.1 (CH᎐O), 122.6, 128.1, 130.0
and 130.8 (pyrrole-C) and 164.6, 171.0, 173.5, 179.1 and 185.9
173.2, 178.9 and 185.7 (C᎐O); m/z (FD) 499 (Mϩ, 100%).
᎐
tert-Butyl 3-(2-methoxycarbonylethyl)-5-hydroxy[(2S,4R)-4-
methoxycarbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-
yl]methyl-4-methylpyrrole-2-carboxylate 35
A solution of tert-butyl ester 7 (5.74 g, 12.3 mmol) in dry tetra-
hydrofuran (150 cm3) under argon was treated with sodium
borohydride (155 mg, 4.10 mmol) portionwise over 30 min with
the temperature maintained at Ϫ5 ЊC, then warmed to room
temperature over 5 min, mixed with dilute hydrochloric acid
(0.5 mol dmϪ3; 210 cm3) and extracted with dichloromethane
(4 × 100 cm3). The combined organic extracts were dried and
evaporated under reduced pressure to give the diastereoiso-
meric alcohols 35 as an oil (ca. 5.74 g, 100%). These alcohols
were generally used as a mixture in the next reaction but for
characterisation they were separated by PLC using 5% MeOH
in CH2Cl2.
(C᎐O); m/z (FD) 409 (Mϩ, 100%).
᎐
tert-Butyl 3-(2-methoxycarbonylethyl)-5-[(2S,4R)-4-methoxy-
carbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-yl]formyl-4-
methylpyrrole-2-carboxylate 7
Lower Rf diastereoisomer (Found: Mϩ, 467.2132. C23H33-
NO9 requires M, 467.2155); λmax(MeOH)/nm 272; νmax(CHCl3)/
cmϪ1 3440, 2950, 1775, 1730 and 1680; δH (400 MHz, CDCl3)
1.25 (3 H, s, CMe), 1.52 (9 H, s, But), 1.86 (1 H, dd, J 13 and 7)
and 2.21 (1 H, dd, J 13 and 10, CH2CH᎐O), 1.97 (3 H, s, 4-Me),
2.47 (2 H, t, J 8, CH2CH2CO), 2.56 and 2.75 (each 1 H, d, J 17,
CH2CO), 2.92–2.96 (2 H, m, CH2CH2CO), 3.54 (1 H, d, J 4,
OH), 3.64 and 3.66 (each 3 H, s, OMe), 4.66–4.68 and 4.84–4.86
(each 1 H, m, CHCHOH) and 9.28 (1 H, br s, NH); δC(100
MHz, CDCl3) 8.9 (4-Me), 20.6 (CH2CH2CO), 23.5 (CMe), 28.3
(CMe3), 34.9, 35.4, 40.9 and 41.8 (CH2CH2CO and CH2CCH2),
51.4 and 51.9 (OMe), 68.3 (CHOH), 79.7 (CHCHOH), 81.0
(CMe3), 117.5, 120.3, 128.2 and 129.0 (pyrrole-C) and 160.8,
Concentrated sulfuric acid (150 mm3) was added dropwise to a
solution of acid 34 (6.32 g, 15.5 mmol) in isobutene (25 cm3)
and dry chloroform (50 cm3). The reaction vessel was then
sealed and the mixture was stirred for 36 h. Saturated aqueous
sodium hydrogen carbonate (5 cm3) was added and the iso-
butene was evaporated under a stream of argon. Saturated
aqueous sodium hydrogen carbonate (100 cm3) was added and
the mixture was extracted with dichloromethane (60 cm3 then
2 × 100 cm3). The combined organic extracts were dried and
evaporated under reduced pressure. Purification by column
chromatography, eluting with hexane–ethyl acetate, gave the
tert-butyl ester 7 (5.75g, 80%) as an oil (Found: Mϩ, 465.1995.
C23H31NO9 requires M, 465.1999); λmax(MeOH)/nm 233 and
171.3, 173.7 and 179.8 (C᎐O); m/z (FD) 467 (Mϩ, 100%).
᎐
2130
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Higher Rf diastereoisomer (Found: Mϩ, 467.2147); λmax
(MeOH)/nm 273; νmax(CHCl3)/cmϪ1 3460, 2980, 1780, 1740 and
1685; δH (400 MHz, CDCl3) 1.25 (3 H, s, CMe), 1.52 (9 H, s,
But), 1.75 (1 H, dd, J 13 and 7, CHAHBCH᎐O), 1.97 (3 H, s,
4-Me), 2.43–2.49 (3 H, m, CHAHBCH᎐O and CH2CH2CO),
2.57 and 2.75 (each 1 H, d, J 17, CH2CO), 2.90–2.98 (2 H, m,
CH2CH2CO), 3.56 (1 H, d, J 2.5, OH), 3.64 and 3.67 (each 3 H,
s, OMe), 4.58–4.63 and 5.23–5.25 (each 1 H, m, CHCHOH)
and 9.20 (1 H, br s, NH); δC(100 MHz, CDCl3) 8.7 (4-Me), 20.6
(CH2CH2CO), 23.5 (CMe), 28.4 (CMe3), 32.9, 35.0, 41.0 and
41.8 (CH2CH2CO and CH2CCH2), 51.5 and 52.0 (OMe), 66.7
(CHOH), 78.4 (CHCHOH), 80.9 (CMe3), 115.8, 119.6, 128.6
next reaction but were separated for characterisation by PLC
using hexane–ethyl acetate (2:1).
Lower Rf diastereoisomer (Found: Mϩ, 509.2227. C25H35-
NO10 requires M, 509.2261); λmax(MeOH)/nm 273; νmax
(CHCl3)/cmϪ1 3460, 1790, 1740 and 1690; δH (400 MHz, CDCl3)
1.26 (3 H, s, CMe), 1.53 (9 H, s, But), 2.01 (3 H, s, 4-Me), 2.06–
2.10 (5 H, m, CH2CHϪO and Ac), 2.47 (2 H, t, J 8, CH2-
CH2CO), 2.51 (2 H, s, CH2CO), 2.94 (2 H, t, J 8, CH2CH2CO),
3.57 and 3.63 (each 3 H, s, OMe), 4.70–4.75 (1 H, m, AcO-
CHCH), 6.04 (1 H, d, J 3.8, AcOCH) and 8.89 (1 H, br s,
NH); δC(100 MHz, CDCl3) 8.7 (4-Me), 20.5 and 20.8 (CH2-
CH2CO and MeCO2), 22.9 (CMe), 28.3 (CMe3), 34.9, 35.6, 40.7
and 41.4 (CH2CH2CO and CH2CCH2), 51.4 and 51.6 (OMe),
67.6 (AcOCH), 77.0 (AcOCHCH), 81.2 (CMe3), 119.6, 121.1,
124.6 and 127.7 (pyrrole-C) and 160.5, 169.5, 170.4, 173.5 and
and 128.8 (pyrrole-C) and 161.0, 171.5, 173.6 and 180.1 (C᎐O);
᎐
m/z (FD) 467 (Mϩ, 100%).
Benzyl 3-(2-methoxycarbonylethyl)-5-hydroxy[(2S,4R)-4-
methoxycarbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-
yl]methyl-4-methylpyrrole-2-carboxylate
The benzyl ester (corresponding to tert-butyl ester 7) (385
mg, 0.772 mmol) was reduced in the same way as described
for 7 to give the diastereoisomeric alcohols (the benzyl esters
corresponding to tert-butyl esters 35) as an oil (ca. 385 mg,
100%). They were separated by PLC using 2% MeOH in
CH2Cl2.
179.0 (C᎐O); m/z (FD) 509 (Mϩ, 100%).
᎐
Higher Rf diastereoisomer (Found: Mϩ, 509.2309); λmax
(MeOH)/nm 271; νmax(CHCl3)/cmϪ1 3450, 2960, 1770, 1740
and 1680; δH (400 MHz, CDCl3) 1.22 (3 H, s, CMe), 1.53 (9 H, s,
But), 1.88 (1 H, dd, J 13 and 7, CHAHBCH᎐O), 2.01–2.11 (7 H,
m, CHAHBCH᎐O, Ac and 4-Me), 2.44–2.48 (2 H, m,
CH2CH2CO), 2.55 and 2.72 (each 1 H, d, J 17, CH2CO), 2.93
(2 H, t, J 8, CH2CH2CO), 3.63 and 3.65 (each 3 H, s, OMe),
4.77–4.80 (1 H, m, AcOCHCH), 5.92 (1 H, d, J 6, AcOCH)
and 9.08 (1 H, br s, NH); δC(100 MHz, CDCl3) 8.7 (4-Me),
20.6 and 20.8 (CH2CH2CO and MeCO2), 23.3 (CMe), 28.3
(CMe3), 34.9, 35.7, 40.7 and 41.5 (CH2CH2CO and
CH2CCH2), 51.4 and 51.8 (OMe), 68.1 (AcOCH), 76.8
(AcOCHCH), 81.3 (CMe3), 119.3, 121.1, 125.9 and 127.8
Lower Rf diastereoisomer (Found: Mϩ, 501.1965. C26H31-
NO9 requires M, 501.1999); λmax(MeOH)/nm 278; νmax(CHCl3)/
cmϪ1 3444, 2955, 2931, 1775, 1733, 1698 and 1603; δH (400
MHz, CDCl3) 1.26 (3 H, s, CMe), 1.88 (1 H, dd, J 13 and 7) and
2.27 (1 H, dd, J 13 and 10, CH2CH᎐O), 1.99 (3 H, s, 4-Me), 2.46
(2 H, t, J 8, CH2CH2CO), 2.57 and 2.78 (each 1 H, d, J 17,
CH2CO), 2.97–3.01 (2 H, m, CH2CH2CO), 3.20 (1 H, d, J 4,
OH), 3.61 and 3.67 (each 3 H, s, OMe), 4.63–4.65 and 4.84–4.86
(each 1 H, m, CHCHOH), 5.26 and 5.30 (each 1 H, d, J 12,
CH2Ph), 7.31–7.40 (5 H, m, Ph) and 9.26 (1 H, br s, NH);
δC(67.7 MHz, CDCl3) 8.9 (4-Me), 20.4 (CH2CH2CO), 23.6
(CMe), 34.6, 35.4, 40.9 and 41.7 (CH2CH2CO and CH2CCH2),
51.5 and 51.9 (OMe), 66.0 and 68.4 (CH2Ph and CHOH), 79.5
(CHCHOH), 117.7, 118.6, 128.1, 128.4, 128.6, 130.0 and 136.0
(pyrrole-C) and 160.6, 169.8, 170.8, 173.5 and 179.1 (C᎐O);
᎐
m/z (FD) 509 (Mϩ, 100%).
Benzyl 3-(2-methoxycarbonylethyl)-5-acetoxy[(2S,4R)-4-
methoxycarbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-yl]-
methyl-4-methylpyrrole-2-carboxylate
The alcohols (the benzyl esters corresponding to tert-butyl
esters 35) (385 mg, 0.772 mmol) were acetylated as described
above for 35 to give the diastereoisomeric acetoxy lactones (the
benzyl esters corresponding to tert-butyl esters 36) as oils. They
were separated by flash chromatography on silica eluting with
hexane–ethyl acetate (1.5:1).
(pyrrole-C and Ph) and 160.7, 171.4, 173.6 and 179.7 (C᎐O);
᎐
m/z (FD) 501 (Mϩ, 100%).
Higher Rf diastereoisomer (Found: Mϩ, 501.1998); λmax
(MeOH)/nm 279; νmax(CHCl3)/cmϪ1 3444, 3020, 1775, 1733,
1688 and 1602; δH (400 MHz, CDCl3) 1.25 (3 H, s, CMe), 1.74 (1
H, dd, J 13 and 7, CHAHBCHCHOH), 1.97 (3 H, s, 4-Me),
2.43–2.49 (3 H, m, CHAHBCHCHOH and CH2CH2CO), 2.56
and 2.74 (each 1 H, d, J 17, CH2CO), 2.95–3.00 (2 H, m,
CH2CH2CO), 3.53 (1 H, br s, OH), 3.60 and 3.68 (each 3 H, s,
OMe), 4.59–4.64 (1 H, m, CHCHOH), 5.23–5.31 (3 H, m,
CHCHOH and CH2Ph), 7.29–7.39 (5 H, m, Ph) and 9.24 (1 H,
br s, NH); δC(67.7 MHz, CDCl3) 8.8 (4-Me), 20.4 (CH2-
CH2CO), 23.6 (CMe), 32.5, 34.6, 41.0 and 41.7 (CH2CH2CO
and CH2CCH2), 51.4 and 52.0 (OMe), 65.8 and 66.6 (CH2Ph
and CHOH), 78.1 (CHCHOH), 116.0, 117.9, 128.1, 128.3,
129.4, 130.4 and 136.1 (pyrrole-C and Ph) and 160.7, 171.6,
Lower Rf diastereoisomer (134 mg, 32%) (Found: Mϩ Ϫ
AcOH, 483.1883. C28H33NO10 requires M Ϫ AcOH, 483.1893);
λmax(MeOH)/nm 276; νmax(CHCl3)/cmϪ1 3020, 1780, 1736 and
1602; δH (400 MHz, CDCl3) 1.26 (3 H, s, CMe), 2.01–2.11 (8 H,
m, CH2CH᎐O, Ac and 4-Me), 2.43–2.49 (4 H, m, CH2CO and
CH2CH2CO), 2.98 (2 H, t, J 8, CH2CH2CO), 3.51 and 3.59
(each 3 H, s, OMe), 4.73–4.78 (1 H, m, AcOCHCH), 5.24–5.31
(2 H, m, CH2Ph), 6.02 (1 H, d, J 4, AcOCH), 7.27–7.39 (5 H, m,
Ph) and 9.08 (1 H, br s, NH); δC(100 MHz, CDCl3) 8.6 (4-Me),
20.3 and 20.7 (CH2CH2CO and MeCO2), 22.8 (CMe), 34.6,
35.6, 40.7 and 41.4 (CH2CH2CO and CH2CCH2), 51.3 and 51.6
(OMe), 65.9 and 67.7 (CH2Ph and AcOCH), 76.9 (AcO-
CHCH), 119.4, 119.9, 125.5, 128.1, 128.2, 128.5, 129.3 and
135.9 (pyrrole-C and Ph) and 160.5, 169.5, 170.3, 173.3 and
173.5 and 180.0 (C᎐O); m/z (FD) 501 (Mϩ, 100%).
᎐
178.9 (C᎐O); m/z (FD) 543 (Mϩ, 100%).
᎐
tert-Butyl 3-(2-methoxycarbonylethyl)-5-acetoxy[(2S,4R)-4-
methoxycarbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-yl]-
methyl-4-methylpyrrole-2-carboxylate 36
Higher Rf diastereoisomer (284 mg, 67%) (Found: Mϩ Ϫ
AcOH, 483.1881); λmax(MeOH)/nm 276; νmax(CHCl3)/cmϪ1
3025, 1780, 1736 and 1603; δH (400 MHz, CDCl3) 1.24 (3 H, s,
CMe), 1.87 (1 H, dd, J 13 and 7, CHAHBCH᎐O), 2.01–2.13 (7
H, m, CHAHBCH᎐O, Ac and 4-Me), 2.44 (2 H, t, J 8,
CH2CH2CO), 2.55 and 2.73 (each 1 H, d, J 17, CH2CO), 2.97 (2
H, t, J 8, CH2CH2CO), 3.59 and 3.63 (each 3 H, s, OMe), 4.81–
4.87 (1 H, m, AcOCHCH), 5.28 and 5.32 (each 1 H, d, J 12,
CH2Ph), 5.95 (1 H, d, J 6, AcOCH), 7.28–7.40 (5 H, m, Ph) and
9.38 (1 H, br s, NH); δC(100 MHz, CDCl3) 8.6 (4-Me), 20.4 and
20.7 (CH2CH2CO and MeCO2), 23.3 (CMe), 34.6, 35.7, 40.6
and 41.5 (CH2CH2CO and CH2CCH2), 51.4 and 51.7 (OMe),
66.1 and 68.1 (CH2Ph and AcOCH), 76.7 (AcOCHCH), 119.3,
119.6, 127.0, 128.2, 128.2, 128.5, 129.5 and 135.8 (pyrrole-C
A solution of alcohols 35 (5.74 g, 12.3 mmol) in dry dichloro-
methane (200 cm3) was treated with 4-dimethylaminopyridine
(3.05 g, 25 mmol) and then acetic anhydride (4.65 cm3, 49.3
mmol), and stirred for 15 min. Water (200 cm3) was added, the
organic layer was separated and the aqueous layer was
extracted with dichloromethane (2 × 100 cm3). The combined
organic layers were washed with brine (100 cm3), dried and
evaporated under reduced pressure. Purification by column
chromatography, eluting with hexane–ethyl acetate (1.5:1),
gave the diastereoisomeric acetoxy lactones 36 as a foam (6.15
g, 98%). The acetoxy lactones were used as a mixture for the
J. Chem. Soc., Perkin Trans. 1, 1997
2131

View Article Online
and Ph) and 160.7, 169.8, 170.7, 173.3 and 179.1 (C᎐O); m/z
MHz, CDCl3) 8.9 (4-Me), 20.6 (CH2CH2CO), 24.7 (CMe), 34.7
(CH2CH2CO), 37.5, 40.9 and 41.4 (CH2CCH2), 51.4 and 52.1
᎐
(FD) 543 (Mϩ, 100%).
(OMe), 66.0 (CH Ph), 96.6 (C᎐CH), 118.6, 120.0, 127.5, 128.1,
᎐
2
tert-Butyl 3-(2-methoxycarbonylethyl)-5-[(4R)-4-methoxy-
carbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-ylidene]-
methyl-4-methylpyrrole-2-carboxylate 37
128.15, 128.5, 130.1 and 136.0 (pyrrole-C and Ph), 148.4
(C᎐CH) and 161.0, 170.8, 173.4 and 177.8 (C᎐O); m/z (FD) 483
᎐
᎐
(Mϩ, 100%).
The acetoxy lactones 36 (2.05 g, 4.03 mmol) were heated at
200 ЊC for 5 min under a stream of argon. Purification by col-
umn chromatography, eluting with hexane–ethyl acetate (5:2),
gave (E)- and (Z)-enol lactones 37 as an oil (1.52 g, 84%). The
enol lactones were used as a mixture for the next reaction but
were separated for characterisation by PLC using hexane–ethyl
acetate (1.7:1).
(2R)-9-tert-Butoxycarbonyl-4-hydroxy-8-(2-methoxycarbonyl-
ethyl)-2-methoxycarbonylmethyl-2,7-dimethyl-2,3,4,5-tetra-
hydrodipyrrin-1(10H)-one 38
A solution of enol lactones 37 (4.20 g, 9.35 mmol) in tetra-
hydrofuran (100 cm3) at room temperature was treated with
concentrated aqueous ammonia (60 cm3) dropwise over 5 min,
stirred for 75 min, mixed with brine (100 cm3) and extracted
with dichloromethane (200 cm3 then 3 × 200 cm3). The com-
bined organic extracts were dried and evaporated under
reduced pressure to give lactam alcohols 38 as a foam, which
was used without further purification in the next reaction, but
for characterisation the isomers were separated by PLC using
5% MeOH in CH2Cl2.
Lower Rf isomer (Found: Mϩ, 449.2022. C23H31NO8 requires
M, 449.2050); λmax(MeOH)/nm 244, 278 and 312; νmax(CHCl3)/
cmϪ1 3460, 3000, 1810, 1735 and 1690; δH (400 MHz, CDCl3)
1.35 (3 H, s, CMe), 1.55 (9 H, s, But), 2.00 (3 H, s, 4-Me), 2.51 (2
H, t, J 8, CH2CH2CO), 2.65 and 2.84 (each 1 H, d, J 17,
CH2CO), 2.77 (1 H, d, J 16.5) and 3.20 (1 H, dd, J 16.5 and 1.7,
CH C᎐C), 2.96–3.00 (2 H, m, CH CH CO), 3.64 and 3.67 (each
᎐
2
2
2
3 H, s, OMe), 5.54 (1 H, br s, C᎐CH) and 9.43 (1 H, br s, NH);
δC(100 MHz, CDCl3) 8.6 (4-Me), 20.6 (CH2CH2CO), 24.1
(CMe), 28.4 (CMe3), 34.9 (CH2CH2CO), 38.6, 40.7 and 40.8
Lower Rf diastereoisomer (Found: Mϩ Ϫ H2O, 448.2224.
C23H34N2O8 requires M Ϫ H2O, 448.2210); λmax(MeOH)/nm
280; νmax(CHCl3)/cmϪ1 3690, 3440, 3340, 1745, 1720 and 1700;
δH (400 MHz, CDCl3) 1.32 (3 H, s, 2-Me), 1.50 (9 H, s, But), 1.93
(4 H, m, 3-HA and 7-Me), 2.29 (1 H, d, J 14, 3-HB), 2.38 (1 H, d,
J 16, CHAHBCO), 2.43–2.50 (3 H, m, CH2CH2CO and CHAHB-
CO), 2.91–2.95 (2 H, m, CH2CH2CO), 2.99 (2 H, s, 5-H2), 3.57
and 3.64 (each 3 H, s, OMe), 4.59 (1 H, br s, OH), 7.37 (1 H, br
s, lactam-NH) and 9.69 (1 H, br s, pyrrole-NH); δC(100 MHz,
CDCl3) 8.8 (7-Me), 21.0 (CH2CH2CO), 25.5 (2-Me), 28.4
(CMe3), 35.1 (CH2CH2CO), 37.4 (C-5), 41.4 and 42.5 (CH2CO
and C-2), 45.7 (C-3), 51.4 and 51.5 (OMe), 80.8 (CMe3), 86.2
(C-4), 118.2, 119.4, 127.7 and 128.2 (pyrrole-C) and 161.4,
᎐
(CH CCH ), 51.4 and 52.0 (OMe), 80.6 (CMe ), 94.5 (C᎐CH),
᎐
2
2
3
118.0, 120.0, 126.4 and 128.2 (pyrrole-C), 144.2 (C᎐CH) and
᎐
160.3, 170.7, 173.7 and 177.4 (C᎐O); m/z (FD) 449 (Mϩ, 100%).
᎐
Higher Rf isomer (Found: Mϩ, 449.2042); λmax(MeOH)/nm
244 and 299; νmax(CHCl3)/cmϪ1 3490, 3000, 1800, 1735, and
1680; δH (400 MHz, CDCl3) 1.34 (3 H, s, CMe), 1.55 (9 H, s,
But), 1.97 (3 H, s, 4-Me), 2.49 (2 H, t, J 8, CH2CH2CO), 2.63
and 2.89 (each 1 H, d, J 17, CH2CO), 2.86 (1 H, d, J 16) and
3.24 (1 H, dd, J 16 and 2.4, CH C᎐C), 2.96 (2 H, t, J 8,
᎐
2
CH2CH2CO), 3.66 and 3.68 (each 3 H, s, OMe), 6.21 (1 H, br s,
C᎐CH) and 8.42 (1 H, br s, NH); δ (100 MHz, CDCl ) 8.8
171.6, 173.7 and 180.9 (C᎐O); m/z (FD) 466 (Mϩ, 100%).
᎐
᎐
C
3
(4-Me), 20.7 (CH2CH2CO), 24.7 (CMe), 28.3 (CMe3), 34.9
(CH2CH2CO), 37.5, 40.9 and 41.4 (CH2CCH2), 51.4 and 52.1
Higher Rf diastereoisomer (Found: Mϩ Ϫ H2O, 448.2197);
λmax(MeOH)/nm 280; νmax(CHCl3)/cmϪ1 3690, 3630, 3440, 1725,
1690 and 1605; δH (400 MHz, CDCl3) 0.99 (3 H, s, 2-Me), 1.50 (9
H, s, But), 1.94 (3 H, s, 7-Me), 2.08 and 2.20 (each 1 H, d, J 15,
3-H2), 2.42 and 2.84 (each 1 H, d, J 18, CH2CO), 2.44–2.48 (2 H,
m, CH2CH2CO), 2.89–2.99 (4 H, m, CH2CH2CO and 5-H2),
3.63 (6 H, s, 2 × OMe), 5.04 (1 H, br s, OH), 7.10 (1 H, br s,
lactam-NH) and 9.60 (1 H, br s, pyrrole-NH); δC(100 MHz,
CDCl3) 8.9 (7-Me), 20.9 (CH2CH2CO), 26.8 (2-Me), 28.4
(CMe3), 35.1 (CH2CH2CO), 37.2 (C-5), 41.6 and 41.7 (CH2CO
and C-2), 46.9 (C-3), 51.4 and 52.1 (OMe), 80.6 (CMe3), 85.9
(C-4), 117.9, 119.3, 127.6 and 128.0 (pyrrole-C) and 161.1,
(OMe), 81.1 (CMe ), 96.7 (C᎐CH), 119.7, 120.3, 126.5 and
᎐
3
128.5 (pyrrole-C), 147.7 (C᎐CH) and 161.0, 170.7, 173.4 and
᎐
177.8 (C᎐O); m/z (FD) 449 (Mϩ, 100%).
᎐
Benzyl 3-(2-methoxycarbonylethyl)-5-[(4R)-4-methoxy-
carbonylmethyl-4-methyl-5-oxotetrahydrofuran-2-ylidene]-
methyl-4-methylpyrrole-2-carboxylate
The acetoxy lactones (the benzyl esters corresponding to tert-
butyl esters 36) (75 mg, 0.138 mmol) were heated at 200 ЊC for 5
min under a stream of argon. Purification by PLC, eluting with
hexane–ethyl acetate (1:1), gave the higher Rf (E)-enol lactone
(28 mg, 42%) and the lower Rf (Z)-enol lactone (30 mg, 45%)
(the benzyl esters corresponding to tert-butyl esters 37) as oils.
(Z)-Isomer (Found: Mϩ, 483.1895. C26H29NO8 requires M,
483.1893); νmax(CHCl3)/cmϪ1 3459, 2955, 1807, 1734 and 1693;
δH (400 MHz, CDCl3) 1.34 (3 H, s, CMe), 1.99 (3 H, s, 4-Me),
2.49 (2 H, t, J 8, CH2CH2CO), 2.65 and 2.85 (each 1 H, d, J 17,
CH2CO), 2.77 (1 H, d, J 17) and 3.19 (1 H, dd, J 17 and 1.8,
173.5, 173.7 and 179.8 (C᎐O); m/z (FD) 466 (Mϩ, 100%).
᎐
(2R)-9-Benzyloxycarbonyl-4-hydroxy–8-(2-methoxycarbonyl-
ethyl)-2-methoxycarbonylmethyl-2,7-dimethyl-2,3,4,5-tetra-
hydrodipyrrin-1(10H)-one
A solution of the (Z)-enol lactone (the benzyl ester correspond-
ing to tert-butyl ester 37) (80 mg, 0.166 mmol) in tetrahydro-
furan (3 cm3) at Ϫ10 ЊC was treated with concentrated aqueous
ammonia (0.5 cm3) dropwise over 20 min, then stirred for 40
min at room temperature, mixed with water (15 cm3) and
extracted with dichloromethane (20 cm3 then 2 × 10 cm3). The
combined extracts were dried and evaporated under reduced
pressure to give a mixture of the lactam alcohols (the benzyl
esters corresponding to tert-butyl esters 38), which was used
without further purification in the next reaction, but for charac-
terisation the isomers were separated by PLC using 5% MeOH
in CH2Cl2.
CH C᎐C), 3.01 (2 H, t, J 8, CH CH CO), 3.60 and 3.66 (each 3
᎐
2
2
2
H, s, OMe), 5.30 (2 H, s, CH Ph), 5.54 (1 H, s, C᎐CH), 7.27–
᎐
2
7.43 (5 H, m, Ph) and 9.51 (1 H, br s, NH); δC(100 MHz,
CDCl3) 8.5 (4-Me), 20.4 (CH2CH2CO), 24.1 (CMe), 34.6
(CH2CH2CO), 38.5, 40.6 and 40.7 (CH2CCH2), 51.3 and 52.0
(OMe), 65.5 (CH Ph), 94.3 (C᎐CH), 118.2, 118.25, 127.3, 127.9,
᎐
2
128.4, 129.7 and 136.2 (pyrrole-C and Ph), 144.8 (C᎐CH) and
᎐
160.2, 170.6, 173.5 and 177.4 (C᎐O); m/z (FD) 483 (Mϩ, 100%).
᎐
(E)-Isomer (Found: Mϩ, 483.1877); λmax(MeOH)/nm 243
and 315; νmax(CHCl3)/cmϪ1 3450, 2955, 1860, 1735 and 1680;
δH (400 MHz, CDCl3) 1.33 (3 H, s, CMe), 1.96 (3 H, s, 4-Me),
2.46 (2 H, t, J 8, CH2CH2CO), 2.64 and 2.87 (each 1 H, d, J 17,
CH2CO), 2.84 (1 H, dd, J 16 and 1.4) and 3.24 (1 H, dd, J 16,
Lower Rf diastereoisomer (Found: Mϩ Ϫ H2O, 482.2056.
C26H32N2O8 requires M Ϫ H2O, 482.2053); νmax(CHCl3)/cmϪ1
3690, 3430, 1730, 1700 and 1605; δH (400 MHz, CDCl3) 1.31 (3
H, s, 2-Me), 1.92–1.95 (4 H, m, 3-HA and 7-Me), 2.30 (1 H, d, J
14, 3-HB), 2.36 (1 H, d, J 16.5, CHAHBCO), 2.42–2.50 (3 H, m,
CHAHBCO and CH2CH2CO), 2.95–2.98 (4 H, m, CH2CH2CO
and 5-H2), 3.54 and 3.60 (each 3 H, s, OMe), 4.13 (1 H, br s,
2.5, CH C᎐C), 2.97–3.01 (2 H, m, CH CH CO), 3.61 and 3.66
᎐
2
2
2
(each 3 H, s, OMe), 5.29 (2 H, s, CH2Ph), 6.19 (1 H, br s,
C᎐CH), 7.30–7.39 (5 H, m, Ph) and 8.57 (1 H, br s, NH); δ (100
᎐
C
2132
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
OH), 5.23 (2 H, s, CH2Ph), 7.21 (1 H, br s, lactam-NH), 7.26–
7.36 (5 H, m, Ph) and 9.81 (1 H, br s, pyrrole-NH); δC(67.7
MHz, CDCl3) 8.9 (7-Me), 20.8 (CH2CH2CO), 25.8 (2-Me), 34.8
(CH2CH2CO), 38.4 (C-5), 41.2 and 42.3 (CH2CO and C-2), 45.8
(C-3), 51.3 and 51.4 (OMe), 65.8 (CH2Ph), 86.0 (C-4), 117.9,
118.8, 128.1, 128.2, 128.3, 128.4, 129.8 and 136.1 (pyrrole-C
3-H2), 2.97 (2 H, t, J 8, CH2CH2CO), 3.59 and 3.63 (each 3 H, s,
OMe), 5.18 (2 H, s, CH2Ph), 5.30 (1 H, br s, 5-H), 7.25–7.32 (5
H, m, Ph), 9.03 and 9.32 (each 1 H, br s, NH); δC(67.7 MHz,
CDCl3) 9.2 (7-Me), 20.8 (CH2CH2CO), 24.3 (2-Me), 34.7
(CH2CH2CO), 39.3, 40.8 and 41.9 (CH2CCH2), 51.5 and 51.8
(OMe), 66.0 (CH2Ph), 91.5 (C-5), 118.3, 128.1, 128.2, 128.4,
129.1, 130.9, 136.1 (pyrrole-C and Ph), 138.1 (C-4) and 160.8,
and Ph) and 161.2, 171.7, 173.8 and 180.8 (C᎐O); m/z (FD) 500
᎐
(Mϩ, 100%).
171.3, 173.7 and 180.1 (C᎐O); m/z (FD) 482 (Mϩ, 100%).
᎐
Higher Rf diastereoisomer (Found: Mϩ Ϫ H2O, 482.2067);
νmax(CHCl3)/cmϪ1 3695, 3425, 1730, 1700 and 1605; δH (400
MHz, CDCl3) 1.10 (3 H, s, 2-Me), 1.96 (3 H, s, 7-Me), 2.13 and
2.24 (each 1 H, d, J 15, 3-H2), 2.43 and 2.88 (each 1 H, d, J 18,
CH2CO), 2.45–2.49 (2 H, m, CH2CH2CO), 2.93 (2 H, m, 5-H2),
2.97–3.03 (2 H, m, CH2CH2CO), 3.61 and 3.67 (each 3 H, s,
OMe), 5.16 (1 H, br s, OH), 5.27 (2 H, s, CH2Ph), 6.21 (1 H, br
s, lactam-NH), 7.30–7.40 (5 H, m, Ph) and 9.43 (1 H, br s,
pyrrole-NH); δC(67.7 MHz, CDCl3) 9.9 (7-Me), 20.8 (CH2-
CH2CO), 27.6 (2-Me), 34.8 (CH2CH2CO), 37.7 (C-5), 41.2 and
41.7 (CH2CO and C-2), 48.4 (C-3), 51.3 and 52.2 (OMe), 65.7
(CH2Ph), 85.3 (C-4), 118.7, 119.3, 127.9, 128.0, 128.2, 128.5,
129.6 and 136.2 (pyrrole-C and Ph) and 160.8, 173.6, 173.8 and
4-(2-Methoxycarbonylethyl)-2-[(2S,3S)-3-methoxycarbonyl-
methyl-3-methyl-5-oxotetrahydrofuran-2-yl]formyl-3,5-
dimethylpyrrole 40
A mixture of acid 8 (1.08 g, 4.98 mmol), 2,2-dipyridyl disulfide
(1.65 g, 7.47 mmol) and triphenylphosphine (1.96 g, 7.47 mmol)
in dry toluene (32 cm3) was stirred under argon at room
temperature for 22 h to give a solution containing thioester 39.
A solution of methylmagnesium chloride in diethyl ether (3 mol
dmϪ3; 6.64 cm3, 19.9 mmol) was added to a stirred solution of
the α-free pyrrole 105 (3.6 g, 19.9 mmol) in dry toluene (86 cm3)
and dry tetrahydrofuran (4 cm3) at Ϫ78 ЊC under argon. The
solution was allowed to warm for 10 min with vigorous stirring
and was then cooled again to Ϫ78 ЊC. The above thioester solu-
tion was then added via double-ended needle under a positive
pressure of argon over a period of 30 min. The solution was
stirred at Ϫ78 ЊC for 1.5 h, then treated with saturated aqueous
ammonium chloride (5 cm3), warmed to room temperature and
mixed with diethyl ether (150 cm3), saturated aqueous ammo-
nium chloride (100 cm3) and water (100 cm3). The organic
phase was separated, washed with 10% aqueous potassium car-
bonate (100 cm3) then water (100 cm3), dried and evaporated
under reduced pressure. Column chromatography, eluting with
hexane–ethyl acetate, gave the ketone 40 (1.64 g, 87%) as a gum
(Found: Mϩ, 379.1608. C19H25NO7 requires M, 379.1631);
λmax(MeOH)/nm 315; νmax(CHCl3)/cmϪ1 3440, 3340, 2920, 1790,
1725 and 1620; δH (400 MHz, CDCl3) 1.09 (3 H, s, CMe), 2.24
and 2.30 (each 3 H, s, Ar–Me), 2.36–2.69 (8 H, m,
CH2CH2CO and CH2CCH2), 3.60 and 3.71 (each 3 H, s,
OMe), 5.51 (1 H, s, CH᎐O) and 10.07 (1 H, s, NH); δC(100
MHz, CDCl3) 11.3 and 11.7 (Ar–Me), 19.1 (CH2CH2CO),
20.8 (CMe), 34.5 (CH2CH2CO), 40.8, 41.7 and 42.2
(CH2CCH2), 51.5 and 52.1 (OMe), 83.6 (CH᎐O), 121.8,
125.5, 132.0 and 133.9 (pyrrole-C), 173.2 (2 C) and 175.0 and
179.2 (C᎐O); m/z (FD) 500 (Mϩ, 100%)
᎐
(2R)-9-tert-Butoxycarbonyl-8-(2-methoxycarbonylethyl)-2-
methoxycarbonylmethyl-2,7-dimethyl-2,3-dihydrodipyrrin-
1(10H)-one 5
A solution of lactam alcohols 38 [from enol lactones 37 (4.20 g,
9.35 mmol)] in dichloromethane (200 cm3) was stirred with
toluene-p-sulfonic acid (25 mg) at room temperature for 35 min.
Saturated aqueous sodium hydrogen carbonate (150 cm3) was
then added and the organic layer was separated. The aqueous
layer was extracted with dichloromethane (3 × 75 cm3) and the
combined organic layers were dried and evaporated under
reduced pressure. Purification by column chromatography,
eluting with dichloromethane–ethyl acetate (3:1), gave the
(E)- and (Z)-lactams 5 as a foam (3.82 g, 91% from the enol
lactones 37). For characterisation the isomers were separated by
PLC and were identical to the compounds previously
synthesised.2
(2R)-9-Benzyloxycarbonyl-8-(2-methoxycarbonylethyl)-2-
methoxycarbonylmethyl-2,7-dimethyl-2,3-dihydrodipyrrin-
1(10H)-one
181.9 (C᎐O); m/z (FD) 379 (Mϩ, 100%).
᎐
A solution of the lactam alcohols (the benzyl esters correspond-
ing to tert-butyl esters 38) [from (Z)-enol lactone (80 mg, 0.166
mmol)] in dichloromethane (4 cm3) was stirred with toluene-p-
sulfonic acid (ca. 1 mg) at Ϫ10 ЊC for 15 min and then evapor-
ated under reduced pressure. Purification by PLC, eluting with
hexane–ethyl acetate (1:1), gave the lower Rf (E)-lactam (22 mg,
27%) and the higher Rf (Z)-lactam (28 mg, 35%) (the benzyl
esters corresponding to tert-butyl esters 5) as oils.
5-Formyl-4-(2-methoxycarbonylethyl)-2-[(2S,3S)-3-methoxy-
carbonylmethyl-3-methyl-5-oxotetrahydrofuran-2-yl]formyl-3-
methylpyrrole 41
A solution of ketone 40 (777 mg, 2.05 mmol) in dry dichloro-
methane (23 cm3) at Ϫ5 ЊC was treated with a solution of
freshly distilled sulfuryl chloride (338 mm3, 4.20 mmol) in dry
dichloromethane (16 cm3) over 1 min, then stirred at Ϫ5 ЊC for
30 min and evaporated under reduced pressure. The residue was
stirred with acetone (20 cm3) and water (10 cm3) for 30 min,
then the acetone was evaporated under reduced pressure and
the residual aqueous solution was extracted with dichloro-
methane (3 × 20 cm3). The combined extracts were dried and
evaporated under reduced pressure to give the aldehyde 41 (650
mg, 81%) as an oil (Found: Mϩ, 393.1445. C19H23NO8 requires
M, 393.1424); λmax(MeOH)/nm 247 and 316; νmax(CHCl3)/cmϪ1
3420, 3280, 2950, 1800, 1720 and 1655; δH (400 MHz, CDCl3)
1.13 (3 H, s, CMe), 2.34 (3 H, s, 3-Me), 2.42 and 2.83 (each 1
H, d, J 17, CH2CO), 2.51–2.59 (4 H, m, CH2CO and
CH2CH2CO), 3.06 (2 H, t, J 7, CH2CH2CO), 3.63 and 3.83
(each 3 H, s, OMe), 5.74 (1 H, s, CH᎐O), 9.92 (1 H, s, CHO)
and 10.95 (1 H, br s, NH); δC(100 MHz, CDCl3) 10.5 (3-Me),
18.5 (CH2CH2CO), 20.9 (CMe), 34.7 (CH2CH2CO), 40.6,
41.9 and 42.3 (CH2CCH2), 51.7 and 52.6 (OMe), 83.23
(CH᎐O), 129.8, 130.2, 131.4 and 131.5 (pyrrole-C) and 172.6,
(E)-Isomer (Found: Mϩ, 482.2049. C26H30N2O7 requires M,
482.2053); λmax(MeOH)/nm 228 and 325; νmax(CHCl3)/cmϪ1
3460, 3410, 1730, 1670 and 1565; δH (400 MHz, CDCl3) 1.28 (3
H, s, 2-Me), 1.95 (3 H, s, 7-Me), 2.47 (2 H, t, J 8, CH2CH2CO),
2.57 and 2.81 (each 1 H, d, J 17, CH2CO), 2.74 (1 H, dd, J 16
and 1.5) and 3.14 (1 H, dd, J 16 and 2, 3-H2), 2.98–3.00 (2 H, m,
CH2CH2CO), 3.61 and 3.65 (each 3 H, s, OMe), 5.30 (2 H, s,
CH2Ph), 5.75 (1 H, br s, 5-H), 7.30–7.41 (5 H, m, Ph), 8.38 and
8.53 (each 1 H, br s, NH); δC(67.7 MHz, CDCl3) 8.9 (7-Me),
20.7 (CH2CH2CO), 25.0 (2-Me), 34.8 (CH2CH2CO), 37.9, 40.8
and 42.1 (CH2CCH2), 51.4 and 51.8 (OMe), 65.9 (CH2Ph), 93.0
(C-5), 117.8, 118.7, 128.0, 128.5, 129.9 and 130.1 (pyrrole-C and
Ph), 136.2 (C-4) and 160.9, 171.2, 173.4 and 179.7 (C᎐O); m/z
᎐
(FD) 482 (Mϩ, 100%).
(Z)-Isomer (Found: Mϩ, 482.2067); λmax(MeOH)/nm 227
and 313; [ϩZn(OAc)2] 236 and 361; νmax(CHCl3)/cmϪ1 3450,
1735, 1675 and 1440; δH (400 MHz, CDCl3) 1.28 (3 H, s, 2-Me),
1.94 (3 H, s, 7-Me), 2.43 (2 H, t, J 8, CH2CH2CO), 2.58 and 2.82
(each 1 H, d, J 17, CH2CO), 2.65 and 3.06 (each 1 H, d, J 16,
172.9, 179.3, 180.4 and 186.7 (C᎐O); m/z (FD) 393 (Mϩ,
᎐
100%).
J. Chem. Soc., Perkin Trans. 1, 1997
2133

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3-(2-Methoxycarbonylethyl)-5-[(2S,3S)-3-methoxycarbonyl-
methyl-3-methyl-5-oxotetrahydrofuran-2-yl]formyl-4-methyl-
pyrrole-2-carboxylic acid 42
tetrahydrofuran (32 cm3) under argon was treated with sodium
borohydride (143 mg, 3.79 mmol) portionwise over 3 h with the
temperature maintained at Ϫ5 ЊC, then stirred for a further 30
min, treated with dilute hydrochloric acid (0.5 mol dmϪ3; 20
cm3) and extracted with dichloromethane (3 × 50 cm3). The
combined organic extracts were dried and evaporated under
reduced pressure to give the diastereoisomeric alcohols 43 (ca.
1.04 g, 100%) as an oil, which was used without further purifi-
cation in the next reaction, but for characterisation the isomers
were separated by PLC using hexane–diethyl ether–methanol
(3:3:1).
A solution of potassium permanganate (720 mg, 4.55 mmol) in
water (54 cm3) and acetone (37 cm3) was added to a solution of
formylpyrrole 41 (1.12 g, 2.85 mmol) in acetone (65 cm3) at 0 ЊC
over 6 h. The mixture was stirred for 4 h at 0 ЊC and then for 8 h
at room temperature. The acetone was evaporated under
reduced pressure and dichloromethane (75 cm3), water (50 cm3)
and sodium metabisulfite (3 g) were added. Concentrated
hydrochloric acid was added dropwise until the pH of the
aqueous layer was 1 and the organic phase was separated. The
aqueous phase was saturated with sodium chloride and
extracted with dichloromethane (2 × 50 cm3). The combined
organic layers were evaporated under reduced pressure and
saturated aqueous sodium hydrogen carbonate (100 cm3) was
added. This mixture was extracted with dichloromethane (50
cm3) and the extract was dried and evaporated under reduced
pressure to give unreacted formylpyrrole 41 (80 mg). The
aqueous phase was acidified to pH 1 with concentrated hydro-
chloric acid, extracted with dichloromethane (4 × 50 cm3),
saturated with sodium chloride and further extracted with
dichloromethane (2 × 50 cm3). The combined organic extracts
were dried and evaporated under reduced pressure to give the
carboxylic acid 42 (908 mg, 88%) as a foam (Found: Mϩ Ϫ
CO2H, 364.1387. C19H23NO9 requires M Ϫ CO2H, 364.1396);
λmax(MeOH)/nm 231 and 307; νmax(CHCl3)/cmϪ1 3300, 3100,
1800, 1720 and 1660; δH (400 MHz, CDCl3) 1.14 (3 H, s, CMe),
2.37 (3 H, s, 4-Me), 2.52 and 2.63 (each 1 H, d, J 17, CH2CO),
2.54–2.60 (3 H, m, CHAHBCO and CH2CH2CO), 2.83 (1 H, d, J
17, CHAHBCO), 3.08 (2 H, t, J 7.7, CH2CH2CO), 3.67 and 3.80
(each 3 H, s, OMe), 5.68 (1 H, s, CH᎐O) and 10.85 (1 H, br s,
NH); δC(100 MHz, CDCl3) 10.6 (4-Me), 19.6 (CH2CH2CO),
20.9 (CMe), 34.3 (CH2CH2CO), 40.6, 42.1 and 42.2
(CH2CCH2), 51.6 and 52.3 (OMe), 83.8 (CH᎐O), 122.9, 129.0,
130.5 and 131.2 (pyrrole-C) and 164.8, 172.5, 173.4, 174.5 and
Lower Rf diastereoisomer (Found: Mϩ, 467.2176. C23H33-
NO9 requires M, 467.2155); λmax(MeOH)/nm 276; νmax(CHCl3)/
cmϪ1 3450, 2950, 1785, 1730 and 1685; δH (400 MHz, CDCl3)
1.38 (3 H, s, CMe), 1.51 (9 H, s, But), 2.00 (3 H, s, 4-Me), 2.22
and 2.34 (each 1 H, d, J 15.5, CH2CO), 2.45–2.50 (2 H, m,
CH2CH2CO), 2.55 and 2.73 (each 1 H, d, J 17, CH2CO), 2.89–
2.96 (3 H, m, OH and CH2CH2CO), 3.64 (6 H, s, 2 × OMe),
4.63 (1 H, d, J 3, CHCHOH), 4.95 (1 H, br s, CHOH) and 9.30
(1 H, br s, NH); δC(100 MHz, CDCl3) 5.4 (4-Me), 20.2 (CMe),
20.6 (CH2CH2CO), 29.7 (CMe3), 35.0 (CH2CH2CO), 40.8, 41.9
and 43.5 (CH2CCH2), 51.5 and 51.8 (OMe), 64.7 (CHOH), 81.1
(CMe3), 87.0 (CHCHOH), 117.3, 120.4, 128.1 and 129.9
(pyrrole-C) and 160.7, 171.1, 173.7 and 175.7 (C᎐O).
᎐
Higher Rf diastereoisomer (Found: Mϩ, 467.2182); λmax
(MeOH)/nm 278; νmax(CHCl3)/cmϪ1 3400, 2950, 1785, 1735 and
1675; δH (400 MHz, CDCl3) 1.22 (3 H, s, CMe), 1.47 (9 H, s,
But), 1.93 (3 H, s, 4-Me), 2.38–2.45 (3 H, m, CH2CH2CO and
CHAHBCO), 2.50 and 2.75 (each 1 H, d, J 15.5, CH2CO), 2.68
(1 H, d, J 17, CHAHBCO), 2.85–2.89 (2 H, m, CH2CH2CO),
3.60 and 3.62 (each 3 H, s, OMe), 3.89 (1 H, d, J 3, OH), 4.35 (1
H, d, J 8, CHCHOH), 4.88 (1 H, dd, J 8 and 3, CHOH) and
9.26 (1 H, br s, NH); δC(100 MHz, CDCl3) 8.7 (4-Me), 19.1
(CMe), 20.5 (CH2CH2CO), 28.2 (CMe3), 34.9 (CH2CH2CO),
40.8 (1 C) and 42.7 (2 C, CH2CCH2), 51.4 and 51.6 (OMe),
65.3 (CHOH), 81.1 (CMe3), 86.0 (CHCHOH), 117.5, 119.4,
128.6 and 131.3 (pyrrole-C) and 161.2, 171.4, 173.7 and 175.1
186.0 (C᎐O); m/z (FD) 409 (Mϩ, 100%).
᎐
(C᎐O).
᎐
tert-Butyl 3-(2-methoxycarbonylethyl)-5-[(2S,3S)-3-methoxy-
carbonylmethyl-3-methyl-5-oxotetrahydrofuran-2-yl]formyl-4-
methylpyrrole-2-carboxylate 6
tert-Butyl 3-(2-methoxycarbonylethyl)-5-acetoxy[(2S,3S)-3-
methoxycarbonylmethyl-3-methyl-5-oxotetrahydrofuran-2-yl]-
methyl-4-methylpyrrole-2-carboxylate 44
Concentrated sulfuric acid (35 mm3) was added dropwise to a
mixture of acid 42 (1.43 g, 3.50 mmol), isobutene (6 cm3) and
chloroform (12 cm3). The reaction vessel was then sealed and
the mixture was stirred for 48 h. Saturated aqueous sodium
hydrogen carbonate (2 cm3) was then added and the isobutene
was evaporated under a stream of argon. Saturated aqueous
sodium hydrogen carbonate (30 cm3) was then added and the
mixture was extracted with dichloromethane (30 cm3 then
2 × 50 cm3). The combined organic extracts were dried and
evaporated under reduced pressure. Purification by column
chromatography, eluting with hexane–ethyl acetate, gave the
tert-butyl ester 6 (1.29 g, 79%) as an oil (Found: Mϩ, 465.1990.
C23H31NO9 requires M, 465.1999); λmax(MeOH)/nm 235 and
308; νmax(CHCl3)/cmϪ1 3425, 3315, 1800, 1720 and 1660; δH (400
MHz, CDCl3) 1.13 (3 H, s, CMe), 1.59 (9 H, s, But), 2.34 (3 H, s,
4-Me), 2.45 and 2.62 (each 1 H, d, J 17.5, CH2CO), 2.48–2.52 (2
H, m, CH2CH2CO), 2.54 and 2.78 (each 1 H, d, J 17, CH2CO),
3.00–3.04 (2 H, m, CH2CH2CO), 3.64 and 3.77 (each 3 H, s,
OMe), 5.64 (1 H, s, CH᎐O) and 10.50 (1 H, br s, NH); δC(100
MHz, CDCl3) 10.6 (4-Me), 19.7 (CH2CH2CO), 20.7 (CMe),
28.2 (CMe3), 34.5 (CH2CH2CO), 40.5, 41.7 and 42.2
(CH2CCH2), 51.4 and 52.3 (OMe), 82.3 (CMe3), 83.3 (CH᎐O),
125.3, 127.6, 129.2 and 130.5 (pyrrole-C) and 159.4, 172.4,
A solution of alcohols 43 (1.04 g, 2.23 mmol) in dry dichloro-
methane (40 cm3) was treated with 4-dimethylaminopyridine
(544 mg, 4.45 mmol) and then acetic anhydride (840 mm3, 8.91
mmol), stirred for 15 min and then mixed with water (20 cm3).
The organic layer was separated and the aqueous layer was
extracted with dichloromethane (3 × 30 cm3). The combined
organic layers were washed with brine (20 cm3), dried and evap-
orated. Purification by column chromatography, eluting with
hexane–diethyl ether (1:3), gave the diastereoisomeric acetoxy
lactones 44 as an oil (1.07 g, 94%), used as a mixture in the next
reaction but separated for characterisation by PLC using
hexane–diethyl ether (2.5:1).
Lower Rf diastereoisomer (Found: Mϩ, 509.2278. C25H35-
NO10 requires M, 509.2261); λmax(MeOH)/nm 274; νmax
(CHCl3)/cmϪ1 3440, 2980, 1790, 1735 and 1680; δH (400 MHz,
CDCl3) 1.06 (3 H, s, CMe), 1.53 (9 H, s, But), 2.03 and 2.06
(each 3 H, s, 4-Me and Ac), 2.26 and 2.72 (each 1 H, d, J 17.5,
CH2CO), 2.45–2.52 (3 H, m, CH2CH2CO and CHAHBCO), 2.60
(1 H, d, J 15.5, CHAHBCO), 2.89–2.97 (2 H, m, CH2CH2CO),
3.62 and 3.69 (each 3 H, s, OMe), 4.66 (1 H, d, J 6,
CHCHOAc), 5.93 (1 H, d, J 6, CHOAc) and 8.97 (1 H, br s,
NH); δC(100 MHz, CDCl3) 8.8 (4-Me), 19.5 and 20.9 (CMe and
MeCO), 20.5 (CH2CH2CO), 28.3 (CMe3), 34.9 (CH2CH2CO),
40.7, 42.0 and 42.8 (CH2CCH2), 51.4 and 51.9 (OMe), 65.6
(CHOAc), 81.2 (CMe3), 85.1 (CHCHOAc), 119.8, 121.1, 125.7
and 127.9 (pyrrole-C) and 160.4, 169.0, 170.6, 173.5 and 173.9
173.1, 174.4 and 185.5 (C᎐O).
᎐
tert-Butyl 3-(2-methoxycarbonylethyl)-5-hydroxy[(2S,3S)-3-
methoxycarbonylmethyl-3-methyl-5-oxotetrahydrofuran-2-
yl]methyl-4-methylpyrrole-2-carboxylate 43
(C᎐O).
᎐
A solution of tert-butyl ester 42 (1.04 g, 2.23 mmol) in dry
Higher Rf diastereoisomer (Found: Mϩ, 509.2300); λmax
2134
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
(MeOH)/nm 270; νmax(CHCl3)/cmϪ1 3420, 2930, 1790, 1730 and
1685; δH (400 MHz, CDCl3) 1.17 (3 H, s, 4-Me), 1.55 (9 H, s,
But), 2.00 and 2.24 (each 1 H, d, J 16, CH2CO), 2.04 and 2.08
(each 3 H, s, 4-Me and Ac), 2.44 and 2.74 (each 1 H, d, J 17,
CH2CO), 2.46–2.50 (2 H, m, CH2CH2CO), 2.92–2.98 (2 H, m,
CH2CH2CO), 3.65 and 3.66 (each 3 H, s, OMe), 4.86 (1 H, d, J
5.5, CHCHOAc), 5.97 (1 H, d, J 5.5, CHOAc) and 9.09 (1 H, br
s, NH); δC(100 MHz, CDCl3) 8.8 (4-Me), 20.5 and 21.0 (CMe
and MeCO), 20.6 (CH2CH2CO), 28.3 (CMe3), 35.0 (CH2CH2-
CO), 40.6, 41.9 and 42.0 (CH2CCH2), 51.5 and 52.0 (OMe),
65.5 (CHOAc), 81.3 (CMe3), 84.5 (CHCHOAc), 119.6, 121.3,
125.6 and 127.6 (pyrrole-C) and 160.5, 169.2, 170.9, 173.5 and
methanol (6 cm3). The solution was evaporated to give the
crude imino ether 48 containing lactam 4. Pure 48 was isolated
chromatographically (Found: Mϩ, 462.2370. C24H34N2O7
requires M, 462.2366); λmax(MeOH)/nm 229 and 346; νmax
(CHCl3)/cmϪ1 3360, 1730, 1675 and 1600; δH (400 MHz, CDCl3)
1.32 (3 H, s, CMe), 1.52 (9 H, s, But), 2.02 (3 H, s, pyrrole-Me),
2.48–2.61 (5 H, m, CH CH CO, CH C᎐N and CH H CO),
᎐
2
2
2
A
B
2.99–3.03 (2 H, m, CH2CH2CO), 3.05 (1 H, d, J 18, CHAHB-
CO), 3.64, 3.65 and 4.05 (each 3 H, s, OMe), 5.29 (1 H, s,
C᎐CH) and 10.78 (1 H, br s, NH); δ (100 MHz, CDCl ) 8.6
᎐
C
3
(pyrrole-Me), 20.6 (CH2CH2CO), 27.6 (CMe), 28.5 (CMe3),
34.9 (CH2CH2CO), 43.1, 43.8 and 44.4 (CH2CCH2), 51.4, 51.6
174.1 (C᎐O).
and 56.6 (OMe), 79.8 (CMe ), 98.6 (C᎐CH), 117.1, 118.7, 128.9
᎐
3
᎐
and 130.4 (pyrrole-C), 157.6 (C᎐CH), 160.5, 171.5 and 173.9
᎐
tert-Butyl (Z)-3-(2-methoxycarbonylethyl)-5-[(3S)-3-methoxy-
carbonylmethyl-3-methyl-5-oxotetrahydrofuran-2-ylidene]-
methyl-4-methylpyrrole-2-carboxylate 45
(C᎐O) and 177.3 (N᎐C).
᎐ ᎐
A solution of the crude imino ether in acetone (6 cm3) and
water (2 cm3) was stirred with toluene-p-sulfonic acid (10 mg)
for 10 h at room temperature. Saturated aqueous sodium
hydrogen carbonate (10 cm3) and dichloromethane (20 cm3)
were added and the organic layer was separated. The aqueous
layer was extracted with dichloromethane (2 × 10 cm3) and the
combined organic extracts were dried and evaporated under
reduced pressure. Purification by PLC, eluting with hexane–
ethyl acetate (3:1), gave lactam 4 (74 mg, 75%).
The acetoxy lactones 44 (251 mg, 0.493 mmol) were heated at
200 ЊC for 5 min under a stream of argon. The resulting oil was
purified by PLC, eluting with diethyl ether–hexane (3:1), to
give the (Z)-enol lactone 45 (202 mg, 91%) as an oil (Found: Mϩ,
449.2066. C23H31NO8 requires M, 449.2049); λmax(MeOH)/nm
213, 242 and 312; νmax(CHCl3)/cmϪ1 3450, 2930, 1815, 1730 and
1680; δH (400 MHz, CDCl3) 1.42 (3 H, s, CMe), 1.53 (9 H, s,
But), 1.98 (3 H, s, 4-Me), 2.47–2.51 (2 H, m, CH2CH2CO), 2.55
and 2.99 (each 1 H, d, J 18, CH2CO), 2.67 (2 H, s, CH2CO),
2.94–2.98 (2 H, m, CH2CH2CO), 3.63 and 3.64 (each 3 H, s,
OMe), 5.45 (1 H, s, CH᎐C) and 9.39 (1 H, br s, NH); δ (100
9-tert-Butoxycarbonyl-8-(2-methoxycarbonylethyl)-3,3,7-tri-
methyl-2,3-dihydrodipyrrin–1(10H)-thione 55
A solution of the lactam 545 (100 mg, 0.256 mmol) in dry
dimethoxyethane (5 cm3) was treated with Lawesson’s reagent
(288 mg, 0.713 mmol) and dry diisopropylethylamine (90
mm3, 0.518 mmol), heated under reflux for 45 min, then
cooled and evaporated under reduced pressure. The residue
was purified by PLC, eluting with ethyl acetate–light petro-
leum (bp 60–80 ЊC) (1:2), to give the thiolactam 55 (91 mg,
87%) as an oil (Found: Mϩ, 406.1901. C21H30N2O4S requires
M, 406.1926); λmax(MeOH)/nm 221, 271 and 343;
[ϩZn(OAc)2] 258 and 394; νmax(CH2Cl2)/cmϪ1 3439, 3380,
1733 and 1680; δH (400 MHz, CDCl3) 1.32 (6 H, s, CMe2),
1.50 (9 H, s, But), 1.93 (3 H, s, 7-Me), 2.50 (2 H, t, J 8,
CH2CH2CO2), 2.87 (2 H, s, CH2CS), 2.94 (2 H, t, J 8,
᎐
C
MHz, CDCl3) 8.6 (4-Me), 20.5 (CH2CH2CO), 27.5 (CMe), 28.3
(CMe3), 34.8 (CH2CH2CO), 39.8, 40.6 and 44.1 (CH2CCH2),
51.3 and 51.8 (OMe), 80.6 (CMe ), 91.8 (CH᎐C), 118.5, 120.2,
᎐
3
126.0 and 128.2 (pyrrole-C), 154.3 (CH᎐C) and 160.2, 170.5,
᎐
171.3 and 173.6 (C᎐O).
᎐
(3R,4Z)-9-tert-Butoxycarbonyl-8-(2-methoxycarbonylethyl)-3-
methoxycarbonylmethyl-3,7-dimethyl-2,3-dihydrodipyrrin-
1(10H)-one 4
Concentrated aqueous ammonia (16 drops) was added over 1 h
to a stirred solution of enol lactone 45 (200 mg, 0.445 mmol) in
tetrahydrofuran (20 cm3) at 0 ЊC. The solution was stirred for a
further 1 h at 0 ЊC and then brine (50 cm3) and dichloromethane
(60 cm3) were added. The organic phase was separated and the
remaining aqueous phase was acidified to pH 1 with concen-
trated hydrochloric acid and extracted with dichloromethane
(2 × 20 cm3). The combined organic layers were dried and
evaporated under reduced pressure. A solution of the resulting
oil in dichloromethane (15 cm3) was stirred with toluene-p-
sulfonic acid (10 mg) at room temperature for 1 h and then
washed with water (10 cm3), dried and evaporated under
reduced pressure. PLC, eluting with 5% methanol in dichloro-
methane, gave the (Z)-lactam 4 as an oil (67 mg, 34%), identical
to the compound prepared previously,2 and the lactone lactam
47 (96 mg, 50%) as an oil (Found: Mϩ, 434.2065. C22H30N2O7
requires M, 434.2053); λmax(MeOH)/nm 277; νmax(CHCl3)/cmϪ1
3400, 3240, 1785 and 1725; δH (400 MHz, CDCl3) 1.41 (3 H, s,
lactone-Me), 1.46 (9 H, s, But), 1.96 (3 H, s, pyrrole-Me), 2.42–
2.49 (3 H, m, CH2CH2CO and CHAHB), 2.55 (1 H, d, J 17,
CHAHB), 2.59 and 2.76 (each 1 H, d, J 18, CH2), 2.85–2.95 (2 H,
m, CH2CH2CO), 3.01 and 3.09 (each 1 H, d, J 15, CH2), 3.65 (3
H, s, OMe), 7.31 (lactam-NH) and 9.78 (pyrrole-NH); δC(100
MHz, CDCl3) 8.7 (pyrrole-Me), 20.6 (lactam-Me), 21.1
(CH2CH2CO), 28.2 (CMe3), 30.6 (pyrrole-CH2), 35.1
(CH2CH2CO), 42.9, 43.3 and 44.7 (CH2CCH2), 51.3 (OMe),
80.9 (CMe3), 101.0 (O᎐C᎐N), 118.6, 119.7, 125.2 and 128.1
CH CH CO ), 3.67 (3 H, s, OMe), 5.32 (1 H, s, CH᎐C) and
᎐
2
2
2
9.00 and 9.53 (each 1 H, br s, NH); δC(100 MHz, CDCl3) 9.3
(7-Me), 20.8 (CH2CH2CO), 28.3 (CMe2 and CMe3), 34.9
(CH2CH2CO), 41.5 (CMe2), 51.5 (OMe), 57.1 (CH2CS), 81.1
(CMe ), 91.4 (CH᎐C), 118.5, 120.5, 127.4 and 129.2 (pyrrole-
᎐
3
C), 152.8 (CH᎐C), 160.9 and 173.6 (C᎐O) and 203.9 (C᎐S);
᎐
᎐
᎐
m/z (FD) 406 (Mϩ, 100%).
13,17-Bis(2-methoxycarbonylethyl)-18-methoxycarbonylmethyl-
2,2,8,8,12-pentamethylisobacteriochlorin 59
A solution of thiolactam 55 (12 mg, 30 µmol) in dry trifluoro-
acetic acid (1 cm3) was stirred at room temperature for 90 min,
then treated with trimethyl orthoformate (160 mm3), stirred for
a further 20 min and evaporated under a stream of argon. PLC,
eluting with diethyl ether–hexane (1:1), gave the formyl thio-
imino ether 52 (7.7 mg, 75%) as an oil; λmax(MeOH)/nm 265
and 392; δH (400 MHz, CD2Cl2) 1.26 (6 H, s, CMe2), 2.06 (3 H, s,
ArMe), 2.55 (2 H, t, J 8, CH2CH2CO2), 2.69 (3 H, s, SMe), 2.72
(2 H, s, CH2CSMe), 3.01 (2 H, t, J 8, CH2CH2CO2), 3.63 (3 H, s,
OMe), 5.65 (1 H, s, CH᎐C), 9.54 (1 H, s, CHO) and 10.82 (1 H,
᎐
br s, NH).
The imine 4912 (31 mg, 69 µmol) was stirred in dry trifluoro-
acetic acid (1 cm3) for 1 h at room temperature. The solvent was
then evaporated under a stream of argon. A solution of the
residue in dichloromethane (10 cm3) was washed with saturated
aqueous sodium hydrogen carbonate (10 cm3), dried (Na2SO4)
and evaporated under reduced pressure. The residual oil was
purified by PLC, eluting with diethyl ether–light petroleum (bp
60–80 ЊC) (3:1), to give the imine 50 (7 mg, 30%) as an oil. (The
purification of this product was carried out as quickly as
(pyrrole-C) and 161.2, 173.5, 173.5 and 174.4 (C᎐O).
᎐
Conversion of lactam lactone 47 into lactam 4
An ethereal solution of diazomethane (6 cm3) was added over 2
h to a solution of the lactam lactone 47 (96 mg, 0.221 mmol)
and a catalytic amount of sodium methoxide (ca. 0.3 mg) in
J. Chem. Soc., Perkin Trans. 1, 1997
2135

View Article Online
possible and the product stored at Ϫ20 ЊC for no more than 8 h
before being used in the next reaction.)
methane (25 cm3 then 10 cm3). The combined organic extracts
were washed with 10% aqueous ammonia (10 cm3), dried
(Na2SO4) and evaporated under reduced pressure. The residual
oil was purified by PLC, eluting with diethyl ether, to give the
(Z)-formyl thioimino ether 53 (7.9 mg, 15%) and the (E)-formyl
thioimino ether (40.2 mg, 77%), as oils.
A solution of the imine 50 (7 mg, 20 µmol) in dry methanol
(0.7 cm3) was added to the formyl thioimino ether 52 (7.7 mg,
22 µmol) and then dry trifluoroacetic acid (36 mm3) was added.
The solution was stirred at room temperature in the dark for 1
h, during which time a green–blue colour developed. Dry tetra-
hydrofuran (5 cm3) was added followed by dry diisopropyl-
ethylamine (150 mm3), which resulted in a change of colour to
deep blue. The solution was then mixed with a solution of
diisopropylethylammonium trifluoroacetate (200 mg) in dry
toluene (1 cm3), transferred to a glass tube and the total volume
made up to 40 cm3 with dry tetrahydrofuran. The solution was
then subjected to four cycles of freeze-pump-thaw degassing
and the tube was sealed under high vacuum and irradiated for
120 h, during which time the solution turned a deep purple–red
colour and developed a bright orange fluorescence. The tube
was opened and the solution was diluted with dichloromethane
(25 cm3), washed with hydrochloric acid (0.2 mol dmϪ3; 25 cm3)
and then saturated aqueous sodium hydrogen carbonate (10
cm3), dried over anhydrous sodium sulfate and evaporated
under reduced pressure. The residue was purified by PLC, elut-
ing with methyl acetate–dichloromethane (1:9), to give the iso-
bacteriochlorin 59 (6 mg, 47%) as a purple solid (Found: Mϩ,
628.3267. C36H44N4O6 requires M, 628.3261); λmax(MeOH)/nm
272, 368, 544 and 587; νmax(CH2Cl2)/cmϪ1 3433, 3368, 1733,
1692 and 1644; δH (400 MHz, CDCl3) 1.47 and 1.50 (each 6 H, s,
2 × CMe2), 2.69 (3 H, s, 12-Me), 2.84 and 3.04 (each 2 H, t,
J 7.5, CH2CH2CO), 3.24, 3.28 and 3.35 (each 3 H, s, OMe),
3.28 and 3.30 (each 2 H, s, 3- and 7-H2), 3.73 and 3.86 (each 2
H, t, J 7.5, CH2CH2CO2), 4.19 (2 H, s, 18-CH2CO), 6.50 (1 H, s,
5-H), 7.33 and 7.56 (each 1 H, s, 10- and 20-H) and 8.86 (1 H, s,
15-H).
(Z)-Isomer (higher Rf): λmax(MeOH)/nm 222, 266 and 389;
δH (400 MHz, C6D6) 1.02 (3 H, s, 2-Me), 1.86 (3 H, s, 7-Me),
2.15–2.39 (5 H, m, CH2CH2CO, CH2CO and 3-HA), 2.87 (2 H,
t, J 8, CH2CH2CO), 2.93 (1 H, dd, J 17 and 1, 3-HB), 3.22 (6 H,
s) and 3.28 (3 H, s, 2 × OMe and SMe), 5.63 (1 H, br s, CH᎐C),
᎐
9.76 (1 H, s, CHO) and 10.73 (1 H, br s, NH).
(E)-Isomer (lower Rf): λmax(MeOH)/nm 222, 265 and 380;
δH (400 MHz, C6D6) 0.94 (3 H, s, 2-Me), 1.75 (3 H, s, 7-Me),
2.18–2.30 (4 H, m, CH2CH2CO and 2 × CHAHB), 2.25 (3 H, s,
SMe), 2.46 (1 H, d, J 18, CHAHB), 2.78 (2 H, t, J 7, CH2-
CH2CO2), 3.09 (1 H, d, J 17, CHAHB), 3.22 and 3.28 (each 3 H,
s, OMe), 6.78 (1 H, br s, CH᎐C), 9.07 (1 H, br s, NH) and 9.72
᎐
(1 H, s, CHO); m/z (FD) 406 (Mϩ, 100%).
tert-Butyl 1-[bis(tert-butoxycarbonyl)methylene]-8-(2-methoxy-
carbonylethyl)-3,3,7-trimethyl-1,2,3,10-tetrahydrodipyrrin-9-
carboxylate
A solution of thiolactam 55 (73 mg, 0.18 mmol) in dry dichloro-
methane (10 cm3) was treated with 1,8-diazabicyclo[5.4.0]-
undec-7-ene (0.13 cm3, 0.876 mmol) followed by a solution of
di-tert-butyl bromomalonate (88 mg, 0.298 mmol) in dry
dichloromethane (2 cm3), stirred for 2 h at room temperature
and evaporated under reduced pressure and dried under high
vacuum. Dry toluene (15 cm3) and triphenylphosphine (200
mg) were added and the mixture was heated at 110 ЊC for 90
min, then cooled, diluted with diethyl ether (50 cm3), washed
with hydrochloric acid (1 mol dmϪ3; 50 cm3) then brine (30
cm3), dried (Na2SO4) and evaporated under reduced pressure.
The residual oil was purified by PLC, eluting with diethyl ether–
hexane (1:1), to give the enamine (54 mg, 51%) as a foam
(Found: Mϩ, 588.3457. C32H48N2O8 requires M, 588.3411);
λmax(MeOH)/nm 273 and 338; [ϩZn(OAc)2] 239, 326 and 407;
νmax(CH2Cl2)/cmϪ1 3626, 3448, 1733, 1686 and 1651; δH (400
MHz, CDCl3) 1.26 (6 H, s, CMe2), 1.47, 1.49 and 1.54 (each 9
H, s, But), 1.93 (3 H, s, 7-Me), 2.54 (2 H, t, J 8, CH2CH2CO2),
2.93 (2 H, s, 2-H2), 3.01 (2 H, t, J 8, CH2CH2CO2), 3.66 (3 H, s,
(2R)-9-tert-Butoxycarbonyl-8-(2-methoxycarbonylethyl)-2-
methoxycarbonylmethyl-2,7-dimethyl-2,3-dihydrodipyrrin-
1(10H)-thione 56
A solution of the lactam 5 (137 mg, 0.306 mmol) in dry toluene
(13 cm3) was treated with Lawesson’s reagent (379 mg, 0.94
mmol) and dry diisopropylethylamine (0.16 cm3, 0.92 mmol)
and heated under reflux for 45 min, then cooled, diluted with
dichloromethane (50 cm3), washed with hydrochloric acid (1
mol dmϪ3; 25 cm3) and then brine (30 cm3), dried (Na2SO4) and
evaporated under reduced pressure. The residual oil was puri-
fied by PLC, eluting with ethyl acetate–light petroleum (1:3), to
give a mixture of the (E)- and (Z)-thiolactams 56 (60 mg, 46%;
ratio 3:1) as an oil. For characterisation, the isomers were
separated by PLC eluting with diethyl ether–hexane (3:2).
(E)-Isomer (lower Rf): λmax(MeOH)/nm 252 and 361; δH (400
MHz, CDCl3) 1.35 (3 H, s, 2-Me), 1.56 (9 H, s, But), 1.98 (3 H, s,
7-Me), 2.50 (2 H, t, J 8, CH2CH2CO2), 2.67 (1 H, d, J 17,
CHAHBCO), 2.89–3.02 (4 H, m, CH2CH2CO2, CHAHBCO and
3-HA), 3.35 (1 H, dd, J 16 and 2, 3-HB), 3.65 and 3.66 (each 3 H,
OMe), 5.22 (1 H, s, CH᎐C) and 8.53 and 10.47 (each 1 H, br s,
᎐
NH); δC(100 MHz, CDCl3) 9.4 (7-Me), 20.7 (CH2CH2CO2),
28.3, 28.4, 28.5 and 28.8 (3 × CMe3 and CMe2), 34.7
(CH2CH2CO2), 39.3 and 46.4 (C-2 and -3), 51.4 (OMe), 80.0,
80.3 and 80.5 (3 × CMe ), 89.1 and 95.2 (C-5 and N᎐C᎐C),
᎐
3
117.9, 119.6, 128.3 and 129.6 (pyrrole-C), 151.8 and 160.3 (C-1
and -4) and 163.9, 166.9, 167.9 and 173.8 (C᎐O); m/z (FD) 588
᎐
(Mϩ, 100%).
(7R)-13,17-Bis(2-methoxycarbonylethyl)-7-methoxycarbonyl-
methyl-2,2,7,12,18-pentamethylisobacteriochlorin 60
s, OMe), 5.91 (1 H, br s, CH᎐C) and 8.50 and 9.19 (each 1 H, br
The above enamine (54 mg, 92 µmol) was stirred in dry tri-
fluoroacetic acid (2 cm3) for 40 min in the dark. The solvent was
then evaporated under a stream of argon and the residue was
dissolved in dry toluene (5 cm3) and re-evaporated under
reduced pressure. A solution of the residual oil in dry toluene (5
cm3) was treated with anhydrous sodium acetate (150 mg)
followed by glacial acetic acid (5 drops), heated at 80 ЊC for 2 h
and then filtered through glass wool. The filtrate was evapor-
ated under reduced pressure and the residual oil was purified
by PLC, eluting with diethyl ether, to give the imine 51 (20.2
mg, 76%) as an oil (this purification was performed as rapidly
as possible to avoid decomposition and the product was
stored at Ϫ20 ЊC for no more than 8 h before being used in
the next reaction); λmax(MeOH)/nm 248 and 337; δH (400
MHz, CD2Cl2) 1.19 (6 H, s, CMe2), 2.03 (3 H, s, ArMe), 2.17
᎐
s, NH); m/z (FD) 464 (Mϩ, 100%).
(Z)-Isomer (higher Rf): λmax(MeOH)/nm 269 and 350;
[ϩZn(OAc)2] 256 and 383; δH (400 MHz, CDCl3) 1.35 (3 H, s,
2-Me), 1.56 (9 H, s, But), 1.96 (3 H, s, 7-Me), 2.52 (2 H, t, J 8,
CH2CH2CO), 2.72 and 2.85 (each 1 H, d, J 17, CH2CO), 2.81 (1
H, d, J 17) and 3.23 (1 H, dd, J 17 and 2, 3-H2), 2.98 (2 H, t, J 8,
CH2CH2CO2), 3.66 and 3.67 (each 3 H, s, OMe), 5.44 (1 H, br s,
CH᎐C) and 8.63 and 9.11 (each 1 H, br s, NH).
᎐
(2R)-8-(2-Methoxycarbonylethyl)-2-methoxycarbonylmethyl-
2,7-dimethyl-1-methylthio–2,3-dihydrodipyrrin-9-carbaldehyde
53
A solution of thiolactam 56 (60 mg, 0.129 mmol) in dry tri-
fluoroacetic acid (3 cm3) was stirred in the dark for 45 min, then
treated with trimethyl orthoformate (160 mm3), stirred for 30
min, mixed with water (5 cm3) and extracted with dichloro-
(3 H, s, MeC᎐N), 2.50–2.55 (4 H, m, CH CH CO and
᎐
2
2
CH C᎐N), 2.71 (2 H, t, J 8, CH CH CO), 3.64 (3 H, s,
᎐
2
2
2
2136
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
OMe), 5.67 (1 H, s, CH᎐C), 6.51 (1 H, d, J 2, ArH) and
10.48 (1 H, br s, NH).
137.3, 142.5, 146.8, 152.6, 162.7, 163.1 and 167.3 (12 ×
aromatic-C), 171.6 and 171.9 (C᎐O) and 173.5 (2 × C᎐O).
᎐
᎐
᎐
A solution of the imine 51 (20.2 mg, 69 µmol) in dry meth-
anol (2 cm3) was stirred with formyl thioimino ether 53 (32.9
mg, 81 µmol) at room temperature in the dark and dry tri-
fluoroacetic acid (126 mm3) was added, which caused a blue
colour to develop. The solution was stirred for 3 h, then dry
tetrahydrofuran (10 cm3) was added followed by diisopropyl-
ethylamine (0.6 cm3), which resulted in a change of colour to
deep red. The solution was then mixed with a solution of diiso-
propylethylammonium trifluoroacetate (700 mg) in dry toluene
(3 cm3), transferred to a glass tube, made up to a total volume
of 40 cm3 with dry tetrahydrofuran and subjected to four cycles
of freeze-pump-thaw degassing. The tube was sealed under
high vacuum and then irradiated for 132 h, during which time
the solution turned to a deep purple–red colour and gave a
bright orange fluorescence. The tube was opened and the
solution was diluted with dichloromethane (25 cm3), washed
with hydrochloric acid (0.2 mol dmϪ3; 25 cm3) then saturated
aqueous sodium hydrogen carbonate (10 cm3), dried (Na2SO4)
and evaporated under reduced pressure. The residual gum was
purified by PLC on plates free of fluorescent indicator, eluting
with methyl acetate–dichloromethane (1:9), to give the iso-
bacteriochlorin 60 (23.8 mg, 55%) as a purple solid (Found: Mϩ,
628.3261. C36H44N4O6 requires M, 628.3261); λmax(MeOH)/nm
275, 367, 396, 508, 542, 582 and 633; νmax(CH2Cl2)/cmϪ1 3368,
3278, 1734 and 1644; δH (400 MHz, CDCl3) 1.48 (6 H, s, CMe2),
1.60 (3 H, s, 7-Me), 2.72 and 2.75 (each 3 H, s, 12- and 18-Me),
2.80 (1 H, d, J 7, CHAHBCO), 2.85–2.91 (5 H, m, 2 × CH2-
CH2CO2 and CHAHBCO), 3.24 (3 H, s, OMe), 3.25 (6 H, s,
2 × OMe), 3.37 (2 H, s, 3-H2), 3.58 and 4.14 (each 1 H, d, J 17,
8-H2), 3.79 (4 H, t, J 7, CH2CH2CO2), 6.60 (1 H, s, 5-H), 7.44
and 7.54 (each 1 H, s, 10- and 20-H) and 8.93 (1 H, s, 15-H);
δC(100 MHz, CDCl3) 10.4 and 10.6 (12-Me and 18-Me), 21.5
and 21.6 (CH2CH2CO), 27.1 (7-Me), 30.0 (CMe2), 36.7
(2 × CH2CH2CO), 42.5, 44.9, 45.3 and 47.6 (CH2CO, C-2, C-7
and C-8), 50.9, 51.0 and 51.1 (OMe), 63.7 (C-3), 89.0 (C-5),
92.0 and 94.7 (C-10 and C-20), 105.6 (C-15), 126.0, 127.0,
134.7, 136.6, 137.4, 144.7, 147.2, 152.2, 159.1 and 162.1
(2R,7R)-13,17-Bis(2-methoxycarbonylethyl)-2,7-bis(methoxy-
carbonylmethyl)-2,7,12,18-tetramethyl-3,8-dioxoisobacterio-
chlorin 64
A mixture of the isobacteriochlorin 62 (34 mg, 50 µmol) and
selenium dioxide (600 mg) was heated under reflux in dry 1,4-
dioxane (30 cm3) for 2 h. The solution was then evaporated
under reduced pressure and dichloromethane (20 cm3) was
added. This solution was filtered and evaporated under reduced
pressure. Purification by PLC, eluting with hexane–methyl
acetate (1:1) and then methyl acetate–dichloromethane (1:10),
gave the dioxoisobacteriochlorin 64 (15 mg, 42%) as a green
solid (Found: Mϩ, 714.2901. C38H42N4O10 requires M,
714.2901); λmax(CHCl3)/nm 401, 416, 436, 540, 591 and 637;
δH (400 MHz, CDCl3) 1.84 and 1.85 (each 3 H, s, 2- and 7-Me),
3.08 and 3.13 (each 3 H, s, 12- and 18-Me), 3.10–3.16 (4 H, m,
2 × CH2CH2CO), 3.27, 3.32, 3.58 and 3.62 (each 3 H, s, OMe),
3.73 and 3.78 (each 1 H, d, J 17, CH2CO), 3.74 and 3.88 (each 1
H, d, J 17.5, CH2CO), 4.14–4.21 (4 H, m, CH2CH2CO) and
8.45, 8.67, 9.38 and 9.56 (each 1 H, s, C᎐CH); δ (100 MHz,
᎐
C
CDCl3) 10.9 and 11.1 (12- and 18-Me), 21.41 and 21.44
(CH2CH2CO), 23.4 and 23.9 (2- and 7-Me), 36.3 (2 × CH2-
CH2CO), 41.7 and 42.0 (CH2CO), 49.4 and 51.8 (C-2 and -7),
51.6 (2 × OMe), 51.72 and 51.75 (OMe), 91.2 and 91.4 (C᎐CH),
᎐
96.7 (2 × C᎐CH), 131.5, 131.8, 132.1, 135.4, 136.2, 138.0, 139.1,
᎐
144.7, 144.9, 145.6, 160.9 and 165.2 (12 × aromatic-C), 170.3
and 170.5 (CO ), 173.2 (2 × CO ) and 207.3 (2 × C᎐O).
᎐
2
2
When the foregoing reaction was run for only 0.5 h, the blue
mono-oxo system 63 accompanied 64 (ratio 1:2) and was sep-
arated from it by PLC using hexane–methyl acetate (1:1)
(Found: Mϩ, 700.3110. C38H44N4O9 requires M, 700.3108); λmax
(CHCl3)/nm 377, 385, 412, 436, 548, 590 and 642; δH (400 MHz,
CDCl3) 1.58 and 1.86 (each 3 H, s, 2- and 7-Me), 2.86 and 3.00
(each 3 H, s, 12- and 18-Me), 2.93 (4 H, t, J 7.5, 2 × CH2-
CH2CO), 3.12 (1 H, d, J 15, CHAHBCO), 3.17–3.21 (4 H, m,
CHAHBCO and OMe), 3.61 (3 H, s, OMe), 3.64 (6 H, s,
2 × OMe), 3.39 and 3.50 (each 1 H, d, J 17, CH2CO), 3.75 and
3.81 (each 2 H, t, J 7.5, CH2CH2CO), 3.89 and 4.44 (each 1 H,
d, J 17.5, 3- or 8-H2) and 7.06, 7.44, 8.63 and 8.69 (each 1 H, s,
(12 × aromatic-C) and 169.8, 171.2 and 173.2 (C᎐O).
᎐
(2R,7R)-13,17-Bis(2-methoxycarbonylethyl)-2,7-bis(methoxy-
carbonylmethyl)-2,7,12,18-tetramethylisobacteriochlorin 62
A solution of imine 61 (19 mg, 55 µmol) in dry methanol (3
cm3) was stirred with formyl thioimino ether 53 (45 mg, 0.11
mmol) at room temperature in the dark and dry trifluoroacetic
acid (126 mm3) was added, which caused a blue–green colour to
develop. The solution was stirred for 3 h, then treated with dry
tetrahydrofuran (10 cm3) followed by diisopropylethylamine
(564 mm3), which resulted in a colour change to deep red, then
mixed with a solution of diisopropylethylammonium trifluoro-
acetate (500 mg) in dry toluene (3 cm3), transferred to a glass
tube, made up to a total volume of 40 cm3 with dry tetrahydro-
furan, and subjected to four cycles of freeze-pump-thaw degas-
sing. The tube was then sealed and irradiated for 90 h, during
which time the solution became a deep purple–red colour
and gave a bright orange fluorescence. The tube was opened
and the solution was diluted with dichloromethane (40 cm3),
washed with dilute hydrochloric acid (0.5 mol dmϪ3; 30 cm3)
then saturated aqueous sodium hydrogen carbonate (40 cm3),
dried and evaporated under reduced pressure. Purification by
PLC on plates free of fluorescent indicator, eluting with
dichloromethane–methyl acetate (10:1), gave the isobacterio-
chlorin 62 as a purple gum (20 mg, 53%), with identical spectro-
scopic data to those reported previously;2 δC(100 MHz, CDCl3)
10.5 (12- and 18-Me), 21.15 and 21.2 (CH2CH2CO), 27.5 and
28.5 (2- and 7-Me), 36.5 (2 × CH2CH2CO), 45.0, 45.2 (2 C),
46.1, 47.3 and 49.5 (2 × CH2CO and C-2, -3, -7 and -8),
51.55 (2 × OMe), 51.6 (2 × OMe), 89.9 (C-5), 92.4 and 93.1
(C-10 and -20), 103.3 (C-15), 125.3, 127.0, 132.0, 134.9, 135.5,
C᎐CH); m/z (FD) 700 (Mϩ, 100%).
᎐
Further oxidation of the mono-oxo system 63, as above, con-
verted it into 64, the identification being by spectroscopic and
chromatographic comparison.
(2R,7R)-17-(2-methoxycarbonylethenyl)-13-(2-methoxycarbonyl-
ethyl)-2,7-bis(methoxycarbonylmethyl)-2,7,12,18-tetramethyl-
3,8-dioxoisobacteriochlorin 2
An aliquot (5.6 cm3) of a solution of osmium tetroxide (100
mg) in dry dichloromethane (71.5 cm3) and dry pyridine (1.43
cm3) was stirred with dioxoisobacteriochlorin 64 (11 mg, 15.4
µmol) in the dark, under argon, at room temperature for 20 h.
Methanol (5 cm3) was then added and hydrogen sulfide bubbled
into the solution. The black precipitate was removed by filtra-
tion through Celite and the filtrate was evaporated under
reduced pressure. PLC gave recovered dioxoisobacteriochlorin
64 (8 mg) and a mixture of diols 65 and 66 (1.5 mg). A solution
of the diols in benzene (5 cm3) was treated with concentrated
hydrochloric acid (4 drops), heated under reflux for 3.5 h and
then evaporated under reduced pressure. Purification by PLC,
eluting with benzene–methyl acetate (10:1), gave metal-free
haem d1 methyl ester 2 as a green solid (0.4 mg, 13% based on
unrecovered 64) and its isomer with the acrylate side-chain on
ring C (0.13 mg, 4% based on unrecovered 64).
Metal-free haem d1 methyl ester 2 (Found: Mϩ, 712.2746.
C38H40N4O10 requires M, 712.2744); λmax(CHCl3)/nm 422, 445,
610 and 660; δH (400 MHz, CDCl3) 1.78 and 1.80 (each 3 H, s,
2- and 7-Me), 3.05 (2 H, t, J 7.5, CH2CH2CO), 3.14, 3.18, 3.25,
3.32, 3.62 and 4.00 (each 3 H, s, 12- and 18-Me and 4 × OMe),
J. Chem. Soc., Perkin Trans. 1, 1997
2137

View Article Online
2 C. J. Aucken, F. J. Leeper and A. R. Battersby, J. Chem. Soc., Perkin
Trans. 1, 1997, 2099.
3.70 and 3.80 (each 1 H, d, J 18, CH2CO), 3.76 (2 H, s,
CH2CO), 4.06–4.10 (2 H, m, CH2CH2CO), 6.91 and 8.98
3 A. R. Battersby, Science, 1994, 264, 1551; F. Blanche, B. Cameron,
J. Crouzet, L. Debussche, D. Thibaut, M. Vuilhorgne, F. J. Leeper
and A. R. Battersby. Angew. Chem., Int. Ed. Engl., 1995, 34, 383.
4 Review: A. R. Battersby and E. McDonald, in B12, ed. D. Dolphin,
Wiley, New York, 1982, vol. 1, p. 107.
(each 1 H, d, J 16, CH᎐CH) and 8.27, 8.43, 9.22 and 9.45 (each
᎐
1 H, s, C᎐CH). This product was identical with a sample of 2
᎐
derived from natural haem d1 by full spectroscopic and CD
comparison.
5 R. L. Mackman, J. Micklefield, M. H. Block, F. J. Leeper and
A. R. Battersby, J. Chem. Soc., Perkin Trans. 1, 1997, 2111.
6 R. E. Ireland, R. C. Anderson, R. Badoud, B. J. Fitzsimmons,
G. J. McGarvey, S. Thaisrivongs and C. S. Wilcox, J. Am. Chem.
Soc., 1983, 105, 1988.
(2R,7R)-13-(2-Methoxycarbonylethenyl)-17-(2-methoxy-
carbonylethyl)-2,7-bis(methoxycarbonylmethyl)-2,7,12,18-tetra-
methyl-3,8-dioxoisobacteriochlorin. (Found: Mϩ, 712.2785);
λmax(CHCl3)/nm 419, 443, 537, 572, 603 and 650; δH (400 MHz,
CDCl3) 1.78 and 1.79 (each 3 H, s, 2- and 7-Me), 3.06 (2 H, t, J
7.5, CH2CH2CO), 3.14, 3.16, 3.18 and 3.40 (each 3 H, s, 12- and
18-Me and 2 × OMe), 3.62–3.84 (7 H, m, OMe and
2 × CH2CO), 4.00 (3 H, s, OMe), 4.04 (2 H, t, J 7.5,
7 S. Hanessian, P. J. Murray and S. P. Sahoo, Tetrahedron Lett., 1985,
26, 5623.
8 K. Tomioka, F. Sato and K. Koga, Heterocycles, 1982, 17, 311.
9 B. H. Lipshutz, R. Crow, S. H. Dimock, E. L. Ellsworth,
R. A. J. Smith and J. R. Behling, J. Am. Chem. Soc., 1990, 112, 4063;
B. H. Lipshutz, E. L. Ellsworth, S. H. Dimock and R. A. J. Smith,
J. Am. Chem. Soc., 1990, 112, 4404.
CH CH CO), 6.94 and 9.04 (each 1 H, d, J 16, CH᎐CH) and
᎐
2
2
8.22, 8.39, 9.27 and 9.41 (each 1 H, s, C᎐CH).
᎐
10 Y. Yamamoto, Acc. Chem. Res., 1987, 20, 243.
11 Reviewed by R. V. Stevens, in B12, ed. D. Dolphin, Wiley, New York,
1982, vol. 1, p. 169.
Acknowledgements
12 P. J. Harrison, Z.-C. Sheng, C, J. R. Fookes and A. R. Battersby,
J. Chem. Soc., Perkin Trans. 1, 1987, 1667.
Grateful acknowledgement is made to the EPSRC for a
studentship (for R. L. M.) and a CASE award (to J. M.) and to
the Deutsche Forschungsgemeinschaft for a postdoctoral
award (to M. B.). We also thank Professor R. Timkovich for
his help and the EPSRC, Zeneca, Roche Products and
F. Hoffmann-La Roche for financial support.
13 C. K. Chang and W. Wu, J. Biol. Chem., 1986, 261, 8593.
14 A. Fässler, A. Kobelt, A. Pfaltz, A. Eschenmoser, C. Bladon,
A. R. Battersby and R. K. Thauer, Helv. Chim. Acta, 1985, 68, 2287.
15 D. Kusch, E. Töllner, A. Lincke and F.-P. Montforts, Angew. Chem.,
Int. Ed. Engl., 1995, 34, 784.
References
1 Preliminary account of part of this work: J. Micklefield,
R. L. Mackman, C. J. Aucken, M. Beckmann, M. H. Block,
F. J. Leeper and A. R. Battersby, J. Chem. Soc., Chem. Commun.,
1993, 275.
Paper 7/00655A
Received 28th January 1997
Accepted 17th March 1997
2138
J. Chem. Soc., Perkin Trans. 1, 1997