Synthesis of the 2,3,4-trisubstituted indole fragments of nosiheptide and glycothiohexide.

Article abstract of DOI:10.1039/b312964k

Two routes to the protected 4-hydroxymethyl-3-methylindole-2-carboxylate fragment 17 of the thiopeptide antibiotic nosiheptide are described starting from methyl 4-methylindole-2-carboxylate 11, itself prepared in two steps, or from 3-amino-4-chlorobenzoic acid 26. The first route can be adapted to the synthesis of a fragment of the related antibiotic glycothiohexide-alpha, the 3,4-bis(hydroxymethyl)indole-2-carboxylate in which the two hydroxymethyl groups are differentiated as in indole 19 or the lactone 20.

Full text of DOI:10.1039/b312964k

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Synthesis of the 2,3,4-trisubstituted indole fragments of
nosiheptide and glycothiohexide
David J. Bentley,a John Fairhurst,b Peter T. Gallagher,b Astrid K. Manteuffel,a
Christopher J. Moodya and Joanne L. Pindera
a Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b Eli Lilly and Company Ltd., Lilly Research Centre, Windlesham, Surrey, UK GU20 6PH
Received 16th October 2003, Accepted 12th December 2003
First published as an Advance Article on the web 29th January 2004
Two routes to the protected 4-hydroxymethyl-3-methylindole-2-carboxylate fragment 17 of the thiopeptide antibiotic
nosiheptide are described starting from methyl 4-methylindole-2-carboxylate 11, itself prepared in two steps, or
from 3-amino-4-chlorobenzoic acid 26. The first route can be adapted to the synthesis of a fragment of the related
antibiotic glycothiohexide-α, the 3,4-bis(hydroxymethyl)indole-2-carboxylate in which the two hydroxymethyl groups
are differentiated as in indole 19 or the lactone 20.
xylene gave the desired indole 8. The modest yields of these
two steps (44 and 55%), coupled with the fact that introduction
of the 3-substituent by formylation (see below) proceeded
poorly, led us to investigate a simpler indole. Repeating the
sequence starting from 2-tolualdehyde 9 gave the 4-methyl-
indole-2-carboxylate 11 in excellent 84% yield over the two
Introduction
The antibiotic nosiheptide 1 (RP9671) was originally isolated
from Streptomyces actuous 40037 in the early 1960s by French
workers,1,2 and its structure, determined by chemical degrad-
ation3 and X-ray crystallography,4,5 is characterised by the pres-
ence of seven heterocyclic rings (five 2,4-disubstituted thiazoles,
steps. The indole 11 was also prepared in an alternative manner
one 2,3,4-trisubstituted indole, one 2,3,5,6-tetrasubstituted
from 2-bromo-3-nitrotoluene by Heck reaction with methyl
pyridine) in a double macrocyclic array. Nosiheptide, which
acrylate to give the 2-nitrocinnamate 12 followed by a phos-
is identical to multhiomycin isolated from Streptomyces anti-
phite mediated deoxygenative cyclisation to give the indole 11
bioticus 8446CC,6 is a member of the thiopeptide antibiotics, a
(Scheme 1).39
growing class of sulfur rich modified cyclic peptides, and has
The bromination of the methyl group in N-protected methyl-
been subject of detailed biosynthetic studies which establish the
indoles is reported in the literature, with the unprotected deriv-
origin of the heterocyclic rings from modification of the amino
atives undergoing electrophilic substitution in the indole ring.40
acid side chains with cyclisation.7–9 Some thiopeptides have
However, it was thought that with the presence of the electron
withdrawing ester in the 2-position of 11 might be sufficient to
prevent bromination in the ring, and thus avoid the additional
protection step. In the event, this was found not to be the case
since treatment of the unprotected indole 11 with NBS and
AIBN, resulted in electrophilic substitution of bromine into the
3-position of the indole. Therefore, protection of the indole
nitrogen with di-tert-butyl dicarbonate to give 13 was followed
by radical bromination of the 4-methyl substituent with NBS,
using AIBN as the radical initiator, gave the required 4-bromo-
methyl compound 14 in good yield. At this stage it was
decided to introduce the required substituent at C-3 by formyl-
ation, since reduction of the formyl group under appropriate
conditions could rise to both the required methyl or hydroxy-
methyl substituents. Treatment of the 4-bromomethyl indole 14
with phosphorus oxychloride and N-methylformanilide (NMF)
pronounced biological activity against Gram-positive bacteria
and anaerobes, including pathogens resistant to antibiotics in
current use, and also against the malaria parasite,10,11 being
powerful inhibitors of protein synthesis in the organism acting
directly on the ribosome and inhibiting the action of GTP-
dependent elongation factors.12–14 Although none of the thio-
peptides are used clinically as yet, nosiheptide is in commercial
use as a feed additive to increase weight gain in poultry and
pigs.15,16
The syntheses of various fragments of nosiheptide have been
reported,17–22 including two syntheses of the unusual 2,3,4-tri-
substituted indole,23,24 a structural unit shared by the closely
related thiopeptide antibiotic glycothiohexide-α 2,25,26 and the
recently isolated nocathiacins,27–29 for example nocathiacin III
3, although in these natural products, the methyl group at the
3-position of the indole has been oxidised to hydroxymethyl. In
in 1,2-dichloroethane yielded the 3-formyl derivative 15 in good
yield, but with complete halide exchange from bromine to
chlorine and concomitant deprotection of the indole nitrogen.
Subsequent Finkelstein reaction of the chloride 15 with sodium
iodide in acetone followed by treatment with aqueous potas-
sium carbonate and protection of the free hydroxyl with tert-
continuation of our interest in the synthesis of the thiopeptide
antibiotics,30 we now report details of flexible routes to the
2,3,4-trisubstituted indole fragment 4 (X = H) of nosiheptide
and the more functionalised fragments 4 (X = OH) and 5 of
glycothiohexide-α.31
butyldimethylsilyl triflate in pyridine gave the desired protected
alcohol 16, a key intermediate, in a moderate yield for the two
steps (Scheme 1).
Results and discussion
Our first approach to the synthesis of a suitably substituted
indole involved the thermal decomposition of an α-azido-
cinnamate derivative, a reaction originally developed by Hemets-
berger et al.,32 and subsequently used by us33–36 and others37 as
an efficient route to a range of indole-2-carboxylate derivatives.
Thus the known 2-tetrahydropyranyloxymethyl benzaldehyde
Our first synthesis of the nosiheptide indole fragment simply
involved reduction of the formyl group; the optimum condi-
tions employed sodium cyanoborohydride in the presence of
zinc iodide,41 and gave the indole 17 which contains suitably
protected functionality for nosiheptide in 63% yield (Scheme 2).
The formyl group in indole 16 also served as a precursor to the
3-hydroxymethyl group found in the glycothiohexide-α indole
fragment although prior protection of the indole nitrogen was
6
38 was condensed with methyl azidoacetate under basic condi-
tions to give the azidocinnamate 7, heating of which in boiling
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 0 1 – 7 0 8
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Scheme 1
Although the above route successfully gave the lactone
20, a suitable intermediate for our projected synthesis of
glycothiohexide-α, it did involve unwanted deprotection and
reprotection steps. Therefore an alternative was investigated,
again starting from the simple 4-methylindole-2-carboxylate
11, but altering the order of steps. Thus formylation using
phosphorus oxychloride and NMF as above gave the alde-
hyde 21, N-protection of which gave the aldehyde ester 22,
both steps proceeding in good yield (Scheme 3). Reduction
of the aldehyde with sodium borohydride and lactonisation of
the resulting 3-hydroxymethylindole 23 with base gave the
lactone 24, although this last step had to be carried out by
careful addition of the base to prevent deprotection of
the indole nitrogen, presumably by the liberated methoxide.43
Reaction of the protected lactone 24 with NBS and AIBN
in carbon tetrachloride gave the bromomethyl compound 25
with no products resulting from bromination of the lactone
methylene group being observed. Finally, Finkelstein reaction
of the bromide 25 with sodium iodide in acetone followed by
treatment with aqueous potassium carbonate and protec-
tion of the free hydroxyl with tert-butyldimethylsilyl triflate in
necessary because of the high reactivity of 3-hydroxymethyl-
indoles.42 Thus reintroduction of the Boc group (92%) was
followed by reduction of the aldehyde with sodium borohydride
to give the required indole 19 in good yield. At this stage,
rather than protect the new hydroxymethyl with a group which
would allow orthogonal deprotection from the existing pro-
tected 4-hydroxymethyl group, it was decided to use the C-2
carboxyl as an internal protecting group. Hence treatment of
the hydroxyester 19 with base gave the lactone 20 in good yield
(Scheme 2).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 0 1 – 7 0 8
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Scheme 2
Scheme 4
Conclusions
In conclusion, we have developed two routes to the protected
4-hydroxymethyl-3-methylindole-2-carboxylate fragment 17 of
the thiopeptide antibiotic nosiheptide, the second of which is
amenable to large-scale working. One route can also be adapted
to the synthesis of a fragment of the related antibiotic glyco-
thiohexide-α, the 3,4-bis(hydroxymethyl)indole-2-carboxylate
in which the two hydroxymethyl groups are differentiated as in
indole 19 or the lactone 20.
Experimental
For general experimental details, see ref. 44.
2-Tetrahydropyranyloxymethylbenzaldehyde 6
(a) 3,4-Dihydropyran (4.0 g, 0.047 mol) was added to a solution
of 2-bromobenzyl alcohol (8.0 g, 0.043 mol) in dichloro-
methane (50 ml) and stirred at room temperature overnight.
The mixture was partitioned between dichloromethane (50 ml)
and water (50 ml). The aqueous layer was further extracted with
dichloromethane (50 ml) and the organic extracts combined,
washed sequentially with water (50 ml) and brine (50 ml),
dried (MgSO4), evaporated in vacuo and purified by column
chromatography on silica, eluting with dichloromethane to
give 2-bromobenzyltetrahydropyranyl ether as a colourless oil
(10.4 g, 90%); νmax (film)/cmϪ1 2954, 2863, 1527, 1445, 1342,
1193, 1127; δH (300 MHz; CDCl3) 7.51 (2H, m, ArH), 7.34 (1H,
t, J 6.5, ArH), 7.16 (1H, m, ArH), 4.85 (1H, d, J 13.3, CHH),
4.77 (1H, m, OCHO), 4.60 (1H, d, J 13.3, CHH ), 3.90 (1H, m,
CHH), 3.59 (1H, m, CHH ), 2.16–1.50 (6H, m, CH2); δC (75
MHz; CDCl3) 137.8 (C), 132.4 (C), 129.0 (CH), 128.7 (CH),
127.3 (CH), 122.7 (CH), 98.4 (CH), 68.6 (CH2), 62.1 (CH2),
30.5 (CH2), 25.5 (CH2), 19.3 (CH2). Spectroscopic data agrees
with those previously reported.45
(b) n-Butyllithium (14.7 ml, 0.023 mol) was added dropwise
to a stirred solution of 2-bromobenzyl tetrahydropyranyl ether
(3.00 g, 0.011 mol) in THF (40 ml) at Ϫ78 ЊC under nitrogen.
The reaction mixture was allowed to warm to 0 ЊC and re-
cooled to Ϫ78 ЊC and DMF (3.0 ml, 0.039 mol) added. The
resulting solution was stirred for 2 h and then allowed slowly to
warm to room temperature. Saturated ammonium chloride
solution (50 ml) was added and the solution extracted with
ether (3 × 60 ml). The combined ethereal extracts were washed
sequentially with water (50 ml) and brine (50 ml), dried
(MgSO4) and evaporated in vacuo to give the title compound 6
Scheme 3
pyridine provided a second route to the protected alcohol 20
(Scheme 3).
Finally, a shorter alternative route to the nosiheptide indole
fragment 17 was developed using a Fischer indole synthesis as
a key step. The starting hydrazine was prepared from the
commercially available 3-amino-4-chlorobenzoic acid 26 by
diazotisation and reduction with tin() chloride, and was
immediately condensed with methyl 2-oxobutanoate to give
the hydrazone 27. Fischer cyclisation of hydrazone 27 using
polyphosphoric acid (PPA) in acetic acid gave the indole 28 in
good yield. The chlorine substituent having served its purpose
in preventing the formation of an alternative indole that
could have resulted from Fischer cyclisation of a simple meta-
substituted phenyl hydrazone was then simply removed by
hydrogenolysis over palladium-on-carbon to give the indole 29.
Reduction of the free carboxylic acid by careful addition of
borane dimethyl sulfide complex was followed by protection of
the resulting alcohol 30 with tert-butyldimethylsilyl chloride to
give the indole 17 (Scheme 4).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 0 1 – 7 0 8
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as a pale yellow oil (2.24 g, 92%); νmax (film)/cmϪ1 2934, 2860,
1691, 1598, 1437, 1205, 1122, 1087; δH (300 MHz; CDCl3) 10.48
(1H, s, CHO), 7.87 (1H, d, J 6.5, ArH), 7.64 (1H, d, J 7.4, ArH),
7.58 (1H, t, J 6.2, ArH), 7.47 (1H, t, J 6.4, ArH), 5.20 (1H, d,
J 14.2, CH2), 4.95 (1H, d, J 11.1, CH2), 3.88 (1H, m, CH2), 3.56
(1H, m, CH2), 1.84–1.52 (6H, m, CH2); δC (75 MHz; CDCl3)
192.7 (C), 140.9 (C), 133.9 (C), 132.0 (C), 128.4 (CH), 127.5
(CH), 98.4 (CH), 66.4 (CH2), 62.3 (CH2), 30.6 (CH2), 25.4
(CH2), 19.4 (CH2). Spectroscopic data agrees with those
previously reported.38
mixture was then stirred at Ϫ30 ЊC for 5 h and then at 4 ЊC
overnight. The solvent was evaporated in vacuo and the residue
partitioned between water (30 ml) and ether (40 ml). The aque-
ous layer was further extracted with ether (30 ml) and the
organic extracts were combined, washed sequentially with
water (30 ml) and brine (30 ml), dried (MgSO4) and evaporated
in vacuo to give the title compound as a pale yellow solid (6.87 g,
84%); mp 44–45 ЊC (from ether) (Found: Mϩ, 217.0846.
C11H11N3O2 requires 217.0851); νmax(Nujol)/cmϪ1 2954, 2860,
2123, 1724, 1376, 1241, 1077; δH (400 MHz; CDCl3) 7.95 (1H,
m, ArH), 7.22 (3H, m, ArH), 7.15 (1H, s, CH), 3.93 (3H, s,
OMe), 2.37 (3H, s, Me); δC (100 MHz; CDCl3) 163.0 (C), 137.6
(C), 131.9 (C), 130.3 (CH), 129.6 (CH), 129.2 (CH), 126.1 (C),
125.8 (CH), 123.5 (CH), 52.9 (Me), 20.1 (Me); m/z (EI) 217
(Mϩ, 3%), 189 (20), 157 (30), 144 (10), 130 (55), 103 (100), 77
(48), 59 (63).
Methyl 2-azido-3-[(2-tetrahydropyranyloxymethyl)phenyl]-
propenoate 7
Sodium metal (1.13 g, 0.049 mol) was added portionwise to
methanol (60 ml) at room temperature. The resulting solution
was cooled to Ϫ20 ЊC and a solution of 2-tetrahydropyranyloxy-
methylbenzaldehyde 6 (3.00 g, 0.014 mol) and methyl azidoac-
etate (6.27 g, 0.054 mol) in methanol (15 ml) was added drop-
wise over 45 min. The reaction mixture was stirred at Ϫ30 ЊC
for 5 h and then 4 ЊC overnight. The solvent was evaporated
in vacuo and the residue partitioned between water (30 ml) and
ether (70 ml). The aqueous layer was further extracted with
ether (2 × 70 ml) and the organic extracts were combined and
washed with water (50 ml) and brine (50 ml), dried (MgSO4),
evaporated in vacuo and purified by column chromatography on
silica eluting with ethyl acetate–light petroleum (1 : 3), to give
the title compound 7 as a yellow oil (1.89 g, 44%) (Found: Mϩ,
317.1382. C16H19N3O4 requires 317.1375); νmax (film)/cmϪ1 2949,
2124, 1719, 1618, 1598; δH (400 MHz; CDCl3) 7.42 (1H, d, J 2.0,
ArH), 7.32 (2H, m, ArH), 7.26 (1H, d, J 10.7, ArH), 4.84 (1H,
d, J 12.2, PhCHH), 4.72 (1H, m, OCHO), 4.50 (1H, d, J 12.2,
Methyl 4-methylindole-2-carboxylate 11
A solution of the methyl 2-azido-(2-methylphenyl)propenoate
10 (2.00 g, 9.0 mmol) in dry xylene (80 ml) was added dropwise
by means of a pressure equalising dropping funnel to a stirred
solution of dry xylene (270 ml) heated under reflux over 1 h.
After the addition was complete, the solution was heated under
reflux for a further 1 h, cooled and the solvent removed in vacuo
to yield the title compound as a yellow solid (1.74 g, 100%) used
without further purification. A sample was recrystallised from
ethyl acetate; mp 135–137 ЊC; (Found: C, 69.6; H, 5.8; N, 7.3.
C11H11NO2 requires C, 69.8; H, 5.9; N, 7.4%) (Found: Mϩ,
189.0795. C11H11NO2 requires 189.0790); νmax (KBr)/cmϪ1 3314,
2965, 2934, 1685, 1531, 1434, 1337, 1255, 1214, 1147; δH (400
MHz; CDCl3) 9.05 (1H, s, NH), 7.21–7.28 (3H, m, ArH),
6.96 (1H, m, 5-H), 3.96 (3H, s, OMe), 2.57 (3H, s, Me);
δC (100 MHz; CDCl3) 162.5 (C), 136.8 (C), 132.3 (C), 127.7 (C),
126.5 (C), 125.6 (CH), 120.8 (CH), 109.4 (CH), 107.5 (CH),
52.0 (Me), 18.6 (Me); m/z (CI) 190 (MHϩ, 100%), 189 (Mϩ, 25),
174 (7), 157 (9), 129 (54), 103 (47), 77 (32).
PhCHH ), 3.80 (3H, s, OMe), 3.60 (1H, m, PhCH᎐), 1.90–1.55
᎐
(8H, m, 4 × CH2); δC (100 MHz; CDCl3) 163.9 (C), 137.2 (C),
131.9 (C), 129.9 (CH), 129.14 (CH), 129.10 (CH), 127.8 (CH),
126.5 (C), 122.9 (CH), 98.1 (CH), 67.3 (CH2), 62.0 (CH2),
52.9 (Me), 30.5 (CH2), 25.5 (CH2), 19.2 (CH2); m/z (EI)
317 (Mϩ, 10%), 289 (100), 273 (30), 188(32), 129 (65), 107 (53),
104 (44).
Methyl 3-(2-methyl-6-nitrophenyl)propenoate 12
2-Bromo-3-nitrotoluene (5.00 g, 23.2 mmol), methyl acrylate
(4.17 ml, 46.3 mmol), palladium acetate (292 mg, 1.16 mmol),
triphenylphosphine (608 mg, 2.32 mmol) and triethylamine
(4.03 ml, 28.9 mmol) were combined in a sealed Young’s tube
and heated to 95 ЊC for 24 h. The residue was dissolved in
methanol, the solvent removed and the crude product purified
by column chromatography (15% ethyl acetate–light petroleum)
to give the title compound 12 (3.77 g, 74%) as a yellow oil
(Found: MHϩ, 222.0769. C11H11NO4 ϩ H requires 222.0766);
νmax (neat)/cmϪ1 2952, 1724, 1527, 1350, 1313, 1279, 1200, 1173;
Methyl 4-(2-tetrahydropyranoxymethyl)indole-2-carboxylate 8
Asolutionofmethyl2-azido-3-[(2-tetrahydropyranyloxymethyl)-
phenyl]propenoate 7 (0.90 g, 3.3 mmol) in dry xylene (30 ml)
was added dropwise, by means of a pressure equalising drop-
ping funnel to a stirred solution of boiling xylenes (100 ml).
After the addition was complete (ca. 45 min), the solution was
heated under reflux for a further 1 h, cooled and concentrated
in vacuo and the residue purified by column chromatography on
silica, eluting with ethyl acetate–light petroleum (1 : 5) to give
the title compound as a pale yellow solid (0.45 g, 55%); mp 106–
108 ЊC (from ether) (Found: C, 66.3; H, 6.6; N, 4.8. C16H19NO4
requires C, 66.4; H, 6.6; N, 4.8%); νmax (KBr)/cmϪ1 3339, 2945,
2827, 1675, 1521, 1434, 1347, 1265, 1163, 1065; δH (400 MHz;
CDCl3) 8.95 (1H, s, NH), 7.35 (2H, m, 6-H, 7-H), 7.30 (1H, s,
3-H), 7.17 (1H, dd, J 6.9, 0.9, 5-H), 5.10 (1H, d, J 11.9,
PhCHH), 4.83 (1H, d, J 11.9, PhCHH ), 4.77 (1H, m, OCHO),
3.95 (3H, s, OMe), 1.95–1.50 (8H, m, 4 × CH2); δC (100 MHz;
CDCl3) 162.4 (C), 137.0 (C), 136.5 (C), 132.3 (C), 127.0 (C),
125.4 (CH), 120.2 (CH), 111.4 (CH), 107.5 (CH), 97.8 (CH),
67.1 (CH2), 62.2 (CH2), 52.0 (Me), 30.6 (CH2), 25.5 (CH2), 19.4
(CH2); m/z (EI) 290 (Mϩ, 7%), 189 (52), 156 (38), 130 (46),
119 (24), 85 (100), 77 (23).
δH (300 MHz; CDCl ) 7.88 (1H, d, J 16.5, CH᎐CHCO Me),
᎐
3
2
7.77 (1H, d, J 8.1, H-5), 7.48 (1H, d, J 7.7, H-3), 7.36 (1H,
apparent t, apparent J 7.9, H-4), 5.97 (1H, d, J 16.5, CH᎐
᎐
CHCO2Me), 3.81 (3H, s, OMe), 2.39 (3H, s, ArMe); δC (75
MHz; CDCl3) 166.4 (C), 149.5 (C), 140.5 (CH), 139.0 (C), 135.2
(CH), 130.2 (C), 129.0 (CH), 124.8 (CH), 122.3 (CH), 52.3
(Me), 21.4 (Me); m/z (CI) 222 (MHϩ, 11%), 190 (100), 141 (44).
Methyl 4-methylindole-2-carboxylate 11
Methyl 3-(2-methyl-6-nitrophenyl)propenoate 12 (1.00 g, 4.52
mmol) was dissolved in triethyl phosphite (4 ml, 22.60 mmol)
and heated under reflux for 20 h. The solvent was removed in
vacuo and the crude product purified by SiO2 chromatography
(15% ethyl acetate: light petroleum) to give the title compound
11 (0.76 g, 89%) as a pale yellow solid; data as above.
Methyl 2-azido-(2-methylphenyl)propenoate 10
Sodium metal (3.17 g, 0.14 mol) was added portionwise to
methanol (100 ml) at room temperature. The resulting solu-
tion was cooled to Ϫ20 ЊC and a solution of o-tolualdehyde 9
(4.50 g, 0.04 mol) and methyl azidoacetate (17.24 g, 0.15 mol) in
methanol (30 ml) was added dropwise over 1 h. The reaction
Methyl 1-tert-butoxycarbonyl-4-methylindole-2-carboxylate 13
Di-tert-butyl dicarbonate (2.31 g, 10.6 mmol) and DMAP
(0.10 g, 0.82 mmol) were added to a stirred solution of methyl
4-methylindole-2-carboxylate 11 (1.00 g, 5.3 mmol) in
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acetonitrile (50 ml). The resulting mixture was stirred at room
temperature overnight and the solvent evaporated in vacuo. The
residue was partitioned between ethyl acetate (50 ml) and water
(50 ml). The aqueous layer was further extracted with ethyl
acetate (2 × 50 ml) and the organic extracts combined, washed
with saturated aqueous sodium hydrogen carbonate, dried
(MgSO4), evaporated in vacuo and purified by column chrom-
atography on silica, eluting with ethyl acetate–light petroleum
(1 : 9), to leave the title compound as a pale yellow oil that
crystallised on standing (1.30 g, 85%); mp 66–68 ЊC (from di-
chloromethane) (Found: C, 66.6; H, 6.7; N, 4.8. C16H19NO4
requires C, 66.4; H, 6.6; N, 4.8) (Found: Mϩ, 289.1318.
C16H19NO4 requires 289.1314); νmax (KBr)/cmϪ1 3000, 2980,
2953, 1733, 1599, 1275, 1209, 1147; δH (300 MHz; CDCl3) 7.93
(1H, dd, J 8.3, 0.6, 7-H), 7.34 (1H, dd, J 8.3, 1.0, 6-H), 7.18 (1H,
s, 3-H), 7.07 (1H, dd, J 7.1, 0.6, 5-H), 3.93 (3H, s, OMe), 2.55
(3H, s, Me), 1.62 (9H, s, CMe3); δC (75 MHz; CDCl3) 162.4 (C),
149.4 (C), 137.8 (C), 131.9 (C), 129.8 (C), 127.3 (C), 127.0
(CH), 123.6 (CH), 113.6 (CH), 112.3 (CH), 84.5 (C), 52.3 (Me),
27.8 (Me), 18.4 (Me); m/z (EI) 289 (Mϩ, 2%), 216 (8), 202 (3),
189 (56), 157 (87), 129 (20), 103 (16), 77 (8), 57 (100).
(27), 215 (32), 201 (13), 200 (83), 163 (24), 162 (15), 157 (25),
156 (69), 129 (50), 128 (100), 102 (54), 101 (41), 77 (31), 76 (28).
Methyl 4-tert-butyldimethylsiloxymethyl-3-formylindole-2-
carboxylate 16
Methyl 4-chloromethyl-3-formylindole-2-carboxylate 15 (100
mg, 0.40 mmol) and sodium iodide (50 mg, 0.33 mmol) were
heated to reflux in acetone (5 ml) for 20 min, and a precipitate
observed. A solution of potassium carbonate (80 mg, 0.58
mmol) in water (3 ml) was added and the solution heated for a
further 30 min. The solvent was evaporated in vacuo and the
residue partitioned between ethyl acetate (10 ml) and water
(10 ml). The aqueous layer was further extracted with ethyl
acetate (10 ml), dried (MgSO4), evaporated in vacuo to give a
yellow solid. The material was then used without further purifi-
cation. TBDMSOTf (110 mg, 0.42 mmol) was added to a solu-
tion of the crude hydroxmethylindole in pyridine (5 ml) at
Ϫ35 ЊC and the resulting mixture stirred at Ϫ35 ЊC for 5 h and
then allowed to warm to room temperature overnight. The sol-
vent was removed in vacuo and the residue partitioned between
ethyl acetate (10 ml) and water (10 ml). The aqueous layer was
further extracted with ethyl acetate (2 × 10 ml), combined
extracts washed with water (3 × 10 ml), dried (MgSO4), evapor-
ated in vacuo and purified by column chromatography on silica,
eluting with ethyl acetate–light petroleum (1 : 3), to give the title
compound as a colourless solid (75 mg, 54%); mp 166–168 ЊC
(from dichloromethane) (Found: C, 61.9; H, 7.2; N, 4.0.
C18H25NO4Si requires C, 62.2; H, 7.3; N, 4.0%) (Found: Mϩ,
347.1554. C18H25NO4Si requires 347.1553); νmax (KBr)/cmϪ1
3304, 2960, 2919, 2843, 1716, 1700, 1260, 1241; δH (400 MHz;
CDCl3) 10.74 (1H, s, CHO), 9.43 (1H, br s, NH), 7.63 (1H, dd,
J 6.2, 1.6, 7-H), 7.45 (1H, t, J 8.2, 6-H), 7.34 (1H, dd, J 7.3, 0.9,
5-H), 5.37 (2H, s, CH2), 4.05 (3H, s, OMe), 1.50 (9H, s, CMe3),
0.16 (6H, s, 2 × Me); δC (100 MHz; CDCl3) 187.4 (CH), 160.8
(C), 138.2 (C), 135.8 (C), 132.0 (C), 126.9 (CH), 122.0 (C),
121.1 (C), 120.6 (CH), 110.3 (CH), 64.6 (CH2), 52.9 (Me), 26.1
(Me), 18.5 (C), Ϫ5.3 (Me); m/z (EI) 347 (Mϩ, 4%), 332 (12), 304
(14), 292 (30), 291 (100), 260 (24), 258 (71), 230 (35), 216 (30),
184 (41), 128 (40).
Methyl 4-bromomethyl-1-tert-butoxycarbonylindole-2-
carboxylate 14
A solution of methyl N-tert-butoxycarbonyl-4-methylindole-2-
carboxylate13 (2.70 g, 9.3 mol), NBS (1.74 g, 9.8 mmol), and
AIBN (77 mg, 0.5 mmol) in carbon tetrachloride (40 ml) was
heated to reflux for 3 h. The reaction mixture was cooled and
filtered and the filtered solid washed with carbon tetrachloride
(2 × 30 ml) The filtrate was evaporated in vacuo to leave a yellow
oil that was purified by column chromatography on silica, elut-
ing with ethyl acetate–light petroleum (1 : 20), to give the title
compound as a pale yellow solid (3.12 g, 91%); mp 96–98 ЊC
(from ether) (Found: C, 52.0; H, 4.8; N, 3.6. C16H18BrNO4
requires C, 52.2; H, 4.9; N, 3.8%) (Found: Mϩ, 367.0418.
C16H1879BrNO4 requires 367.0420); νmax (KBr)/cmϪ1 2979, 2951,
1739, 1652, 1460, 1436, 1256, 1173, 1035; δH (400 MHz; CDCl3)
8.08 (1H, d, J 8.4, 7-H), 7.36 (1H, t, J 7.4, 6-H), 7.29 (2H, m,
3-H and 5-H), 4.73 (2H, s, CH2Br), 3.95 (3H, s, OMe), 1.63 (9H,
s, CMe3); δC (100 MHz; CDCl3) 162.1 (C), 149.0 (C), 138.1 (C),
130.9 (C), 130.6 (C), 126.9 (CH), 126.5 (C), 123.9 (CH), 115.6
(CH), 112.4 (CH), 85.0 (C), 52.4 (Me), 30.4 (CH2), 27.8 (Me);
m/z (EI) 369/367 (Mϩ, 3%), 269 (6), 257 (6), 189 (15), 188 (100),
156 (32), 129 (12), 128 (12), 57 (40).
Methyl 4-tert-butyldimethylsiloxymethyl-3-methylindole-2-
carboxylate 17
Sodium cyanoborohydride (0.140 g, 2.2 mmol) and zinc iodide
(0.140 g, 0.43 mmol) were added to a solution of methyl 4-tert-
butyldimethylsiloxymethyl-3-formylindole-2-carboxylate
16
(0.100 g, 0.29 mmol) in 1,2-dichloroethane (10 ml) and the
resulting mixture heated under reflux for 1 h. The reaction mix-
ture was cooled and poured into an ice cold sodium hydrogen
carbonate solution (20 ml). The mixture was extracted with
ethyl acetate (3 × 20 ml), dried (MgSO4) and purified by column
chromatography on silica eluting with ethyl acetate–light
petroleum (1 : 4) to give the title compound as a colourless oil
(0.063 g, 63%); mp 136–137 ЊC (from ether) (Found: C, 64.6; H,
8.3; N, 4.0. C18H27NO3Si requires C, 64.8; H, 8.2; N, 4.2%);
νmax (KBr)/cmϪ1 3338, 2954, 2927, 2889, 1675, 1265, 1111;
δH (400 MHz; CDCl3) 8.72 (1H, br s, NH), 7.27 (2H, m, 6-H,
7-H), 7.15 (1H, m, 5-H), 5.17 (2H, s, CH2), 3.95 (3H, s, OMe),
2.83 (3H, s, Me), 0.94 (9H, s, CMe3), 0.10 (6H, s, 2 × SiMe);
δC (75 MHz, CDCl3) 163.4 (C), 136.8 (C), 136.7 (C), 126.1 (C),
125.8 (CH), 123.4 (C), 121.5 (C), 119.3 (CH), 111.5 (CH), 64.1
(CH2), 52.1 (Me), 26.4 (Me), 18.8 (C), 12.5 (Me), Ϫ4.7 (Me);
m/z (EI) 333 (Mϩ, 7%), 276 (11), 203 (82), 171 (100), 170 (47),
142 (69), 115 (50), 84 (14).
Methyl 4-chloromethyl-3-formylindole-2-carboxylate 15
Phosphorus oxychloride (0.21 g, 1.35 mmol) and N-methyl-
formanilide (0.18 g, 1.35 mmol) were stirred at room temper-
ature for 15 min. A solution of methyl 1-tert-butoxycarbonyl-4-
bromomethylindole-2-carboxylate 14 (0.34 g, 0.87 mmol) in
1,2-dichloroethane (15 ml) was added and the resulting mixture
heated to reflux for 40 h. The reaction mixture was poured onto
a solution of sodium acetate (1 g) and ice–water (30 ml) and
stirred for 15 min. Dichloromethane (20 ml) was added and
the aqueous layer further extracted with dichloromethane (2 ×
20 ml), dried (MgSO4), evaporated in vacuo and purified by
column chromatography on silica, eluting with ethyl acetate–
light petroleum (1 : 5), to give the title compound as a pale
yellow solid (0.17 g, 78%); mp 186–188 ЊC (from chloroform)
(Found: C, 57.0; H, 3.7; N, 5.4. C12H10ClNO3 requires C, 57.3;
H, 4.0; N, 5.6) (Found: Mϩ, 251.0354. C12H1035ClNO3 requires
251.0349); νmax (KBr)/cmϪ1 3315, 2914, 1716, 1649, 1398, 1239,
1198, 1168, 1034; δH (300 MHz; CDCl3) 10.82 (1H, s, CHO),
9.69 (1H, br s, NH), 7.45 (3H, m, 5-H, 6-H and 7-H), 5.43 (2H,
s, CH2), 4.12 (3H, s, OMe); δC (100 MHz; CDCl3) 187.5 (CHO),
160.7 (C), 136.3 (C), 133.6 (C), 133.2 (C), 126.8 (CH), 125.9
(CH), 122.8 (C), 121.4 (C), 112.6 (CH), 53.1 (Me), 47.0 (CH2);
m/z (CI) 253/251 (Mϩ, 18/54%), 238/236 (25/80), 218 (28), 216
Methyl 1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxymethyl-
3-formylindole-2-carboxylate 18
Di-tert-butyl dicarbonate (87 mg, 0.40 mmol) and DMAP
(10 mg, 0.08 mmol) were added to a stirred solution of methyl
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 0 1 – 7 0 8
705

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4-tert-butyldimethylsiloxymethyl-3-formylindole-2-carboxylate
16 (92 mg, 27.0 mmol) in acetonitrile (5 ml). The resulting mix-
ture was stirred at room temperature for 30 min and the solvent
evaporated in vacuo. The residue was partitioned between ethyl
acetate (10 ml) and water (10 ml). The aqueous layer was fur-
ther extracted with ethyl acetate (2 × 10 ml) and the organic
extracts washed with saturated aqueous sodium hydrogen carb-
onate (20 ml), dried (MgSO4), evaporated in vacuo and purified
by column chromatography on silica, eluting with ethyl acetate–
light petroleum (1 : 4), to give the title compound (109 mg, 92%)
as a yellow oil (Found: MHϩ, 448.2151. C23H33NO6Si requires
448.2155); νmax (film)/cmϪ1 2950, 2930, 2848, 1752, 1675, 1536,
1260, 1115; δH (300 MHz; CDCl3) 10.28 (1H, s, CHO), 8.14
(1H, dd, J 7.8, 1.6, 7-H), 7.44 (2H, m, 5-H, 6-H), 5.12 (2H, s,
CH2), 4.03 (3H, s, OMe), 1.68 (9H, s, CMe3), 0.90 (9H, s,
SiCMe3), 0.07 (6H, s, 2 × Me); δC (75 MHz; CDCl3) 186.8 (CH),
162.8 (C), 148.2 (C), 136.2 (C), 135.8 (C), 135.2 (C), 126.5
(CH), 123.4 (C), 122.6 (C), 121.0 (CH), 114.7 (CH), 86.9 (C),
64.8 (CH2), 53.4 (Me), 27.9 (Me), 25.9 (Me), 18.3 (C), Ϫ5.2
(Me); m/z (CI) 448 (MHϩ, 100%), 348 (85), 316 (30), 216 (22).
(CH2), 64.8 (CH2), 28.1 (Me), 25.9 (Me), 18.4 (C), Ϫ5.1 (Me);
m/z (CI) 418 (MHϩ, 60%), 379 (78), 362 (81), 335 (14), 244 (24),
194 (39), 146 (100), 2132 (55), 91 (86).
Methyl 3-formyl-4-methylindole-2-carboxylate 21
A mixture of phosphorus oxychloride (8.50 g, 55 mmol) and
N-methylformanilide (7.50 g, 55 mmol) were stirred at room
temperature for 15 min. A solution of methyl 4-methylindole-2-
carboxylate 11 (7.00 g, 36 mmol) in 1,2-dichloroethane (120 ml)
was added and the resulting mixture heated under reflux for
2.5 h. The reaction mixture was then poured onto a solution of
sodium acetate (5.0 g) and ice–water (100 ml) and the mixture
stirred for 15 min. The mixture was extracted with dichloro-
methane (3 × 150 ml) and the combined organic layers dried
(MgSO4), evaporated in vacuo and purified by column chromato-
graphy on silica, eluting with ethyl acetate–light petroleum (1 : 3),
to give the title compound as a yellow solid (7.87 g, 98%); mp 188–
189 ЊC (from ether) (Found: C, 66.1; H, 4.9; N, 6.4. C12H11NO3
requires C, 66.4; H, 5.1; N, 6.5%) (Found: Mϩ, 217.0742.
C12H11NO3 requires 217.0739); νmax (KBr)/cmϪ1 3426, 2914, 2852,
1708, 1649, 1511, 1449, 1383, 1193, 1065; δH (400 MHz; CDCl3)
10.80 (1H, s, CHO), 9.46 (1H, s, NH), 7.30 (2H, m, 6-H, 7-H),
7.15 (1H, m, 5-H), 4.05 (3H, s, OMe), 2.83 (3H, s, Me); δC (100
MHz; CDCl3) 187.0 (CHO), 161.0 (C), 136.1 (C), 135.1 (C), 126.8
(CH), 125.4 (CH), 124.5 (C), 122.3 (C), 109.4 (CH), 52.9 (Me),
23.2 (Me), one ArC not observed; m/z (CI) 217 (Mϩ, 59%), 202
(100), 184 (99), 157 (32), 128 (56), 102 (47), 77 (30).
Methyl 1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxymethyl-
3-hydroxymethylindole-2-carboxylate 19
Sodium borohydride (4.7 mg, 0.12 mmol) was added to a stirred
solution of methyl 1-tert-butoxycarbonyl-4-tert-butyldimethyl-
siloxymethyl-3-formylindole-2-carboxylate 18 (110 mg, 0.25
mmol) in degassed methanol (10 ml) and the resulting mixture
stirred at room temperature for 10 min. Acetone (1 ml) was
added and the solvent removed in vacuo. The residue was taken
up in dichloromethane (10 ml) and water (10 ml). The aqueous
layer was further extracted with dichloromethane (2 × 10 ml).
The combined extracts were dried (MgSO4), and the solvent
evaporated in vacuo and purified by column chromatography on
silica, eluting with ethyl acetate–light petroleum (1 : 5), to give
the title compound as a pale yellow oil (90 mg, 81%) that crystal-
lised on standing; mp 157–159 ЊC (from ether) (Found Mϩ,
449.2235. C23H35NO6Si requires 449.2234); νmax (KBr)/cmϪ1
3431, 2950, 2925, 2883, 1731, 1323, 1117, 1004; δH (400 MHz;
CDCl3) 8.11 (1H, d, J 7.8, 7-H), 7.36 (1H, apparent t, apparent
J 7.5, 6-H), 7.21 (1H, d, J 7.3, 5-H), 5.13 (2H, s, CH2OTBS),
4.92 (2H, d, J 6.0, CH2OH), 3.96 (3H, s, OMe), 3.92 (1H, t,
J 6.0, CH2OH ), 1.62 (9H, s, CMe3), 0.90 (9H, s, SiCMe3), 0.09
(6H, s, 2 × Me); δC (100 MHz; CDCl3) 163.1 (C), 149.0 (C),
137.4 (C), 133.9 (C), 128.8 (C), 126.3 (CH), 125.0 (C), 125.4
(C), 124.2 (CH), 115.1 (CH), 84.9 (C), 64.9 (CH2), 55.9 (CH2),
52.5 (Me), 27.9 (Me), 25.9 (Me), 18.3 (C), Ϫ5.1 (Me); m/z (EI)
449 (Mϩ, 2%), 446 (17), 394 (33), 319 (47), 303 (28), 274 (30),
262 (100), 218 (70), 189 (53), 180 (47).
Methyl 1-tert-butoxycarbonyl-3-formyl-4-methylindole-2-
carboxylate 22
Di-tert-butyl dicarbonate (8.04 g, 36.0 mmol) and DMAP (0.34
g, 2.8 mmol) were added to a stirred solution of 3-formyl-4-
methylindole-2-carboxylate 21 (4.0 g, 18.0 mmol) in acetonitrile
(140 ml). The resulting mixture was stirred at room temperature
overnight and the solvent evaporated in vacuo. The residue was
partitioned between ethyl acetate (100 ml) and water (100 ml).
The aqueous layer was further extracted with ethyl acetate (2 ×
100 ml) and the organic extracts combined, washed with satur-
ated aqueous sodium hydrogen carbonate solution (50 ml),
dried (MgSO4), evaporated in vacuo and purified by column
chromatography on silica, eluting with ethyl acetate–light
petroleum (1 : 5), to give the title compound (4.60 g, 80%)
as a yellow solid; mp 196–108 ЊC (from ether) (Found: C,
64.3; H, 6.0; N, 4.3. C17H19NO5 requires C, 64.3; H, 6.0; N,
4.4%) (Found: Mϩ, 317.1264. C17H19NO5 requires 317.1263);
νmax (KBr)/cmϪ1 3001, 2960, 2883, 1698, 1685, 1531, 1106;
δH (400 MHz; CDCl3) 10.36 (1H, s, CHO), 8.05 (1H, dd, J 8.5,
0.8, 7-H), 7.32 (1H, dd, J 8.5, 7.4, 6-H), 7.17 (1H, dd, J 7.4, 0.8,
5-H), 4.03 (3H, s, OMe), 2.75 (3H, s, Me), 1.66 (9H, s, CMe3);
δC (100 MHz; CDCl3) 185.6 (CH), 162.7 (C), 148.2 (C), 136.5
(C), 135.9 (C), 132.3 (C), 126.7 (CH), 126.6 (CH), 124.3 (C),
121.7 (C), 113.1 (CH), 86.8 (C), 53.3 (Me), 27.9 (Me), 22.6
(Me); m/z (EI) 317 (Mϩ, 1%), 217 (81), 202 (93), 184 (100), 157
(65), 129 (93), 102 (70), 90 (12), 77 (29).
4-tert-Butoxycarbonyl-8-tert-butylsiloxymethyl-1,3-dihydro-4H-
furo[3,4-b]indol-3-one 20
Sodium hydride (4 mg, 0.15 mmol) was added portionwise to a
stirred solution of methyl 1-tert-butoxycarbonyl-4-tert-butyl-
dimethylsiloxymethyl-3-hydroxymethylindole-2-carboxylate 19
(65 mg, 0.15 mmol) in THF over 1 h. The resulting solution was
stirred at room temperature for a further 3 h. Water (10 ml) and
dichloromethane (10 ml) were added and the aqueous layer fur-
ther extracted with dichloromethane (2 × 10 ml). The combined
organic extracts were dried (MgSO4) and purified by column
chromatography on silica eluting with ethyl acetate–light
petroleum (1 : 9) to give the title compound as a colourless oil
(54 mg, 89%) (Found: MHϩ, 418.2040. C22H31NO5Si ϩ H
requires 418.2050); νmax (film)/cmϪ1 2950, 2929, 2858, 1772,
1736, 1255, 1137; δH (400 MHz; CDCl3) 8.30 (1H, d, J 8.6, 5-H),
7.47 (1H, dd, J 8.6, 7.3, 6-H), 7.20 (1H, d, J 7.3, 7-H), 5.36 (2H,
s, CH2), 4.88 (2H, s, CH2OTBS), 1.71 (9H, s, OCMe3), 0.89 (9H,
s, SiCMe3), 0.07 (6H, s, 2 × Me); δC (100 MHz; CDCl3) 160.9
(C), 148.8 (C), 143.4 (C), 142.7 (C), 134.6 (C), 128.5 (CH),
127.9 (C), 122.0 (CH), 120.7 (C), 116.3 (CH), 85.4 (C), 66.6
Methyl 1-tert-butoxycarbonyl-3-hydroxymethyl-4-methylindole-
2-carboxylate 23
Sodium borohydride (18 mg, 0.47 mmol) was added to a stirred
solution of methyl 1-tert-butoxycarbonyl-3-formyl-4-methyl-
indole-2-carboxylate 22 (300 mg, 0.95 mmol) in DME (10 ml),
and the mixture heated under reflux for 1 h. Water (20 ml), citric
acid to pH∼3 and ether (20 ml) were added and the aqueous
layer was further extracted with ether (2 × 20 ml), dried
(MgSO4), evaporated in vacuo and purified by column chrom-
atography on silica, eluting with ethyl acetate–light petroleum
(1 : 3), to give the title compound as a yellow oil (150 mg,
49%) (Found: Mϩ, 319.1418. C17H21NO5 requires 319.1420);
νmax (film)/cmϪ1 3436, 2986, 2955, 1736, 1577, 1460, 1321, 1255;
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 0 1 – 7 0 8
706

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δH (400 MHz; CDCl3) 7.94 (1H, d, J 7.5, 7-H), 7.24 (1H, ∼t,
J 7.5, 6-H), 6.99 (1H, d, J 7.3, 5-H), 4.83 (2H, s, CH2OH), 3.91
(3H, s, OMe), 2.80 (1H, s, CH2OH ), 2.70 (3H, s, Me), 1.59 (9H,
s, CMe3); δC (100 MHz; CDCl3) 187.8 (C), 163.4 (C), 149.2 (C),
137.0 (C), 132.6 (C), 128.4 (C), 126.2 (CH), 125.1 (C), 124.8
(CH), 112.5 (CH), 84.7 (C), 55.4 (CH2), 52.5 (Me), 27.8 (Me),
19.6 (Me); m/z (EI) 319 (Mϩ, 6%), 219 (18), 186 (21), 170 (9),
158 (15), 143 (21), 130 (13), 115 (10), 57 (100).
which was used directly without any further purification.
TBDMSOTf (0.12 g, 0.6 mmol) was added to a stirred of solu-
tion of the crude 4-tert-butoxycarbonyl-4-hydroxymethyl-1,3-
dihydro-4H-furo[3,4-b]indol-3-one in pyridine (5 ml) at Ϫ35 ЊC
and the resulting solution stirred at Ϫ35 ЊC for 5 h and then
allowed to warm to room temperature overnight. The pyridine
was removed in vacuo and the residue taken up in ethyl acetate
(15 ml) and water (15 ml). The aqueous layer was further
extracted with ethyl acetate (2 × 10 ml), and the combined
organic extracts washed with water (2 × 20 ml), dried (MgSO4)
and purified by column chromatography on silica eluting with
ethyl acetate–light petroleum (1 : 9) to give the title compound
(78 mg, 68%) as a colourless oil; data as above.
4-tert-Butoxycarbonyl-8-methyl-1,3-dihydro-4H-furo[3,4-b]-
indol-3-one 24
Sodium hydride (1.0 g, 2.36 mmol) was added portionwise to a
stirred solution of methyl N-tert-butoxycarbonyl-3-formyl-4-
methylindole-2-carboxylate 23 (1.50 g, 4.70 mmol) in THF
(50 ml) over 30 min. The resulting solution was stirred at room
temperature for 3 h. Water (30 ml) and ether (30 ml) were
added. The aqueous layer was extracted with ether (2 × 50 ml)
and the ethereal extracts dried (MgSO4), evaporated in vacuo
and the material recrystallised from ether to give the title
compound (1.23 g, 91%) as colourless needles; mp 159–160 ЊC
(from ether) (Found: C, 66.8; H, 5.9; N, 4.8. C16H17NO4
requires C, 66.9; H, 6.0; N, 4.9%) (Found Mϩ, 287.1153.
C16H17NO4 requires 287.1158); νmax (KBr)/cmϪ1 2976, 1768,
1732, 1140; δH (400 MHz; CDCl3) 8.18 (1H, d, J 8.5, 5-H), 7.42
(1H, dd, J 8.5, 7.3, 6-H), 7.14 (1H, dt, J 7.3, 0.8, 7-H), 5.39 (2H,
s, CH2), 2.52 (3H, s, Me), 1.71 (9H, s, CMe3); δC (100 MHz;
CDCl3) 160.7 (C), 148.8 (C), 143.0 (C), 142.8 (C), 131.4 (C),
129.0 (CH), 127.4 (C), 124.2 (CH), 122.0 (C), 114.5 (CH), 85.3
(C), 65.6 (CH2), 28.1 (Me), 19.2 (Me); m/z (EI) 287 (Mϩ, 5%),
187 (100), 158 (94), 143 (71), 130 (54), 115 (48), 103 (55), 89
(51), 57 (84).
Methyl 2-oxobutanoate (5-carboxy-2-chlorophenyl) hydrazone
27
Sodium nitrite (2.41 g, 34.99 mmol) in water (12 ml) was added
dropwise to a solution of 3-amino-4-chlorobenzoic acid 26
(5.00 g, 29.15 mmol) in conc.. HCl (23 ml) and water (23 ml) at
0 ЊC not allowing the temperature to rise above 4 ЊC. The result-
ing yellow solution was allowed to stir at 0 ЊC for 10 min. Tin()
chloride dihydrate (19.76 g, 87.46 mmol) in conc. HCl (20 ml)
was then added and the mixture stirred for a further 10 min at
0 ЊC. Methyl 2-oxobutanoate (12.8 g, 58.31 mmol) was then
added to the resulting white suspension and the mixture heated
to 90 ЊC for 1 h. The reaction mixture was allowed to cool and
the product extracted into ethyl acetate ( 5 × 100 ml). The
organic extracts were washed repeatedly with hydrochloric acid
(3 M, 6 × 300 ml), dried (MgSO4) and the solvent removed in
vacuo to give the title compound 27 (8.29 g, 100%) as a cream
solid; mp 228–230 ЊC (Found: MHϩ, 285.0641. C12H1335ClN2O4
ϩ H requires 285.0642); νmax (KBr)/cmϪ1 3498, 1685, 1579,
1294, 1238, 1151, 1138, 1127; δH (300 MHz; DMSO) 13.16 (1H,
v br s, COOH), 12.36 (1H, br s, NH), 8.10 (1H, d, J 1.8, ArH),
7.56 (1H, d, J 8.3, ArH), 7.48 (1H, dd, J 1.8, 8.3, ArH), 3.83
(3H, s, OMe), 2.55 (2H, q, J 7.3, CH2Me), 1.14 (3H, t, J 7.3,
CH2Me); δC (75 MHz; DMSO) 167.0 (C), 163.8 (C), 140.0 (C),
134.2 (C), 131.3 (C), 130.1 (CH), 122.7 (CH), 121.9 (C), 114.5
(CH), 52.6 (Me), 26.3 (CH2), 11.9 (Me).
4-tert-Butoxycarbonyl-4-bromomethyl-1,3-dihydro-4H-furo-
[3,4-b]indol-3-one 25
A solution of 4-tert-butoxycarbonyl-4-methyl-1,3-dihydro-4H-
furo[3,4-b]indol-3-one 24 (0.30 g, 1.0 mmol), NBS (0.20 g, 1.1
mmol), and AIBN (9 mg, 0.05 mmol) in carbon tetrachloride
(20 ml) was heated under reflux for 4.5 h. The reaction mixture
was cooled and filtered and the precipitate washed with carbon
tetrachloride (2 × 20 ml). The filtrate was evaporated in vacuo to
leave a pale yellow oil that was purified by column chromato-
graphy on silica, eluting with ethyl acetate–light petroleum
(1 : 4) to give the title compound (0.21 g, 55%) as a colourless
solid; mp 100–102 ЊC (from dichloromethane) (Found: MHϩ,
366.0339. C16H1679BrNO4 requires 366.0341); νmax (KBr)/cmϪ1
2996, 2954, 2925, 1767, 1734, 1460, 1363, 1168, 1040; δH (300
MHz; CDCl3) 8.35 (1H, dd, J 8.8, 0.8, 5-H), 7.48 (1H, dd, J 8.8,
7.1, 6-H), 7.32 (1H, d, J 7.0, 7-H), 5.52 (2H, s, CH2), 4.62 (2H, s,
CH2Br), 1.72 (9H, s, CMe3); δC (75 MHz; CDCl3) 162.7 (C),
143.3 (C), 141.1 (C), 130.9 (C), 128.8 (C), 127.6 (C), 124.5
(CH), 122.9 (CH), 119.1 (C), 117.9 (CH), 68.3 (C), 60.4 (CH2)
28.1 (CH2), 25.2 (Me); m/z (CI) 385/383 (M ϩ NH4, 19%), 366/
364 (13), 329/327 (100), 305 (96), 288 (97), 283 (28), 279 (45),
266 (10), 263 (37).
7-Chloro-2-methoxycarbonyl-3-methylindole-4-carboxylic acid
28
A solution of 27 (8.29 g, 29.14 mmol) in acetic acid (146 ml)
was heated to 90 ЊC and polyphosphoric acid (15 ml) was
added and the reaction mixture stirred for 2 h at 90 ЊC. The
reaction mixture was then allowed to cool and the solvent
removed in vacuo. The residue was suspended in water, filtered
and dried in vacuo to give the title compound 28 (6.81 g, 87%)
as a cream solid; mp 243–245 ЊC (Found: MHϩ, 268.0374.
C12H935ClNO4 ϩ H requires 268.0376); νmax (neat)/cmϪ1 3602,
3255, 1715, 1687, 1231, 1179; δH (300 MHz; DMSO) 13.12 (1H,
br s, COOH), 11.86 (1H, s, NH), 7.42 (2H, s, ArH), 3.90 (3H, s,
OMe), 2.60 (3H, s, ArMe); δC (75 MHz; DMSO) 168.8 (C),
161.8 (C), 134.0 (C), 126.7 (C), 126.3 (C), 125.7 (C), 123.6
(CH), 122.2 (CH), 119.9 (C), 119..8 (C), 51.8 (Me), 11.8 (Me);
m/z (CI) 270/268 (MHϩ, 29/100%), 238/236 (20/63).
4-tert-Butoxycarbonyl-4-tert-butylsiloxymethyl-1,3-dihydro-4H-
furo[3,4-b]indol-3-one 20
2-Methoxycarbonyl 3-methylindole-4-carboxylic acid 29
Sodium iodide (45 mg, 0.30 mmol) was added to a solution of
4-tert-butoxycarbonyl-4-bromomethyl-1,3-dihydro-4H-
Palladium on carbon (10%; 3.44 g) was added to a solution of
28 (9.2 g, 34.39 mmol) in methanol (172 ml) which was purged
with hydrogen and stirred under a balloon of hydrogen for 48 h.
The reaction mixture was then filtered through a pad of Celite
which was rinsed with methanol, and the solvent removed in
vacuo to give the title compound 29 (6.8 g, 85%) as a pale cream
solid; mp 191–194 ЊC (Found: MHϩ, 234.0777. C12H11NO4 ϩ H
requires 234.0766); νmax (KBr)/cmϪ1 3242, 2960, 2617, 1700,
1667, 1388, 1260, 1230, 1199; δH (400 MHz; DMSO) 12.92 (1H,
v br s, CO2H), 11.85 (1H, br s, NH), 7.61 (1H, dd, J 8.2, 1.1,
furo[3,4-b]indol-3-one 25 (100 mg, 0.27 mmol) in acetone (5 ml)
and the resulting mixture heated under reflux for 20 min, during
which time the reaction mixture turned cloudy. Potassium
carbonate (80 mg, 0.60 mmol) in water (2 ml) was added and
the mixture heated for a further 20 min. The reaction mixture
was cooled and solvent removed in vacuo and the residue taken
up in dichloromethane (10 ml) and water (10 ml). The aqueous
layer was further extracted with dichloromethane (2 × 10 ml),
dried (MgSO4) and concentrated in vacuo to leave a yellow solid
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 7 0 1 – 7 0 8
707

View Article Online
10 P. Tavecchia, M. Kurz, L. Colombo, R. Bonfichi, E. Selva,
ArH), 7.37 (1H, dd, J 7,2, 1.1, ArH), 7.27 (1H, dd, 8.2, 7.2,
ArH), 3.91 (3H, s, OMe), 2.63 (3H, s, Me); δC (100 MHz;
DMSO) 169.4 (C), 162.2 (C), 137.0 (C), 127.5 (C), 124.4 (C),
123.8 (CH), 121.4 (CH), 118.5 (C), 115..8 (CH), 51.6 (Me), 11.7
(Me); m/z (CI) 234 (MHϩ, 63%), 202 (100), 190 (54), 176 (47),
158 (46).
S. Lociuro, E. Marzorati and R. Ciabatti, Tetrahedron, 1996, 52,
8763.
11 M. J. Rogers, E. Cundliffe and T. F. McCutchan, Antimicrob. Agents
Chemother., 1998, 42, 715.
12 E. Cundliffe and J. Thompson, J. Gen. Microbiol., 1981, 126, 185.
13 Y. Y. Xing and D. E. Draper, Biochemistry, 1996, 35, 1581.
14 D. E. Draper, in The Many Faces of RNA, ed. D. S. Eggleston, C.
D. Prescott and N. D. Pearson, San Diego, 1998, 113.
15 C. H. McGinnis, C. A. Johnson and J. E. Fox, Poultry Sci., 1978, 57,
1641; M. Casteels, H. Bekaert and F. X. Buysse, Rev. Agric.
(Brussels), 1980, 33, 1069.
16 S. Horii and N. Oku, J. AOAC Int., 2000, 83, 17.
17 M. Iwakawa, Y. Kobayashi, S. Ikuta and J. Yoshimura, Chem. Lett.,
1982, 1975.
18 C. Shin, Y. Nakamura, Y. Yamada, Y. Yonezawa, K. Umemura and
J. Yoshimura, Bull. Chem. Soc. Jpn., 1995, 68, 3151.
19 K. Umemura, T. Tate, M. Yamaura, J. Yoshimura, Y. Yonezawa and
C. Shin, Synthesis, 1995, 1423.
Methyl 4-hydroxymethyl-3-methylindole-2-carboxylate 30
Borane dimethylsulfide complex (7.75 ml, 15.52 mmol) was
added dropwise to a solution of 29 (3.00 g, 12.93 mmol) in THF
(13 ml) at 0 ЊC. The reaction mixture was then heated to 60 ЊC
for 18 h, cooled and the solvent removed in vacuo. The residue
was partitioned between ethyl acetate (50 ml) and saturated
sodium hydrogen carbonate (50 ml) and the layers separated.
The aqueous phase was further extracted with ethyl acetate
(1 × 50 ml), the organic extracts dried (MgSO4) and the solvent
removed in vacuo to give the title compound 30 (2.19 g, 78%) as a
yellow solid; mp 192–195 ЊC (Found: MHϩ, 220.0972. C12H13-
NO3 ϩ H requires 220.0973); νmax (neat)/cmϪ1 3257, 2945, 2909,
2254, 1700, 1450, 1255, 1045, 1020, 999; δH (300 MHz; DMSO)
7.31 (1H, d, J 8.1, H-7), 7.18 (1H, dd, J 8.1, 7.0, H-6), 7.02 (1H,
d, J 7.0, H-5), 5.16 (1H, t, J 5.4, CH2OH), 4.89 (2H, d, J 5.4,
CH2OH), 3.87 (3H, s, OMe), 2.76 (3H, s, Me); δH (300 MHz;
DMSO) 162.4 (C), 136.9 (C), 136.8 (C), 125.3 (C), 124.6 (CH),
122.7 (C), 119.5 (C), 118.7 (CH), 111.7 (CH), 61.6 (CH2), 51.4
(Me), 11.7 (Me); m/z (CI) 220 (MHϩ, 26%), 219 (Mϩ, 46), 202
(100), 188 (50).
20 K. Koerber-Plé and G. Massiot, J. Heterocycl. Chem., 1995, 32,
1309.
21 K. Umemura, H. Noda, J. Yoshimura, A. Konn, Y. Yonezawa and
C. G. Shin, Tetrahedron Lett., 1997, 38, 3539.
22 K. Umemura, H. Noda, J. Yoshimura, A. Konn, Y. Yonezawa and
C. G. Shin, Bull. Chem. Soc. Jpn., 1998, 71, 1391.
23 K. Koerber-Plé and G. Massiot, Synlett, 1994, 759.
24 C. Shin, Y. Yamada, K. Hayashi, Y. Yonezawa, K. Umemura,
T. Tanji and J. Yoshimura, Heterocycles, 1996, 43, 891.
25 P. T. Northcote, D. Williams, J. K. Manning, D. B. Borders,
W. M. Maiese and M. D. Lee, J. Antibiotics, 1994, 47, 894.
26 P. T. Northcote, M. Siegel, D. B. Borders and M. D. Lee,
J. Antibiotics, 1994, 47, 901.
27 K. L. Constantine, L. Mueller, S. Huang, S. Abid, K. S. Lam,
W. Y. Li and J. E. Leet, J. Am. Chem. Soc., 2002, 124, 7284.
28 J. E. Leet, W. Y. Li, H. A. Ax, J. A. Matson, S. Huang, R. Huang,
J. L. Cantone, D. Drexler, R. A. Dalterio and K. S. Lam, J. Antibiot.,
2003, 56, 232.
29 W. Y. Li, J. E. Leet, H. A. Ax, D. R. Gustavson, D. M. Brown,
L. Turner, K. Brown, J. Clark, H. Yang, J. Fung-Tomc and K. S.
Lam, J. Antibiot., 2003, 56, 226.
30 M. C. Bagley, K. E. Bashford, C. L. Hesketh and C. J. Moody, J. Am.
Chem. Soc., 2000, 122, 3301; C. J. Moody, R. A. Hughes, S. P.
Thompson and L. Alcaraz, J. Chem. Soc., Chem. Commun., 2002,
1760.
31 A similar indole substitution pattern can be obtained by photo-
chemical ring contraction of 5-substituted quinoline-N-oxides;
C. Kaneko, A. Yamamoto and H. Atsushi, Chem. Pharm. Bull.,
1979, 27, 946.
Methyl 4-(tert-butyldimethylsiloxymethyl)-3-methylindole-2-
carboxylate 17
tert-Butyldimethylchlorosilane (1.81 g, 12.0 mmol) was added
to a solution of imidazole (1.02 g, 15.0 mmol) in DMF (10 ml)
and the mixture stirred for 15 min. A solution of 30 (2.19 g,
10.0 mmol) in DMF (10 ml) was then added and the reaction
mixture stirred for 18 h. The reaction mixture was diluted with
water (50 ml) and the product extracted with ethyl acetate
(2 × 50 ml). The combined extracts were washed with brine
(100 ml), dried (MgSO4) and the solvent removed in vacuo. The
product was purified by column chromatography (20% ethyl
acetate–light petroleum) to give the title compound 17 (1.36 g,
41%) as a pale yellow solid; data as above.
32 H. Hemetsberger, D. Knittel and H. Weidman, Monatsh. Chem.,
1970, 101, 161.
33 C. J. Moody, J. Chem. Soc., Perkin Trans. 1, 1984, 1333.
34 A. R. MacKenzie, C. J. Moody and C. W. Rees, Tetrahedron, 1986,
42, 3259.
35 T. Martin and C. J. Moody, J. Chem. Soc., Perkin Trans. 1, 1988, 241.
36 G. B. Jones and C. J. Moody, J. Chem. Soc., Perkin Trans. 1, 1989,
2455.
Acknowledgements
We thank Lilly Research and the EPSRC for CASE Awards
(to J.L.P. and A.K.M.), and the EPSRC Mass Spectrometry
Service at Swansea for mass spectra.
37 For example, see: D. L. Boger, T. Ishizaki, H. Zarrinmayeh,
P. A. Kitos and O. Suntornwat, J. Org. Chem., 1990, 55, 4499;
M. S. Reddy and J. M. Cook, Tetrahedron Lett., 1994, 35, 5413.
38 V. P. Baillargeon and J. K. Stille, J. Am. Chem. Soc., 1986, 108,
452.
39 For early work, see: R. J. Sundberg, J. Org. Chem., 1965, 30, 3604;
J. I. G. Cadogan, M. Cameron-Wood, R. K. Mackie and R. J. G.
Seaarle, J. Chem. Soc., 1965, 4831. For a more recent example, see:
A. S. Cotterill, C. J. Moody and J. R. A. Roffey, Tetrahedron, 1995,
51, 7223.
40 R. Y. Liu, P. W. Zhang, T. Gan and J. M. Cook, J. Org. Chem., 1997,
62, 7447.
41 C. K. Lau, C. Dufresne, P. C. Bélanger, S. Piétré and J. Scheigetz,
J. Org. Chem., 1986, 51, 3038.
42 R. J. Sundberg, The Chemistry of Indoles, Academic Press, New
York, 1970.
43 Methoxide readily removes Boc groups from indole, for examples,
see: K. J. Doyle and C. J. Moody, Synthesis, 1994, 1021.
44 J. C. A. Hunt, P. Laurent and C. J. Moody, J. Chem. Soc.,
Perkin Trans. 1, 2002, 2378.
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