Syntheses of showdomycin and its anomer using N-(triisopropylsilyl)pyrrole as a synthetic equivalent for the maleimide C3-anion

Article abstract of DOI:10.1055/s-2003-41026

Showdomycin (1) and its anomer (2) have been prepared in four steps from readily available trichloroacetimidate 9. The key step involves reaction of the last compound with the title pyrrole 3 so as to form a chromatographically separable mixture of the pyrrole C-glycosides 10 and 11. These pyrroles are desilylated then oxidized to the corresponding maleimides using PCC.

Full text of DOI:10.1055/s-2003-41026

PAPER
1837
Syntheses of Showdomycin and its Anomer Using N-(Triisopropylsilyl)pyrrole
as a Synthetic Equivalent for the Maleimide C3-Anion
S
ynthesis of Show
a
domycin
U
t
sing
a
Maleimide
C
3-Anion
h
Synthon a L. Hungerford, David J. Armitt, Martin G. Banwell*
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
Fax +61(2)61258114; E-mail: mgb@rsc.anu.edu.au
Received 9 July 2003; revised 22 July 2003
Dedicated, with affection and admiration, to Professor Wolfgang Steglich on the occasion of his 70th birthday.
previously described1 conditions involving BF3·Et2O as
Abstract: Showdomycin (1) and its anomer (2) have been prepared
promoter. It was expected that anchimeric assistance ex-
erted by the C2 acetyl group would direct glycosylation
and give the -product 5 preferentially. Disappointingly,
in four steps from readily available trichloroacetimidate 9. The key
step involves reaction of the last compound with the title pyrrole 3
so as to form a chromatographically separable mixture of the pyr-
role C-glycosides 10 and 11. These pyrroles are desilylated then ox- however, none of this hoped-for pyrrole C-glycoside was
idized to the corresponding maleimides using PCC.
observed. Rather, the acetal 6 (obtained in 65% yield as a
1:1 mixture of epimers) was obtained10 and this must arise
Key words: nucleosides, pyrroles, trichloroacetimidates, C-glyco-
sides, maleimides, oxidation
through reaction of 3 with the C1 -C2 -bridged acetoxoni-
um ion produced by ionization of trichloroacetimidate 4.
In a further attempt to generate the desired C-1 -adduct,
reaction of the title pyrrole 3 with the readily available tet-
ra-ester 711 in the presence of SnCl4 was examined7d but
only the bis-pyrrole 8 (72%) was obtained.12
We have recently reported1 that various glycosyl trichlo-
roacetimidates react with simple pyrroles in the presence
of Lewis acids to give pyrrole C-glycosides, compounds
which have considerable potential in the preparation of a
significant range of other C-glycosides. In that connection
we now detail the application of such methodology to the
preparation of the naturally occurring C-riboside (+)-
showdomycin (1) and its anomer 2 (Figure 1).
O
NH
HO
O
HO
O
O
TIPS
TIPS
O
N
N
HO HO
NH
(+)-Showdomycin was first isolated from Streptomyces
showdoensis by Nishimura and co-workers in the early
1960’s2 and was shown to exhibit antibacterial proper-
ties.3 Although the subject of debate,4 this effect has been
attributed5 to the presence of the maleimide residue which
reacts, in a hetero-Michael addition reaction, with biolog-
ically relevant thiols, thus inactivating membrane proteins
involved in nutrient transport into the target bacterial
cells. Compound 1 also displays antitumour activity.
Thus, it inhibits the growth of L1210 leukemia, HeLa and
Ehrlich ascites tumour cells.6 As a consequence of such
features, numerous synthetic studies have been undertak-
en and routes to the (+)-, (–)- and ( )-modifications of
showdomycin have all been described.7 A difficulty often
encountered in such work is the elaboration of the male-
imide unit from precursors such as aldehydes, furans, -
keto-esters and acid anhydrides. Herein we demonstrate
that the readily available N-(triisopropylsilyl)pyrrole (3),
which was first introduced by Muchowski,8 acts as a very
effective synthetic equivalent for the maleimide C3-an-
ion.7r
HO HO
O
1
2
3
CCl3
AcO
AcO
O
NH
O
O
AcO AcO
AcO AcO
4
5
AcO
5'
BzO
O
4
OAc
1'
4'
O
3' 2'
3
2
O
5
O
1
AcO
BzO BzO
N
6
7
TIPS
TIPS
1'
N
5'
4'
2'
BzO
5
3'
2"
OH
3
1
1"
In our initial approaches to showdomycin the readily
available tri-O-acetyl ribosyl trichloroacetimidate 49 was
reacted with pyrrole 3 using a minor modification of our
4
TIPS
2
N
3"
4"
BzO BzO
5"
8
Figure 1
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 13 08 2003.
Art Id.1437-210X,E;2003,0,12,1837,1843,ftx,en;Z11003SS.pdf.
DOI: 10.1055/s-2003-41026
© Georg Thieme Verlag Stuttgart · New York

1838
N. L. Hungerford et al.
PAPER
The ultimately successful route to showdomycin, which achieving conversion 12
13 involved reaction of the
circumvented the abovementioned problems by employ- former with PCC15 in the presence of dried 4 Å molecular
ing a non-participating protecting group at C2 , is shown sieves and under such conditions the maleimide was
in Scheme 1 and began with reaction of the acetonide-pro- formed in 72% yield. Global deprotection of the previous-
tected ribosyl trichloroacetimidate 91 with pyrrole 3 under ly reported7f,j,p compound 13 was achieved under the
our previously defined1 conditions. In this manner a chro- specified7f conditions (TFA–H2O, 4:1; 18 °C; 1.5 h) thus
matographically separable mixture of the pyrrole C-gly- affording showdomycin in 95% yield. The spectral and
coside 10 (40%) and its anomer 11 (21%) was obtained. physical data derived from nucleoside 1 obtained by this
The lack of selectivity associated with this process is at- means proved an excellent match for those reported7k pre-
tributed to the operation of a facile, BF3·Et2O-catalyzed viously. Furthermore, the cell parameters measured for
anomerization process, which results in the interconver- this crystalline material (see experimental section)
sion of these products via an open-chain intermediate. In- matched those reported16 previously thus providing un-
deed, in control experiments it has been shown that equivocal proof of structure.
anomers 10 and 11 interconvert at –50 °C in the presence
of the Lewis acid and under such conditions the -anomer
predominates. In contrast, treatment of the -anomer with
80% aq HOAc at 50 °C for 3 h affords mixtures in which
The elaboration of compound 10 to 1 -epi-showdomycin
(2) (Scheme 2) followed the same simple route used in the
formation of showdomycin itself. Thus, desilylation of
pyrrole 10 with TBAF8 afforded compound 14 (88%)
the required -anomer is the major component. The as-
which was then oxidized to maleimide 15 (71%) using
signment of structure to each of these anomers follows
PCC in the presence of 4 Å molecular sieves. Exhaustive
1
from H,1H NOESY experiments. Specifically, and in
deprotection of this last material with TFA–H2O (4:1)
keeping with expectations,13 in the relevant spectrum of
then afforded 1 -epi-showdomycin (2), the physical and
compound 10 an NOE was observed between H1 and
H5 . In the equivalent spectrum of anomer 11 NOEs were
observed between H1 and H4 as well as between the
endo-methyl protons of the acetonide moiety and H1 .
spectral data for which proved identical with those
reported7k,17 previously.
The ready and completely regioselective reaction of pyr-
role 3 with electrophiles, including glycosyl trichloroace-
timidates, and the ease of oxidation of the resulting 3-
substituted pyrroles with PCC suggests that this easily ac-
cessible material is an effective synthetic equivalent for
the maleimide C3-anion and potentially applicable to the
The next step in the elaboration of compound 11 into tar-
get 1 involved desilylation of the former, with tetrabutyl-
ammonium fluoride (TBAF),8 thus affording pyrrole 12
(77%). The oxidation of this last material to compound 13
was first carried out using sodium hypochlorite under con-
preparation of a wide range of analogues of nucleosides
ditions reported by Steglich and co-workers14 for conver-
such as showdomycin.
sion of a 3,4-disubstituted pyrrole into the corresponding
maleimide. While this procedure did indeed produce the
target maleimide it was, not unexpectedly,14 contaminated
Melting points were measured on a Reichert hot-stage microscope
1
apparatus and are uncorrected. H and 13C NMR spectra were re-
with a chlorinated derivative that proved difficult to re-
duce to 13. Ultimately the most effective means for
corded on a Varian Inova 500 spectrometer operating at 500 MHz
and 126 MHz respectively. In certain cases a Gemini 300 NMR
R
5
CCl3
N
1
TBDPSO
TBDPSO
2
TBDPSO
4
5'
O
5'
NH
O
3
O
O
1'
4'
4'
1'
compound 3
3'
2'
3' 2'
2
+
3
CH2Cl2, BF3•Et2O,
CaH2, –50 °C
O
O
O
O
N
1
O
O
TIPS
4
5
11 R = TIPS
12 R = H
TBAF, THF,
0 °C
9
10
O
PCC, 4 Å MS,
CH2Cl2, 18 °C
NH
TBDPSO
O
O
TFA–H2O, 4:1
18 °C
1
O
O
13
Scheme 1
Synthesis 2003, No. 12, 1837–1843 © Thieme Stuttgart · New York

PAPER
Synthesis of Showdomycin Using a Maleimide C3-Anion Synthon
1839
TBDPSO
combined organic extracts were dried (Na2SO4), filtered and con-
centrated under reduced pressure. The residue was subject to flash
chromatography (silica gel; EtOAc–hexane 1:99 1:3) thus afford-
ing two fractions, A and B. Concentration of fraction A [Rf 0.3(4)]
afforded dioxolane 6a (24 mg, 36%). Concentration of fraction B
[Rf 0.3(0)] afforded dioxolane 6b (19 mg, 29%).
O
TBAF, THF,
0 °C
10
O
O
NH
14
Compound 6a (2S-isomer)
[ ]D20 +38.1 (c 0.2, CHCl3).
PCC, 4 Å MS,
CH2Cl2, 18 °C
TBDPSO
IR (NaCl): 2948, 2869, 1746, 1465, 1372, 1238, 1147, 1084, 1017
cm–1.
O
O
1H NMR (300 MHz, CD3OD): = 1.09 [d, 18 H, J = 7.5 Hz, 3 ×
CH(CH3)2], 1.47 [sept, 3 H, J = 7.5 Hz, 3 × CH(CH3)2], 1.75 (s, 3
H, CH3), 2.05 (s, 3 H, CH3CO), 2.12 (s, 3 H, CH3CO), 4.15–4.19
(m, 1 H, H5 ), 4.29–4.39 (m, 2 H, H4 , H5 ), 4.63 (dd, 1 H, J = 4.8,
3.8 Hz, H5), 4.71 (dd, 1 H, J = 9.1, 4.8 Hz, H3 ), 5.80 (d, 1 H,
J = 3.8 Hz, H4), 6.17 (dd, 1 H, J = 2.7, 1.5 Hz, H4 ), 6.74 (m, 2 H,
H2 , H5 ).
2
O
O
NH
TFA–H2O, 4:1
18 °C
O
15
Scheme 2
13C NMR (126 MHz, CD3OD): = 12.8, 18.2, 20.5, 20.6, 27.9,
63.7, 73.8, 77.0, 78.6, 106.2, 109.5, 112.4, 122.0, 125.9, 130.0,
171.8, 172.4.
ESMS (+): m/z (%) = 504 (M + Na+, 10), 482 (M + H+, 20), 266
(100).
HRMS: m/z calcd for C24H40NO7Si (M + H)+: 482.2574; found:
482.2559.
spectrometer, operating at 300 MHz (1H NMR) and 75 MHz (13C
NMR) was employed. Spectra were acquired at 20 °C in CDCl3,
which had been filtered through basic alumina prior to use, or in
CD3OD. Signals arising from the residual protio-forms of the sol-
vent were used as the internal standard. Chemical shifts were re-
corded as values in parts per million (ppm). The assignments of
signals observed in the various NMR spectra were often assisted by
conducting DEPT, homonuclear (1H/1H) correlation spectroscopy
(gDQFCOSY), NOE and/or heteronuclear (1H/13C) correlation
spectroscopy (gHMQC or gHMBC) experiments. Infrared spectra
were recorded on a Perkin–Elmer 1800 Series FTIR Spectrometer.
Samples were analyzed as KBr disks (for solids) or as thin films on
NaCl plates (for oils). Low resolution mass spectra were recorded
on a Micromass–Waters LC-ZMD single quadrupole liquid chro-
matograph-MS or VG Quattro II triple quadrupole MS instrument
using electrospray techniques in positive and/or negative ionization
mode. High resolution mass spectra were acquired by liquid sec-
ondary ion MS methods on a Kratos Analytical Concept ISQ instru-
ment (located at the University of Tasmania) or a Thermoquest
Mat95XL high resolution mass spectrometer (located at CSIRO
Molecular Science, Melbourne). Optical rotations were measured
with a Perkin–Elmer 241 polarimeter at the sodium-D line (589 nm)
and the concentrations (c) (g/100 mL) indicated using spectroscopic
grade chloroform unless otherwise specified. The measurements
were carried out in a cell with a path length (l) of 1 dm. Specific ro-
tations [ ]D were calculated (at the temperature listed) using the
equation [ ]D = 100. /(c.l) and are given in 10–1.deg.cm2.g–1. Ele-
mental analyses were performed by the Australian National Univer-
sity’s Microanalytical Services Unit based at the Research School
of Chemistry, Canberra, Australia. The unit cell parameters were re-
corded on a Nonius Kappa CCD instrument. CH2Cl2 was distilled
from CaH and THF was distilled, under nitrogen, from sodium ben-
zophenone ketyl. Where necessary, reactions were performed under
a nitrogen atmosphere.
Anal. Calcd for C24H39NO7Si: C, 59.85; H, 8.16; N, 2.91. Found C,
59.37; H, 8.50; N, 2.63%.
Compound 6b (2R-isomer)
[ ]D20 +95.8 (c 0.5, CHCl3).
IR (thin film, NaCl): 2948, 2869, 1747, 1464, 1370, 1238, 1148,
1083, 1017 cm–1.
1H NMR (300 MHz, CD3OD): = 1.11 [d, 18 H, J = 7.5 Hz, 3 ×
CH(CH3)2], 1.48 [sept, 3 H, J = 7.5 Hz, 3 × CH(CH3)2], 1.61 (s, 3
H, CH3), 2.00 (s, 3 H, CH3CO), 2.08 (s, 3 H, CH3CO), 3.93–4.02
(m, 2 H, H4 , H5 ), 4.13–4.21 (m, 1 H, H5 ), 4.65 (dd, 1 H, J = 8.9,
5.0 Hz, H3 ), 4.93 (dd, 1 H, J = 5.0, 4.0 Hz, H5), 5.93 (d, 1 H,
J = 4.0 Hz, H4), 6.32 (dd, 1 H, J = 2.8, 1.5 Hz, H4 ), 6.75 (dd, 1 H,
J = 2.8, 2.2 Hz, H5 ), 6.89 (dd, 1 H, J = 2.2, 1.5 Hz, H2 ).
13C NMR (126 MHz, CD3OD): = 12.8, 18.3, 20.5, 20.6, 29.1,
63.8, 74.4, 77.3, 79.1, 106.1, 110.1, 113.6, 122.4, 125.5, 130.1,
171.7, 172.3.
ESMS (+): m/z (%) = 504 (M + Na+, 10), 482 (M + H+, 65), 266
(100).
HRMS: m/z calcd for C24H40NO7Si (M + H)+: 482.2574; found:
482.2559.
Anal. Calcd for C24H39NO7Si: C, 59.85; H, 8.16; N, 2.91. Found C,
59.28; H, 8.05; N, 3.00.
Compound 8
A magnetically stirred mixture of compound 711 (40 mg, 0.079
mmol), CaH2 (powdered, excess) and N-(triisopropylsilyl)pyrrole
(3) (0.088 g, 0.39 mmol) in CH2Cl2 (4 mL) was maintained at 18 °C
for 10 min then neat SnCl4 (28 L, 0.062 g, 0.23 mmol) was added,
dropwise, and the resulting mixture stirred for 1 h. TLC analysis
(silica gel; EtOAc–hexane, 1:2) after this time showed one major
product (Rf 0.6), the reaction mixture was poured into NaHCO3 (20
mL of a sat. aq soln) which was extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were dried (Na2SO4), filtered and
concentrated under reduced pressure and the residue thus obtained
was purified by flash chromatography (silica gel; EtOAc–hexane,
Compounds 6a and 6b
A magnetically stirred mixture of trichloroacetimidate 49 (58 mg,
0.138 mmol), CaH2 (powdered, excess) and N-(triisopropylsi-
lyl)pyrrole 38 (170 L, 0.154 g, 0.69 mmol) in CH2Cl2 (8 mL) was
maintained at r.t. for 0.5 h, then cooled to –50 °C. Neat BF3·OEt2
(44 L, 49 mg, 0.34 mmol) was then added, dropwise, and the reac-
tion mixture stirred for 1 h at –50 °C. TLC analysis (silica gel;
EtOAc–hexane, 1:3) after this time showed no residual starting ma-
terial (Rf 0.1) and the formation of two major products [Rf 0.3(4)
and 0.3(0)]. As a consequence, Et3N (100 L) was added, at –50 °C,
and the reaction mixture was then poured into NaHCO3 (20 mL of
a sat. aq soln), which was extracted with CH2Cl2 (3 × 20 mL). The
1:99
1:6). Concentration of the appropriate fractions (Rf 0.2)
yielded bis-pyrrole 8 (51 mg, 72%) as a white foam.
Synthesis 2003, No. 12, 1837–1843 © Thieme Stuttgart · New York

1840
N. L. Hungerford et al.
PAPER
[ ]D20 +19.0 (c 0.8, CHCl3).
bined organic extracts were dried (Na2SO4), filtered and concentrat-
ed under reduced pressure. The residue was purified by flash
IR (Thin film, NaCl): 3490, 2947, 2868, 1725, 1464, 1452, 1269,
1101, 1070, 884, 711 cm–1.
chromatography (silica gel; EtOAc–hexane, 1:99
1:20
1:12)
and concentration of the appropriate fractions (Rf 0.1; EtOAc–hex-
ane, 1:20) yielded a 1:1 mixture of pyrroles 10 and 11 (20 mg, 87%
combined yield).
1H NMR (500 MHz, CDCl3): = 0.93–1.00 (m, 36 H, 12 × CH3),
1.21–1.35 [m, 6 H, 6 × CH(CH3)2], 3.19 (d, 1 H, J = 7.3 Hz, 4-OH),
4.34 (m, 1 H, H4), 4.40 (dd, 1 H, J = 11.7, 6.3 Hz, H5), 4.58–4.63
(m, 2 H, H1, H5), 5.47 (dd, 1 H, J = 5.9, 3.9 Hz, H3), 6.20 (a-t, 1 H,
J = 6.3 Hz, H2), 6.30 (dd, 1 H, J = 2.4, 1.0 Hz, H4 or H4 ), 6.34
(dd, 1 H, J = 2.4, 1.0 Hz, H4 or H4 ), 6.56 (br s, 1 H, H2 or H2 ),
6.61 (br s, 1 H, H2 or H2 ), 6.63 (a-t, 1 H, J = 2.4 Hz, H5 or H5 ),
6.68 (a-t, 1 H, J = 2.4 Hz, H5 or H5 ), 7.33–7.43 (m, 6 H, ArH),
7.48–7.57 (m, 3 H, ArH), 7.93–8.07 (m, 6 H, ArH).
13C NMR (126 MHz, CDCl3): = 11.5, 11.6, 17.7, 38.2, 65.8, 69.5,
75.1, 76.5, 110.5, 111.4, 122.3(7), 122.4(3), 123.8, 124.2(6),
124.3(1), 125.8, 128.1(8), 128.2(1), 128.4, 129.4, 129.7, 129.7(7),
129.8(1), 129.9, 130.0, 132.8, 133.3, 165.8, 166.3, 166.6.
Method B: A magnetically stirred mixture of trichloroacetimidate 9
(683 mg, 1.19 mmol), CaH2 (powdered, excess) and N-(triisopro-
pylsilyl)pyrrole 38 (588 L, 532 mg, 2.38 mmol) in CH2Cl2 (50 mL)
was maintained at r.t. for 0.33 h, then cooled to –50 °C. Neat
BF3·OEt2 (151 L, 0.169 g, 1.19 mmol) was then added, dropwise,
and the reaction mixture was stirred for 1 h at –50 °C. TLC analysis
(EtOAc–hexane, 1:4) showed no residual starting material (Rf 0.5)
and the formation of two major products [Rf 0.6 and Rf 0.5(5)]. As
a consequence Et3N (200 L) was added, at –50 °C, and the reaction
mixture then poured into a sat. aq soln of NaHCO3 (50 mL) then ex-
tracted with CH2Cl2 (3 × 50 mL). The combined organic extracts
were dried (Na2SO4), filtered and concentrated under reduced pres-
sure. The ensuing residue was subject to flash chromatography (sil-
ESMS(+): m/z (%) = 913 (M + Na+, 50), 891 (M + H+, 50), 668 (80),
546 (100).
HRMS: m/z calcd for C52H71N2O7Si2 (M + H)+: 891.4800; found:
891.4795.
ica gel; EtOAc–hexane 1:99
1:20) and concentration of the
appropriate fractions yielded pyrroles 10 (304 mg, 40%) and 11
(155 mg, 21%), respectively, each of which was obtained as a clear,
colorless oil.
Compound 9
A magnetically stirred mixture of 5-O-tert-butyldiphenylsilyl-2,3-
O-isopropylidene-D-ribofuranose18 (550 mg, 1.28 mmol), trichloro-
acetonitrile (322 L, 464 mg, 3.21 mmol) and Cs2CO3 (42 mg,
0.128 mmol) in anhyd CH2Cl2 (8 mL) was maintained at 18 °C for
5 h. TLC analysis (silica gel; EtOAc–hexane, 1:4) after this time
showed almost complete conversion of starting material (Rf 0.2)
into product (Rf 0.5). As a consequence, the reaction mixture was
diluted with CH2Cl2 (20 mL) and washed with H2O (20 mL). The
separated aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and
the combined organic extracts washed with brine (20 mL) then
dried (Na2SO4), filtered and concentrated under reduced pressure to
give a light-yellow oil. This material was subject to rapid flash chro-
matography (short silica gel pad; EtOAc–hexane, 1:5) and concen-
tration of the appropriate fractions (Rf 0.4) afforded
trichloroacetimidate 91 (683 mg, 93%) as an unstable and clear, col-
orless syrup.
Compound 10
Rf 0.14 (EtOAc–hexane, 1:20).
[ ]D20 –20.7 (c 0.9, CHCl3).
IR (Thin film, NaCl): 3072, 2945, 2867, 1735, 1472, 1428, 1380,
1370, 1261, 1210, 1112, 1095, 1073, 1017 cm–1.
1H NMR (500 MHz, CDCl3): = 1.08–1.12 [m, 27 H, 9 × CH3 (t-
Bu, i-Pr)], 1.38 (s, 3 H, CH3), 1.43 [sept, 3 H, J = 7.8 Hz,
CH(CH3)2], 1.56 (s, 3 H, CH3), 3.79 (dd, 1 H, J = 10.7, 3.9 Hz, H5 ),
3.88 (dd, 1 H, J = 10.7, 4.4 Hz, H5 ), 4.19 (a-t, 1 H, J = ca. 4.2 Hz,
H4 ), 4.78 (dd, 1 H, J = 5.9, 3.4 Hz, H2 ), 5.02 (d, 1 H, J = 5.9 Hz,
H3 ), 5.21 (d, 1 H, J = 3.4 Hz, H1 ), 6.44 (dd, 1 H, J = 2.4, 1.5 Hz,
H4), 6.75 (a-t, 1 H, J = 2.4 Hz, H5), 6.82 (a-t, 1 H, J = 1.5 Hz, H2),
7.37–7.47 (m, 6 H, ArH), 7.68–7.72 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): = 11.6, 17.8, 19.1, 25.1, 26.4, 26.8,
65.4, 79.2, 83.1, 83.4(7), 83.5(0), 110.8, 112.1, 120.5, 124.1,
127.5(7), 127.7(3), 127.7(5), 129.7, 129.8, 132.9, 133.0, 135.5,
135.6.
[ ]D20 –38.3 (c 1.6, CHCl3).
IR (thin film, NaCl): 3342, 3072, 2933, 2859, 1670, 1472, 1428,
1373, 1317, 1264, 1211, 1161, 1113, 1071, 969, 927, 870, 824, 797,
739, 702, 647, 614, 569, 504 cm–1.
1H NMR (300 MHz, CDCl3): = 1.07 [s, 9 H, (CH3)3CSi], 1.35 (s,
3 H, CH3), 1.53 (s, 3 H, CH3), 3.59 (a-t, 1 H, J = 10.4 Hz, H5), 3.74
(dd, 1 H, J = 10.4, 5.0 Hz, H5), 4.49 (dd, 1 H, J = 10.7, 5.0 Hz, H4),
4.72 (d, 1 H, J = 6.0 Hz, H2 or H3), 4.84 (d, 1 H, J = 6.0 Hz, H2 or
H3), 6.23 (s, 1 H, H1), 7.33–7.47 (m, 6 H, ArH), 7.59–7.68 (m, 4 H,
ArH), 8.43 (br s, 1 H, NH).
ESMS (+): m/z (%) = 672 (M + K+, 8), 656 (M + Na+, 10), 634 (M
+ H+, 100).
HRMS: m/z calcd for C37H56NO4Si2 (M + H)+: 634.3748; found:
634.3754.
Compound 11
Rf 0.08 (EtOAc–hexane, 1:20).
[ ]D20 –11.7 (c 0.5, CHCl3).
13C NMR (75 MHz, CDCl3): = 19.2, 25.0, 26.4, 26.9, 63.7, 81.7,
84.7, 87.8, 90.7, 106.2, 112.8, 127.6, 129.7, 129.8, 132.7, 133.2,
135.5(2), 135.5(8), 160.3.
IR (Thin film, NaCl): 3072, 2947, 2868, 1733, 1472, 1428, 1382,
1370, 1261, 1212, 1104, 1076, 1017 cm–1.
1H NMR (500 MHz, CDCl3): = 1.07–1.10 [m, 27 H, 9 × CH3 (t-
Bu, i-Pr)], 1.41 (s, 3 H, CH3), 1.42 [sept, 3 H, J = 7.8 Hz,
CH(CH3)2], 1.62 (s, 3 H, CH3), 3.82 (dd, 1 H, J = 11.2, 4.4 Hz, H5 ),
3.87 (dd, 1 H, J = 11.2, 3.9 Hz, H5 ), 4.14 (a-dt, 1 H, J = 4.4, 3.9
Hz, H4 ), 4.69 (dd, 1 H, J = 6.8, 4.9 Hz, H2 ), 4.88 (dd, 1 H, J = 6.8,
3.9 Hz, H3 ), 4.92 (d, 1 H, J = 4.9 Hz, H1 ), 6.31 (dd, 1 H, J = 2.4,
1.5 Hz, H4), 6.74 (a-t, 1 H, J = 2.4 Hz, H5), 6.78 (m, 1 H, H2),
7.33–7.45 (m, 6 H, ArH), 7.70–7.75 (m, 4 H, ArH).
Compounds 10 and 11
Method A: A magnetically stirred mixture of trichloroacetimidate 9
(21 mg, 0.037 mmol), CaH2 (powdered, excess) and N-(triisopro-
pylsilyl)pyrrole 38 (45 L, 0.041 g, 0.183 mmol) in CH2Cl2 (2 mL)
was maintained at 18 °C for 0.33 h then cooled to –50 °C. Neat
BF·OEt2 (12 L, 0.013 g, 0.92 mmol) was added, dropwise, and the
reaction mixture then stirred for 10 min at –50 °C. TLC analysis
(EtOAc–hexane, 1:4) after this time showed no residual starting
material (Rf 0.5) and the formation of two major products [Rf 0.6
and Rf 0.5(5)]. As a consequence, Et3N (50 L) was added, at
–50 °C, and the reaction mixture then poured into a sat. aq soln of
NaHCO3 (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The com-
13C NMR (126 MHz, CDCl3): = 11.6, 17.8, 19.2, 25.6, 26.8, 27.5,
63.9, 81.2, 82.0, 84.0, 86.4, 108.9, 114.0, 121.6, 124.4, 124.7,
127.5(8), 127.6(4), 129.5, 129.6, 133.3, 133.4, 135.6, 135.7.
Synthesis 2003, No. 12, 1837–1843 © Thieme Stuttgart · New York

PAPER
Synthesis of Showdomycin Using a Maleimide C3-Anion Synthon
1841
+
ESMS (+): m/z (%) = 656 (M + Na+, 12), 651 (M + NH4 , 10), 634
J = 2.2 Hz, H4), 7.37–7.47 (m, 6 H, ArH), 7.57 (br s, 1 H, NH),
7.63–7.67 (m, 4 H, ArH).
(M + H+, 100).
HRMS: m/z calcd for C37H56NO4Si2 (M + H)+: 634.3748; found:
634.3736.
13C NMR (126 MHz, CDCl3): = 19.2, 25.4, 26.8, 27.4, 63.9, 79.7,
81.8, 84.2, 85.1, 114.6, 127.8, 128.6, 129.9(1), 129.9(3), 132.9,
135.5, 135.6, 148.2, 169.4, 169.6.
Anal. Calcd for C37H55NO4Si2: C, 70.09; H, 8.74: N, 2.21. Found:
C, 69.75; H, 9.00; N, 2.36.
ESMS (+): m/z (%) = 546 (M + K+, 10), 530 (M + Na+, 50), 525 (M
+ NH4 , 20), 508 (M + H+, 10), 430 (100).
+
Compound 12
HRMS: m/z calcd for C28H34NO6Si (M + H)+: 508.2155; found:
TBAF (1.0 M soln in THF, 172 L, 0.172 mmol) was added, drop-
wise, to a magnetically stirred 0 °C soln of compound 11 (0.110 g,
0.172 mmol) in THF (6 mL). After 10 min, TLC analysis (EtOAc–
hexane, 1:4) showed complete conversion of starting material (Rf
0.6) into a single product (Rf 0.2). Consequently, the reaction mix-
ture was diluted with CH2Cl2 (50 mL) and washed with H2O (30
mL). The separated aqueous layer was extracted further with
CH2Cl2 (2 × 20 mL) and the combined organic layers washed with
brine (20 mL) then dried (Na2SO4), filtered and concentrated under
reduced pressure. The residue thus obtained was subject to flash
chromatography (silica gel; EtOAc–hexane, 1:4) and concentration
of the appropriate fractions (Rf 0.2) gave pyrrole 12 (64 mg, 77%)
as a clear, colorless oil.
508.2161.
Showdomycin (1)
Compound 13 (14 mg, 0.028 mmol) was dissolved in TFA–H2O
(4:1, 1.0 mL) and the resulting soln stirred at 18 °C for 1.5 h. TLC
analysis (silica gel) after this time showed complete consumption of
starting material (Rf 0.2 in EtOAc–hexane, 1:4) and the formation
of a single major product (Rf 0.3 in MeOH–EtOAc, 5:95). As a con-
sequence the reaction mixture was concentrated under reduced
pressure and the residue subjected to flash chromatography (silica
gel; MeOH–EtOAc, 2:98). Concentration of the appropriate frac-
tions (Rf 0.25) afforded showdomycin (1) (6 mg, 95%) as a white
crystalline solid. Recrystallization (benzene–acetone) of this mate-
rial afforded compound 1 as colorless needles, mp 148–149 °C
[Lit.7o 150 °C); NB widely varying mp values (144–161 °C) have
been reported2,7 for showdomycin].
[ ]D20 –7.0 (c 1.1, CHCl3).
IR (Thin film, NaCl): 3391, 2932, 2858, 1428, 1382, 1212, 1112,
1074 cm–1.
[ ]D20 +47.5 (c 0.1, H2O) {Lit.7j [ ]D +47.1 to +49.9, H2O}.
1H NMR (500 MHz, CDCl3): = 1.08 [s, 9 H, (CH3)3CSi), 1.38 (s,
3 H, CH3], 1.61 (s, 3 H, CH3), 3.82 (m, 1 H, H5 ), 3.85 (m, 1 H, H5 ),
4.15 (a-dt, 1 H, J = 4.4, 3.9 Hz, H4 ), 4.65 (dd, 1 H, J = 6.8, 5.4 Hz,
H2 ), 4.83 (dd, 1 H, J = 6.8, 3.9 Hz, H3 ), 4.90 (d, 1 H, J = 5.4 Hz,
H1 ), 6.24 (m, 1 H, H4), 6.73 (dd, 1 H, J = 4.9, 2.4 Hz, H2 or H5),
6.78 (m, 1 H, H2 or H5), 7.34–7.45 (m, 6 H, ArH), 7.69–7.73 (m, 4
H, ArH), 8.17 (br s, 1 H, NH).
13C NMR (126 MHz, CDCl3): = 19.3, 25.6, 26.8, 27.5, 64.0, 80.9,
81.9, 84.0, 86.2, 106.7, 114.2, 115.8, 118.4, 122.3, 127.6, 127.7,
129.5(8), 129.6(5), 133.3, 133.4, 135.6, 135.7.
IR (KBr): 3462, 3404, 3231, 1769, 1717, 1703, 1639, 1449, 1371,
1360, 1330, 1207, 1124, 1102, 1083, 1064, 1039, 867 cm–1.
1H NMR (500 MHz, CD3OD): = 3.64 (dd, 1 H, J = 12.2, 4.4 Hz,
H5 ), 3.79 (dd, 1 H, J = 12.2, 2.9 Hz, H5 ), 3.94 (ddd, 1 H, J = 5.9,
4.4, 2.9 Hz, H4 ), 4.02 (a-t, 1 H, J = 5.4 Hz, H3 ), 4.12 (a-t, 1 H,
J = 4.9 Hz, H2 ), 4.70 (dd, 1 H, J = 4.9, 2.0 Hz, H1 ), 6.67 (d, 1 H,
J = 2.0 Hz, H4).
13C NMR (126 MHz, CD3OD): = 63.0, 72.5, 76.6, 79.4, 85.4,
130.2, 149.7, 172.9, 173.1.
ESMS (+): m/z (%) = 287 (M + K+, 77), 252 (M + Na+, 80), 85
(100).
ESMS (–): m/z (%) = 228 (M – H–, 70), 126 (100), 113 (70).
ESMS (+): m/z (%) = 977 (2 M + Na+, 30), 955 (2 M + H+, 20), 516
(M + K+, 60), 500 (M + Na+, 100), 495 (M + NH4 , 70), 478 (M +
+
H+, 30), 400 (60).
HRMS: m/z calcd for C28H36NO4Si (M + H)+: 478.2414; found:
478.2404.
Unit cell parameters (as recorded at 200 K): a = 15.439, b = 6.551,
c = 11.472; = 121.12. Mosaic spread = 0.72°.
Compound 13
Compound 14
A magnetically stirred mixture of compound 12 (40 mg, 0.084
mmol), powdered 4 Å molecular sieves (40 mg) and PCC (90 mg,
0.42 mmol) in anhyd CH2Cl2 (1.5 mL) was maintained at 18 °C for
16 h. TLC analysis (EtOAc–hexane, 1:3) after this time showed
complete conversion of starting material (Rf 0.35) into a single
product (Rf 0.3). Consequently, the reaction mixture was diluted
with Et2O (20 mL) then filtered through a pad of Celite, which was
washed with Et2O (50 mL). The combined filtrates were concentrat-
ed under reduced pressure to yield an orange residue, which was
subject to flash chromatography (silica gel; EtOAc–hexane, 1:4).
Concentration of the appropriate fractions (Rf 0.2) yielded maleim-
ide 13 (31 mg, 72%), as a clear, colorless oil.
TBAF (1.0 M soln in THF, 280 L, 0.28 mmol) was added, drop-
wise, to a magnetically stirred soln of compound 10 (175 mg, 0.28
mmol) in THF (10 mL) maintained at 0 °C. After 10 min TLC anal-
ysis (silica gel; EtOAc–hexane, 1:4) showed complete conversion
of starting material (Rf 0.6) into a single product (Rf 0.1). As a con-
sequence, the reaction mixture was diluted with CH2Cl2 (50 mL)
and washed with H2O (30 mL). The aqueous layer was extracted
with additional CH2Cl2 (2 × 30 mL) and the combined organic
phases washed with brine (20 mL) then dried (Na2SO4), filtered and
concentrated under reduced pressure. The residue thus obtained was
subject to flash chromatography (silica gel; EtOAc–hexane, 1:3)
and concentration of the appropriate fractions (Rf 0.2) gave pyrrole
14 (116 mg, 88%) as a clear, colorless oil.
[ ]D20 +11.8 (c 0.7, CH2Cl2) and [ ]D20 +9.6 (c 0.7, CHCl3), {Lit.7j,p
[ ]D +8.5 (c 0.9, CH2Cl2), [ ]D +10.3 (c 0.8, CHCl3)}.
[ ]D20 –19.6 (c 0.7, CHCl3).
IR (Thin film, NaCl): 3306, 2932, 2858, 1725, 1383, 1347, 1214,
1113, 1080 cm–1.
IR (Thin film, NaCl): 3392, 2932, 2858, 1428, 1380, 1209, 1112,
1073 cm–1.
1H NMR (500 MHz, CDCl3): = 1.05 [s, 9 H, (CH3)3CSi], 1.36 (s,
3 H, CH3), 1.60 (s, 3 H, CH3), 3.78 (dd, 1 H, J = 11.7, 3.9 Hz, H5 ),
3.84 (dd, 1 H, J = 11.7, 3.9 Hz, H5 ), 4.22 (a-dt, 1 H, J = 3.9, 3.4
Hz, H4 ), 4.70 (dd, 1 H, J = 6.3, 4.4 Hz, H2 ), 4.74 (dd, 1 H, J = 6.3,
3.4 Hz, H3 ), 4.86 (dd, 1 H, J = 4.4, 2.0 Hz, H1 ), 6.49 (a-t, 1 H,
1H NMR (500 MHz, CDCl3): = 1.08 [s, 9 H, (CH3)3CSi], 1.36 (s,
3 H, CH3), 1.58 (s, 3 H, CH3), 3.77 (dd, 1 H, J = 10.7, 3.9 Hz, H5 ),
3.87 (dd, 1 H, J = 10.7, 4.4 Hz, H5 ), 4.18 (a-t, 1 H, J = ca. 3.9 Hz,
H4 ), 4.75 (dd, 1 H, J = 6.3, 3.4 Hz, H2 ), 5.00 (d, 1 H, J = 6.3 Hz,
H3 ), 5.24 (d, 1 H, J = 3.4 Hz, H1 ), 6.36 (m, 1 H, H4), 6.77 (dd, 1
Synthesis 2003, No. 12, 1837–1843 © Thieme Stuttgart · New York

1842
N. L. Hungerford et al.
PAPER
H, J = 4.6, 2.2 Hz, H2 or H5), 6.89 (m, 1 H, H2 or H5), 7.37–7.46
ESMS (+): m/z (%) = 252 (M + Na+, 18), 230 (M + H+, 40), 130
(m, 6 H, ArH), 7.66–7.71 (m, 4 H, ArH), 8.19 (br s, 1 H, NH).
(100).
13C NMR (126 MHz, CDCl3): = 19.1, 24.9, 26.4, 26.8, 65.6, 79.2,
83.1, 83.4, 83.7, 109.2, 112.2, 117.5, 117.8, 118.7, 127.8, 129.7(6),
129.8(5), 132.9, 133.0, 135.5(6), 135.6(1).
ESMS (–): m/z (%) = 228 (M – H–, 70), 126 (100).
HRMS: m/z calcd for C9H9NO5 (M – H2O)+·: 211.0481; found:
211.0483.
ESMS (+): m/z (%) = 500 (M + Na+, 100).
HRMS: m/z calcd for C28H36NO4Si (M + H)+: 478.2414; found:
478.2402.
Acknowledgments
We thank the Australian Research Council for financial support
including the provision of a post-Doctoral stipend to NH. Helpful
discussions with Drs Vito Ferro and Rob Don (Progen Industries,
Brisbane) are gratefully acknowledged. Mr Noel Davies (Universi-
ty of Tasmania) and Dr Carl Braybrook (CSIRO Molecular Science,
Melbourne) are thanked for the acquisition of mass spectral data.
We also thank Dr Alison Edwards for measuring crystal data for
showdomycin.
Compound 15
A magnetically stirred mixture of compound 14 (16 mg, 0.034
mmol), powdered 4 Å molecular sieves (16 mg) and PCC (0.036 g,
0.168 mmol) in anhyd CH2Cl2 (0.5 mL) was maintained at 18 °C for
16 h. TLC analysis (silica gel; EtOAc–hexane, 1:3) after this time
showed complete conversion of the starting material (Rf 0.2) into a
single product (Rf 0.3). As a consequence, the reaction mixture was
diluted with Et2O (20 mL) then filtered through Celite, which was
washed with Et2O (50 mL). The combined filtrates were concentrat-
ed under reduced pressure to yield a light-yellow oil, which was
subject to flash chromatography (silica gel; EtOAc–hexane, 1:3).
Concentration of the appropriate fractions (Rf 0.3) afforded maleim-
ide 15 (12 mg, 71%) as a clear, colorless oil.
References
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[ ]D20 –52.9 (c 0.2, CHCl3).
IR (Thin film, NaCl): 3307, 2932, 1723, 1428, 1374, 1210, 1113,
1072 cm–1.
1H NMR (500 MHz, CDCl3): = 1.08 [s, 9 H, (CH3)3CSi], 1.31 (s,
3 H, CH3), 1.37 (s, 3 H, CH3), 3.73 (dd, 1 H, J = 11.2, 3.2 Hz, H5 ),
3.86 (dd, 1 H, J = 11.2, 3.2 Hz, H5 ), 4.24 (a-t, 1 H, J = ca. 3.2 Hz,
H4 ), 4.90 (d, 1 H, J = 5.9 Hz, H3 ), 5.08 (dd, 1 H, J = 5.9, 4.6 Hz,
H2 ), 5.18 (dd, 1 H, J = 4.6, 2.2 Hz, H1 ), 6.56 (dd, 1 H, J = 2.2, 1.6
Hz, H4), 7.16 (br s, 1 H, NH), 7.38–7.47 (m, 6 H, ArH), 7.61–7.65
(m, 4 H, ArH).
13C NMR (126 MHz, CDCl3): = 19.0, 25.0, 26.1, 26.8, 65.7, 78.5,
82.2, 83.4, 84.5, 113.0, 127.8(9), 127.9(1), 128.4, 130.0, 130.1,
132.5, 135.5, 135.6, 147.6, 169.6, 170.0.
ESMS (+): m/z (%) = 530 (M + Na+, 100).
HRMS: m/z calcd for C28H34NO6Si (M + H)+: 508.2155; found:
508.2180.
1 -epi-Showdomycin (2)
(7) (a) Kalvoda, L.; Farkas, J.; Sorm, F. Tetrahedron Lett. 1970,
2297. (b) Trummlitz, G.; Moffatt, J. G. J. Org. Chem. 1973,
38, 1841. (c) Kalvoda, L. J. Carbohydr. Nucleosides
Nucleotides 1976, 3, 47. (d) Inoue, T.; Kuwajima, I. J.
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1980, 58, 2024. (f) Kozikowski, A. P.; Ames, A. J. Am.
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Bull. 1987, 35, 433. (m) Kametani, T.; Kawamura, K.;
Honda, T. J. Am. Chem. Soc. 1987, 109, 3010.
Compound 15 (7 mg, 0.014 mmol) was dissolved in TFA–H2O (4:1,
0.5 mL) and the resulting soln stirred at 18 °C for 1.5 h. TLC anal-
ysis (silica gel) after this time showed complete consumption of
starting material (Rf 0.3 in EtOAc–hexane, 1:3) and the formation
of a single major product (Rf 0.3 in MeOH–EtOAc, 5:95). As a con-
sequence the reaction mixture was concentrated under reduced
pressure and the residue subject to flash chromatography (silica gel,
MeOH–EtOAc, 2:98). Concentration of the appropriate fractions
(Rf 0.2) afforded 1 -epi-showdomycin (2, 3 mg, 94%) as a white,
crystalline solid, mp 137–139 °C (Lit.7k,17 139–140 °C).
[ ]D20 –75.6 (c 0.1, H2O) {Lit.7k,17 [ ]D –76 (c 0.1, H2O), [ ]D –77 (c
0.7, H2O)}.
IR (KBr): 3423 (br), 2925, 2855, 1711, 1639, 1460, 1376, 1344,
1118, 1090, 1047, 826, 812 cm–1.
1H NMR (500 MHz, CD3OD): = 3.62 (dd, 1 H, J = 12.2, 4.4 Hz,
H5 ), 3.83 (dd, 1 H, J = 12.2, 2.4 Hz, H5 ), 3.93 (ddd, 1 H, J = 8.8,
4.4, 2.4 Hz, H4 ), 4.22 (dd, 1 H, J = 8.8, 4.4 Hz, H3 ), 4.33 (a-t, 1
H, J 3.9 Hz, H2 ), 4.92 (dd, 1 H, J = 3.9, 2.4 Hz, H1 ), 6.51 (d, 1 H,
J = 2.4 Hz, H4).
13C NMR (126 MHz, CD3OD): = 62.9, 73.7, 74.0, 78.1, 83.3,
129.8, 149.5, 173.0, 173.4.
(n) Gonzalez, M. S. P.; Aciego, R. M. D.; Herrera, F. J. L.
Tetrahedron 1988, 44, 3715. (o) Barton, D. H. R.; Ramesh,
M. J. Am. Chem. Soc. 1990, 112, 891. (p) Kang, S. H.; Lee,
S. B. Tetrahedron Lett. 1995, 36, 4089. (q) Kang, S. H.;
Lee, S. B. J. Chem. Soc., Chem. Commun. 1995, 1017.
(r) Trost, B. M.; Kallander, L. S. J. Org. Chem. 1999, 64,
5427.
Synthesis 2003, No. 12, 1837–1843 © Thieme Stuttgart · New York

PAPER
Synthesis of Showdomycin Using a Maleimide C3-Anion Synthon
1843
(8) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell,
Spanu, P. Tetrahedron 1992, 48, 5619. (b) Cornia, M.;
Capacchi, S.; Del Pogetto, M.; Pelosi, G.; Fava, G. G.
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(10) For related examples of this type of reaction see (a) Ohoui,
H.; Jones, G. H.; Moffatt, J. G.; Maddox, M. L.; Christensen,
A. T.; Byram, S. K. J. Am. Chem. Soc. 1975, 97, 4602.
(b) Yokoyama, Y. S.; Elmoghayar, M. R. H.; Kuwajima, I.
Tetrahedron Lett. 1982, 23, 2673.
(13) Bernstein, M. A.; Morton, H. E.; Guindon, Y. J. Chem. Soc.,
Perkin Trans. 2 1986, 1155.
(14) Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995, 51,
9941.
(15) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
(16) Tsukuda, Y.; Koyama, H. J. Chem. Soc., B 1970, 1709.
(17) Aslani-Shotorbani, G.; Buchanan, J. G.; Edgar, A. R.;
Shanks, C. T.; Williams, G. C. J. Chem. Soc., Perkin Trans.
1 1981, 2267.
(11) Compound 7 can be purchased from the Aldrich Chemical
Company.
(18) Dudfield, P. J.; Le, V.-D.; Lindell, S. D.; Rees, C. W. J.
Chem. Soc., Perkin Trans. 1 1999, 2929.
(12) For related examples of this type of reaction see
(a) Casiraghi, G.; Cornia, M.; Rassu, G.; Del Sante, C.;
Synthesis 2003, No. 12, 1837–1843 © Thieme Stuttgart · New York