A Total Synthesis of the Marine Alkaloid Discoipyrrole D

Article abstract of DOI:10.1021/acs.joc.7b01192

A total synthesis of the diastereoisomeric pair of compounds, 4, assigned to the marine alkaloid discoipyrrole D is reported. A series of palladium-catalyzed cross-coupling and other reactions was employed to assemble the relevant 1,2,3,4-tetrasubstituted pyrrole (16) that was engaged in MoOPH-mediated oxidative cyclization, then conjugate addition, and redox processes to complete the synthesis. This work serves to confirm the structure (4) originally assigned to discoipyrrole D.

Full text of DOI:10.1021/acs.joc.7b01192

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Article
A Total Synthesis of the Marine Alkaloid Discoipyrrole D
Yiwen Zhang, and Martin G Banwell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01192 • Publication Date (Web): 15 Aug 2017
Downloaded from http://pubs.acs.org on August 15, 2017
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A Total Synthesis of the Marine Alkaloid Discoipyrrole D
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Yiwen Zhang and Martin G. Banwell*
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Research School of Chemistry, Institute of Advanced Studies
The Australian National University, Canberra, ACT 2601, Australia
OH
HO
(a) UllmannꢀGoldberg
OH
crossꢀcoulping;
(b) SuzukiꢀMiyaura
c
crossꢀcoupling;
e
NH
a
N
d
b
NH
(c) Heck reaction;
(d) MoOPHꢀmediated
oxidative cyclization;
(e) Asymmetric
HO
b
O
O
O
conjugate addition
4 (discoipyrrole D)
ABSTRACT: A total synthesis of the diastereoisomeric pair of compounds, 4, assigned to
the marine alkaloid discoipyrrole D is reported. A series of palladiumꢀcatalysed crossꢀ
coupling and other reactions was employed to assemble the relevant 1,2,3,4ꢀtetraꢀsubstituted
pyrrole (16) that was engaged in MoOPHꢀmediated oxidative cyclization then conjugate
addition and redox processes to complete the synthesis. This work serves to confirm the
structure (4) originally assigned to discoipyrrole D.
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INTRODUCTION
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In 2013 MacMillan and coꢀworkers reported on the isolation (from a marine bacterium) and
structural elucidation of the alkaloids 1ꢀ4 (Figure 1), named discoipyrroles AꢀD
respectively.1 The occurrence of these compounds as racemic or (in the case of compound 4)
diastereoisomeric mixtures suggested that they were produced by nonꢀenzymatic means and
the same group was able to mimic the proposed biogenesis in a oneꢀpot total synthesis of
compound 1. This involved “incubating” a DMSO solution of pꢀhydroxysattabacin, pꢀ
hydroxybenzalehyde and anthranilic acid at 50 °C in the presence of 1% trifluoroacetic
acid.1,2 The generation of analogues of the discoipyrroles by related means could well lead to
the identification of compounds that show even more potent inhibition of the discoidin
domain receptorꢀ2 signalling pathway than the natural products themselves. In a similar vein,
May and coꢀworkers were able to produce a brominated analogue of discoipyrrole A bisꢀOꢀ
methyl ether and elaborate this, through Heckꢀtype chemistry followed by, inter alia, an
organocatalyzed asymmetric conjugate addition of an indole trifluoroborate, to discoipyrrole
D bisꢀOꢀmethyl ether.3
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HO
HO
OH
HO
OH
N
NH
NH
R
HO
N
OH
HO
O
O
O
O
O
O
O
1 (R = OH, discoipyrrole A)
2 (R = H, discoipyrrole B)
3 (discoipyrrole C)
4 (discoipyrrole D)
Figure 1: Discoipyrroles AꢀD (1ꢀ4, respectively).
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Seemingly, however, the sensitivity of the 3Hꢀbenzo[d]pyrrolo[1,3]oxazineꢀ3,5ꢀdione core
associated with this last compound to the conditions normally used to cleave aryl methyl
ethers prevented the completion of a synthesis of the natural product, viz. discoipyrrole D.3
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In 2016 we reported4 a distinctly different route to compounds 1 and 2 that involved the
assembly, through UllmannꢀGoldberg5 and SuzukiꢀMiyaura crossꢀcoupling chemistries,6 of a
tetraꢀsubstituted pyrrole that could be engaged in an oxoperoxymolybdenum (pyridine)
hexamethylphosphoric triamide7 or MoOPHꢀmediated oxidative cyclization reaction8
resulting in the assembly of the 3Hꢀbenzo[d]pyrrolo[1,3]oxazineꢀ3,5ꢀdione core of
discoipyrroles A and B. We have since used this modular approach to the discoipyrroles in
the construction of a range of analogues.9 As an extension of such work we now report on the
amalgamation of this chemistry with certain aspects of May’s approach3 to discoipyrrole D in
the successful synthesis of this natural product that serves to confirm the structure originally
assigned to it by MacMillan and coꢀworkers.1
RESULTS AND DISCUSSION
The two major considerations associated with our devising an approach to discoipyrrole D
were, (i), the nature of the protecting group to be used to mask the phenolic hydroxyl groups
present in the target and, (ii), the timing of MoOPHꢀmediated oxidative cyclization reaction
that establishes the 3Hꢀbenzo[d]pyrrolo[1,3]oxazineꢀ3,5ꢀdione core associated with
compound 4. After some preliminary experimentation we elected to employ the MOM group
to protect the phenolic hydroxyls and to also delay the key oxidative cyclization reaction as
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long as possible because of the seemingly “fragile” nature of the core heterocyclic ring
system associated with the discoipyrroles.3
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The reaction sequence leading to the tetrasubstituted pyrrole that was to be engaged in the
pivotal oxidative cyclization reaction is shown in Scheme 1 and started with the
regioselective UllmannꢀGoldberg arylation of the parent heterocycle 5 with methyl 5ꢀbromoꢀ
2ꢀiodobenzoate (6) under conditions reported by Buchwald and coꢀworkers.5 Product 7
(99%) obtained by this means was subjected to a VilsmeierꢀHaack reaction10 and thus
affording the pyrroleꢀ2ꢀcarboxaldehyde 8 (83%) that was itself subjected to a regiocontrolled
diꢀiodination reaction using molecular iodine in the presence of silver trifluoroacetate and
thereby producing compound 9 (77%). Twoꢀfold SuzukiꢀMiyaura cross coupling of diꢀiodide
9 with commercially available pꢀhydroxyphenylboronic acid (10) then gave the triꢀarylated
pyrrole 11 (84%) that was protected, under conventional conditions, as the corresponding
bisꢀMOM ether 12 (99%). Wittig olefination of the aldehyde residue associated with the last
compound was accomplished using in situ generated isopropylenetriphenylphosphorane11
and by such means the olefin 13 (79%) was obtained. This was immediately hydrogenated
using dihydrogen in the presence of Adam’s catalyst and so affording the isobutylated
pyrrole 14 (99%) that was itself engaged in a Heck reaction with 3,3ꢀdiethoxypropꢀ1ꢀene
using Pd(OAc)2 as the catalyst source. The ester residue associated with product 15 (65%)
was saponified using sodium hydroxide in methanol and upon acidification of the ensuing
mixture with aqueous HCl, so as to generate the free acid, the acetal moiety was also
hydrolyzed and thus affording the cinnamaldehyde 16 (99%), the substrate required for the
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pivotal oxidation reaction. All the spectral data acquired on this tetrasubstituted pyrrole were
in complete accord with the illustrated structure.
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Scheme 1: Synthesis of pyrrole 16 required for the pivotal oxidative cyclization reaction.
NH
CuI,
Br
Br
Br
5
I2
DMF, POCl3
THF
1,10ꢀphenanthroline
Cs2CO3
I
AgOCOCF3
+
N
N
N
Br
I
toluene
90 °C
0 to 20 °C
16 h, 77%
0 to 20 °C, 1 h
83%
CO2Me
CHO
CO2Me
CHO
CO2Me
16 h, 99%
8
7
9
I
CO2Me
Pd(PPh3)2Cl2
Na2CO3
6
HO
B(OH)2
HO
MeCN, water
60 °C, 16 h
84%
10
MOMO
MOMO
Ph3P=C(Me)2
THF
MOMꢀCl
Br
Br
Br
–78 to 22 °C
Hünig's base
16 h, 79%
CH2Cl2
0 to 22 °C
16 h, 99%
N
N
N
MOMO
MOMO
HO
CO2Me
CO2Me
CHO
CO2Me
CHO
11
13
12
THF
22 °C, 48 h
99%
H2
PtO2•H2O
OEt
OEt
(i) aq. NaOH
MeOH/THF
O
MOMO
MOMO
MOMO
acrolein diethyl acetal
Pd(OAc)2, KCl
50 °C, 16 h
(ii) H3O+ workꢀup
Br
K2CO3, Bu4NOAc
99%
DMF, 80 °C
N
N
N
MOMO
48 h, 65%
MOMO
MOMO
CO2Me
CO2Me
CO2H
16
14
15
In keeping with earlier observations,4 when compound 16 was treated with freshly prepared
MoOPH in methanol at ambient temperatures the anticipated oxidative cyclization reaction
took place and after chromatographic purification of the major reaction product compound 17
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was obtained in 50% yield as a yellow oil (Scheme 2). No other characterizable materials
could be isolated from the reaction mixture. The 13C NMR spectrum of compound 17
displayed twentyꢀnine of the expected thirty resonances including three at δC 193.8, 193.2
and 167.4 ppm that are attributed to carbonyl carbons associated with the ketone, aldehyde
and lactone residues, respectively. In the corresponding infraꢀred spectrum C=O stretching
bands are evident at 1740, 1702 and 1679 cm–1 while molecular associated ions at m/z 606
[(M + Na)+] and 584 [(M + H)+] dominate the EI mass spectrum.
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Scheme 2: MoOPHꢀmediated oxidative cyclization of pyrrole 16 leading to the formation of
3Hꢀbenzo[d]pyrrolo[1,3]oxazineꢀ3,5ꢀdione 17
The completion of the synthesis of target compound 4 is shown in Scheme 3 and proved to
be a rather straightforward matter. Thus, following the protocols reported by May and coꢀ
workers,3 compound 17 was subjected to a reaction with the readily prepared and NꢀBocꢀ
protected indole C3ꢀtrifluorborate salt 1812 in the presence of the freshly prepared catalyst
(R)ꢀ3,3’ꢀ(C7F7)2ꢀBINOL3 and so affording the rather unstable product 19 as a 1:1 mixture of
diastereoisomers. This outcome clearly indicates that the existing stereogenic center within
substrate 17 has no impact on the configuration of C1 established during the conjugate
addition reaction. By analogy with the work of May, this addition reaction is presumed to
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have proceeded with a high degree of stereochemical control and such that the illustrated Sꢀ
configuration has been established at the new stereogenic center. May’s threeꢀstep protocol
was then employed to manipulate the indoleꢀbearing carbon sideꢀchain of compound 19 so as
introduce the associated hydroxyl groups. Specifically, then, a Dꢀprolineꢀcontrolled oxidation
involving nitrosobenzene13 was used to introduce a 2°ꢀphenyaminoxy moiety in a
stereocontrolled fashion and this was followed by reduction of the aldehyde moiety using
sodium triacetoxyborohydride. Treatment of the ensuing 2ꢀaminoxyalcohol with
nitrosobenzene resulted in cleavage of the aminoxy residue and so producing diol 20 (36%)
that was also obtained as a 1:1 mixture of diastereoisomers. Subjection of this material to
analysis on chiral HPLC column very similar to that used by May and coꢀworkers and using
a range of solvent systems only showed peaks due to two diastereoisomers and none
attributable to the corresponding enantiomers. In the final steps of the reaction sequence,
compound 20 was treated with trifluoroacetic acid (to cleave to Boc group) and then aqueous
HCl (to cleave the MOM ethers) and thereby affording compound 4 in 60% yield and as a
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lightꢀyellow oil. H and 13C NMR spectroscopic analyses of this material revealed the
presence of aliphatic impurities although the aromatic regions of each spectrum were very
clean. The origins of these impurities probably reflect the fragile nature of the 3Hꢀ
benzo[d]pyrrolo[1,3]oxazineꢀ3,5ꢀdione core of the compound and its partial degradation
under the acidic conditions necessarily employed in the final steps of the synthesis. Much
cleaner samples of compound 4 were obtained after purification under reverseꢀphase HPLC
conditions.
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All the spectral data acquired on the HPLCꢀpurified sample of compound 4, which indicated
that it had been generated as a 1:1 mixture of diastereoisomers, proved a good match with
those reported by MacMillan and coꢀworkers1 on discoipyrrole D (see SI for a tabulated
comparison of the 13C NMR spectral data sets). Subjection of this material to analysis on
chiral HPLC column very similar to that used as described above (and, once again, using a
range of solvent systems) only showed peaks due to two diastereoisomers and none
attributable to the corresponding enantiomers.
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Scheme 3: Completion of the synthesis of discoipyrrole D (4)
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The synthetic material was optically active {[α]D = +25 (c 0.2, MeOH)}. However, in the
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absence of any published specific rotation data on the title natural product not much more
can be said about the absolute configuration of the alkaloid.
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CONCLUSION
The total synthesis of discoipyrrole D reported here serves to confirm the basic structure (but
not the absolute configuration) assigned to it by MacMillan and coꢀworkers. This work also
highlights the capacity of the protocols reported by May and his colleagues to effect the
organocatalyzed asymmetric conjugate addition of hetereoaryl trifluoroborates to
cinnamaldehydes (in particular). In addition, the present study reveals more about the
functionality that can be tolerated during the MoOPHꢀmediated formation of the aboveꢀ
mentioned heterocyclic core and the various reaction conditions that can be used without
adversely affecting this same and often rather fragile motif.
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EXPERIMENTAL SECTION
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General Protocols. Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra
were recorded at 18 °C in baseꢀfiltered CDCl3 on a spectrometer operating at 400 MHz for
proton and 100 MHz for carbon nuclei. 1H NMR data are recorded as follows: chemical shift
(δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity is defined
as s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or combinations of the
above. In relevant cases, the signal due to residual CHCl3 appearing at δH 7.26 and the central
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resonance of the CDCl3 “triplet” appearing at δC 77.0 were used to reference H and 13C
NMR spectra, respectively. Samples were analyzed by infrared spectroscopy (νmax) as thin
films on KBr plates or as neat material resting on the sampling port. Lowꢀ and highꢀ
resolution electron impact (EI) mass spectra were recorded on a doubleꢀfocusing, tripleꢀ
sector machine. Lowꢀ and highꢀresolution ESI mass spectra were recorded on a tripleꢀ
quadrupole mass spectrometer operating in either positive or negative ion mode. Melting
points are uncorrected. HPLC analyses were performed on a HPLC system equipped with a
photodiode array detector and either a C18 reversed phase (150 mm x 4.6 mm, 3 ꢀM silica
gel), Chiralpak IA (250 mm × 4.6 mm, amylose trisꢀ(3,5ꢀdimethylphenylcarbamate) coated
on 5 ꢀM silica gel) or Chiralpak IC (250 mm × 4.6 mm, cellulose tris (3,5ꢀ
dichlorophenylcarbamate) coated on 5 ꢀM silica gel) column. Analytical thin layer
chromatography (TLC) was performed on aluminumꢀbacked 0.2 mm thick silica gel 60 F254
plates. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip followed by heating. These dips included phosphomolybdic acid/ceric
sulfate/sulfuric acid (conc.)/water (37.5 g : 7.5 g : 37.5 g : 720 mL), potassium
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permanganate/potassium carbonate/5% sodium hydroxide aqueous solution/water (3 g : 20 g
: 5 mL : 300 mL), and pꢀanisaldehyde or vanillin/sulfuric acid (conc.)/ethanol (15 g : 2.5 mL
: 250 mL). Flash chromatographic separations were carried out following protocols defined
by Still et al.14 with silica gel 60 (40ꢀ63 ꢀm) as the stationary phase and using the ARꢀ or
HPLCꢀgrade solvents indicated. Starting materials, reagents, drying agents, and other
inorganic salts were generally commercially available and were used as supplied.
Tetrahydrofuran (THF), methanol and dichloromethane were dried using a solvent
purification system that is based upon a technology originally described by Grubbs et al.15
Where necessary, reactions were performed under a nitrogen atmosphere.
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Specific Chemical Transformations. Methyl 5-Bromo-2-(1H-pyrrol-1-yl)benzoate (7). A
magnetically stirred and degassed mixture of pyrrole (2) (1.39 g, 20.8 mmol), commercially
available compound 4 (6.45 g, 18.9 mmol), CuI (359 mg, 1.9 mmol), 1,10ꢀphenanthroline
(680 mg, 3.8 mmol) and Cs2CO3 (9.30 g, 28.4 mmol) in anhydrous toluene (40 mL) was
heated at 100 °C under a nitrogen atmosphere for 48 h. The cooled reaction mixture was then
passed through a pad of TLCꢀgrade silica and the filtrate concentrated under reduced
pressure. The residue so formed was subjected to flash chromatography (silica, 30:1 v/v
hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (Rf =
1
0.5 in 8:1 v/v hexane/ethyl acetate), compound 7 (5.21 g, 99%) as a clear, colorless syrup. H
NMR (400 MHz, CDCl3)
δ 7.85 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.5 and 2.4 Hz, 2H), 7.18
(m, 1H), 6.71 (m, 2H), 6.25 (m, 2H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
166.1,
139.4, 135.3, 133.5, 129.4, 128.3, 122.0, 120.5, 110.2, 52.8; IR νmax 2950, 1729, 1594, 1563,
1498, 1435, 1400, 1329, 1288, 1267, 1238, 1123, 1094, 1015, 966, 922, 826, 727 cm–1; MS
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(ESI, +ve): m/z 282 and 280 [(M+H)+, both 50%], 250 and 248 (96 and 100); HRMS (ESI,
+ve): (M+H)+ Calcd for C12H1179BrNO2 279.9973; Found 279.9972.
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Methyl 5-Bromo-2-(2-formyl-1H-pyrrol-1-yl)benzoate (8). Anhydrous DMF/THF (90 mL
of a 4:5 v/v mixture) maintained with magnetic stirring at 0 °C under a nitrogen atmosphere
was treated with POCl3 (5.50 mL, 59.5 mmol) and the resulting orange reaction mixture was
stirred at 0 °C for 0.75 h before being treated, dropwise, with a solution of compound 7 (6.47
g, 23.2 mmol) in anhydrous THF (40 mL). The mixture soꢀformed was warmed to 22 °C then
stirred at this temperature for 3 h before being quenched with ice (100 g). The ensuing
mixture was neutralized using NaHCO3 (saturated aqueous solution) then extracted with
diethyl ether (3 × 150 mL). The combined organic phases were washed with brine (1 × 300
mL) before being dried (Na2SO4), filtered and then concentrated under reduced pressure. The
residue thus obtained was subjected to flash chromatography (silica, 12:1 v/v hexane/ethyl
acetate elution) to afford, after concentration of the appropriate fractions (Rf = 0.3 in 4:1 v/v
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hexane/ethyl acetate), compound 8 (5.89 g, 83%) as a clear, colorless syrup. H NMR (400
MHz, CDCl3) δ 9.48 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.3 and 2.4 Hz, 1H), 7.19
(d, J = 8.3 Hz, 1H), 7.09 (dd, J = 4.0 and 1.7 Hz, 1H), 6.94 (m, 1H), 6.43 (broadened s, 1H),
13
3.68 (s, 3H); C NMR (100 MHz, CDCl3)
δ 178.7, 164.1, 138.5, 135.6, 134.0, 133.2, 131.6,
130.4, 129.9, 123.8, 122.5, 110.9, 52.6; IR νmax 3100, 2843, 1727, 1646, 1489, 1415, 1361,
1284, 1246, 1088, 1075, 1039, 836, 761, 745 cm–1; MS (ESI, +ve): m/z 332 and 330
[(M+Na)+, 95 and 100%], 310 and 308 (both 6); HRMS (ESI, +ve): (M+H)+ Calcd for
C13H1179BrNO3 307.9922; Found 307.9927.
Methyl 5-Bromo-2-(5-formyl-2,3-diiodo-1H-pyrrol-1-yl)benzoate (9). A magnetically
stirred mixture of compound 8 (5.89 g, 19.2 mmol) and CF3COOAg in dry THF (80 mL)
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maintained at 0 °C under a nitrogen atmosphere was treated with molecular iodine (9.99 g,
39.3 mmol) and the resulting deepꢀred reaction mixture was warmed to 22 °C over 16 h
while being protected from light. After this time the reaction mixture was filtered through a
pad of TLCꢀgrade silica and the filtrate concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography (silica, 9:1 v/v hexane/THF elution) to
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afford, after concentration of the appropriate fractions (Rf = 0.5 in 4:1 v/v hexane/ethyl
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acetate), compound 9 (8.21 g, 77%) as an amorphous solid. H NMR (400 MHz, CDCl3)
δ
9.13 (s, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.4 and 2.3 Hz, 1H), 7.21 (s, 1H), 7.09 (d,
J = 8.4 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
176.5, 163.2, 139.4, 138.5,
136.3, 134.7, 131.8, 130.0, 129.7, 124.0, 100.2, 78.1, 52.9; IR νmax 3446, 3110, 2950, 1730,
1670, 1488, 1435, 1380, 1351, 1287, 1254, 1096, 835 cm–1; MS (ESI, +ve) m/z 584 and 582
[(M+Na)+, 100 and 97%], 562 and 560 [(M+H)+, both 33]; HRMS (ESI, +ve): (M+H)+ Calcd
79
for C13H9 Br127I2NO3 559.7855; Found 559.7855.
Methyl 5-Bromo-2-(5-formyl-2,3-bis(4-hydroxyphenyl)-1H-pyrrol-1-yl)benzoate (11). A
magnetically stirred and degassed mixture of compound 9 (1.62 g, 2.91 mmol), commercially
available boronic acid 10 (910 mg, 6.40 mmol), Pd(PPh3)2Cl2 (163 mg, 0.23 mmol) and
Na2CO3 (1.23 g, 11.64 mmol) in acetonitrile/water (75 mL of a 3:2 v/v mixture) was heated
at 60 °C for 48 h while being maintained under a nitrogen atmosphere throughout this period.
The cooled reaction mixture was passed through a pad of TLCꢀgrade silica and the filtrate
concentrated under reduced pressure. The residue thus obtained was subject to flash
chromatography (silica, 2:1 v/v hexane/ethyl acetate elution) to afford, after concentration of
the appropriate fractions (Rf = 0.3 in 1:1 v/v hexane/ethyl acetate), compound 11 (1.20 g,
1
84%) as a paleꢀyellow foam. H NMR (400 MHz, CD3OD)
δ 9.38 (s, 1H), 8.00 (d, J = 2.3
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Hz, 1H), 7.69 (dd, J = 8.3 and 2.3 Hz, 1H), 7.36 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.07 (d, J =
8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 3.69
(s, 3H) (signals due to protons of phenolic hydroxyl groups not observed); 13C NMR (100
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MHz, CD3OD)
δ 180.1, 165.6, 159.0, 157.2, 142.0, 138.7, 136.3, 134.3, 133.9, 133.6, 133.3,
132.5, 130.2, 127.1, 127.0, 124.5, 123.0, 122.3, 116.2, 116.1, 53.0; IR νmax 3315, 2954, 2873,
1732, 1712, 1636, 1612, 1457, 1434, 1419, 1258, 1230, 1159, 1100, 830, 736 cm–1; MS (ESI,
+ve) m/z 516 and 514 [(M+Na)+, 93 and 100%], 494 and 492 [(M+H)+, 20 and 19]; HRMS
(ESI, +ve): (M+Na)+ Calcd for C25H1879BrNO5Na 514.0266; Found 514.0265.
Methyl 5-Bromo-2-(5-formyl-2,3-bis(4-(methoxymethoxy)phenyl)-1H-pyrrol-1-yl)benz-
oate (12). A magnetically stirred solution of compound 11 (1.26 g, 2.57 mmol) and N,Nꢀdiꢀ
isopropylethylamine (3.32 g, 25.7 mmol) in dry dichloromethane (25 mL) maintained at 0 °C
under a nitrogen atmosphere was treated with freshly prepared MOMCl (12 mL of an 2.14 M
solution in dry dichloromethane, 25.7 mmol). The resulting lightꢀyellow reaction mixture
was warmed to 22 °C over 16 h then treated, successively, with NH4Cl (50 mL of a saturated
aqueous solution) and water (100 mL) before being extracted with ethyl acetate (3 × 100
mL). The combined organic phases were washed with brine (1 × 150 mL) then dried
(Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was
subjected to flash chromatography (silica, 4:1 v/v hexane/ethyl acetate elution) and
concentration of the appropriate fractions (Rf = 0.6 in 1:1 v/v hexane/ethyl acetate) gave
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compound 12 (1.51 g, 99%) as a paleꢀyellow foam. H NMR (400 MHz, CDCl3)
δ 9.47 (s,
1H), 8.04 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 8.4 and 2.3 Hz, 1H), 7.24 (s, 1H), 7.13 (d, J = 8.8
Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.95−6.89 (complex m, 4H), 6.81 (d, J = 8.8 Hz, 2H), 5.14
(s, 2H), 5.11 (s, 2H), 3.70 (s, 3H), 3.47 (s, 3H), 3.45 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
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178.5, 164.0, 157.4, 156.0, 139.5, 137.2, 135.3, 133.8, 132.5, 132.2, 132.0, 130.9, 129.2,
128.2, 125.2, 123.4, 123.0, 122.4, 116.2, 116.0, 94.5, 94.4, 56.3, 56.1, 52.6; IR νmax 2953,
2902, 2827, 1732, 1662, 1461, 1286, 1235, 1151, 1077, 994, 836 cm–1; MS (ESI, +ve) m/z
604 and 602 [(M+Na)+, 100 and 97%], 582 and 580 [(M+H)+, 33 and 28]; HRMS (ESI, +ve):
(M+Na)+ Calcd for C29H2679BrNO7Na 602.0790; Found 602.0794.
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Methyl 2-(2,3-bis(4-(Methoxymethoxy)phenyl)-5-(2-methylprop-1-en-1-yl)-1H-pyrrol-1-
yl)-5-bromobenzoate (13). A magnetically stirred suspension of iꢀPrPPh3I (1.44 g, 3.16
mmol) in dry THF (20 mL) maintained at −78 °C under a nitrogen atmosphere was treated
with nꢀBuLi (1.82 mL of a 1.6 M solution in hexane, 2.91 mmol), and the ensuing red
suspension stirred at −78 °C for 0.5 h before being added, over 0.17 h, to a magnetically
solution of compound 12 (1.41 g, 2.43 mmol) in dry THF (40 mL) maintained at −78 °C. The
reaction mixture thus formed was transferred to an iceꢀwater bath and maintained at ca. 0 °C
for 1 h then treated, successively, with NH4Cl (10 mL of a saturated aqueous solution) and
water (40 mL) before being extracted with ethyl acetate (3 × 50 mL). The combined organic
phases were washed with brine (1 × 100 mL) then dried (Na2SO4), filtered and concentrated
under reduced pressure. The residue thus obtained was subjected to flash chromatography
(silica, 15:1 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate
fractions (Rf = 0.6 in 4:1 v/v hexane/ethyl acetate), compound 13 (1.16 g, 79%) as a paleꢀ
1
yellow foam. H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.4 and
2.4 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.90 (m, 4H), 6.78 (d, J = 8.8
Hz, 2H), 6.45 (s, 1H), 5.49 (s, 1H), 5.14 (s, 2H), 5.11 (s, 2H), 3.64 (s, 3H), 3.48 (s, 3H), 3.46
(s, 3H), 1.97 (s, 3H), 1.77 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 164.9, 156.4, 155.3, 137.6,
135.3, 135.0, 133.6, 132.8, 132.3, 132.2(4), 132.2(0), 130.4, 129.5, 129.1, 126.0, 122.8,
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121.4, 116.1, 115.9, 114.5, 109.4, 94.7, 94.6, 56.2, 56.0, 52.6, 27.0, 20.3; IR νmax 2951, 2900,
1733, 1515, 1486, 1284, 1232, 1151, 1077, 999, 834, 731 cm–1; MS (ESI, +ve) m/z 630 and
628 [(M+Na)+, 100 and 90%], 608 and 606 [(M+H)+, 38 and 40]; HRMS (ESI, +ve): (M+H)+
Calcd for C32H3379BrNO6 606.1491; Found 606.1494.
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Methyl 5-bromo-2-(5-isobutyl-2,3-bis(4-(methoxymethoxy)phenyl)-1H-pyrrol-1-yl)benz-
oate (14). A magnetically stirred mixture of compound 13 (4.72 g, 7.80 mmol) in dry THF
(100 mL) was treated with PtO2•H2O (573 mg, 2.34 mmol) and the ensuing black suspension
stirred at 22 °C under a balloon of hydrogen for 48 h then filtered through a pad of TLCꢀ
grade silica. The filtrate was concentrated under reduced pressure and the residue subjected
to flash chromatography (silica, 9:1 v/v hexane/ethyl acetate elution) to afford, after
concentration of the appropriate fractions (Rf = 0.6 in 4:1 v/v hexane/ethyl acetate),
compound 14 (4.70 g, 99%) as a paleꢀyellow foam. 1H NMR (400 MHz, CDCl3)
δ 7.92 (d, J
= 2.4 Hz, 1H), 7.60 (dd, J = 8.4 and 2.4 Hz, 1H), 7.18−7.11 (complex m, 3H), 6.91−6.85
(complex m, 4H), 6.76 (d, J = 8.7 Hz, 2H), 6.24 (s, 1H), 5.13 (s, 2H), 5.10 (s, 2H), 3.64 (s,
3H), 3.47 (s, 3H), 3.46 (s, 3H), 2.25 (dd, J = 15.2 and 7.0 Hz, 1H), 2.16 (dd, J = 15.2 and 7.2
Hz, 1H), 1.70 (m, 1H), 0.88 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 164.8, 156.3, 155.1,
138.0, 135.2, 133.9, 133.8, 132.8, 132.3, 132.2, 130.7, 129.6, 128.9, 126.4, 122.0, 121.6,
116.1, 115.8, 107.8, 94.7, 94.6, 56.3, 56.1, 52.6, 36.3, 27.8, 22.7(8), 22.7(5); IR νmax 2952,
2899, 1737, 1515, 1486, 1283, 1233, 1151, 1078, 999, 836 cm–1; MS (ESI, +ve) m/z 610 and
608 [(M+H)+, 100 and 92%], 632 and 630 [(M+Na)+, 90 and 88]; HRMS (ESI, +ve): (M+H)+
Calcd for C32H3579BrNO6 608.1648; Found 608.1647.
Methyl (E)-5-(3,3-Diethoxyprop-1-en-1-yl)-2-(5-isobutyl-2,3-bis(4-(methoxymethoxy)-
phenyl)-1H-pyrrol-1-yl)benzoate (15). A magnetically stirred mixture of compound 14
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(647 mg, 1.06 mmol), acrolein diethyl acetal (1.38 g, 10.6 mmol), tetraꢀnꢀbutylammonium
acetate (640 mg, 2.12 mmol), K2CO3 (220 mg, 1.59 mmol), KCl (80 mg, 1.06 mmol) and
Pd(OAc)2 (120 mg, 0.53 mmol) in anhydrous DMF (10 mL) was heated at 100 °C in a sealed
tube for 48 h. The cooled reaction mixture was filtered through a pad of TLCꢀgrade silica and
the filtrate concentrated under reduced pressure. The residue thus obtained was subjected to
flash chromatography (silica, 9:1 v/v hexane/ethyl acetate elution) to afford, after
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concentration of the appropriate fractions (Rf = 0.5 in 4:1 v/v hexane/ethyl acetate),
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compound 15 (453 mg, 65%) as a clear, yellow oil. H NMR [400 MHz, (CD3)2CO]
δ 7.86
(s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.00 (d, J
= 8.5 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.80 (m, 3H), 6.36 (dd, J = 16.2 and 4.9 Hz, 1H),
6.27 (s, 1H), 5.15 (s, 2H), 5.10 (m, 3H), 3.73−3.64 (complex m, 5H), 3.55 (m, 2H), 3.43 (s,
3H), 3.39 (s, 3H), 2.33 (dd, J = 15.0 and 7.1 Hz, 1H), 2.23 (dd, J = 15.0 and 7.2 Hz, 1H),
13
1.70 (m, 1H), 1.20 (m, 6H), 0.89 (m, 6H); C NMR [100 MHz, (CD3)2CO]
δ 166.5, 157.4,
156.2, 138.9, 137.4, 134.5, 133.3, 132.8, 132.2, 131.9, 131.4, 130.7, 129.7, 129.5, 127.7,
122.6, 116.9, 116.5, 108.5, 101.9, 95.4, 95.3, 61.7, 56.3, 56.1, 52.7, 37.2, 28.6, 23.1, 15.9,
15.8; IR νmax 2853, 2898, 1719, 1515,1302, 1232, 1198, 1150, 1077, 997, 921, 837, 788 cm–
1; MS (ESI, +ve): m/z 680 [(M+Na)+, 15%], 658 [(M+H)+, 100]; HRMS (ESI, +ve): (M+H)+
Calcd for C39H48NO8 658.3380; Found 658.3389.
(E)-2-(5-Isobutyl-2,3-bis(4-(methoxymethoxy)phenyl)-1H-pyrrol-1-yl)-5-(3-oxoprop-1-
en-1-yl)benzoic acid (16). A magnetically stirred solution of compound 15 (453 mg, 0.69
mmol) in THF/water/ethanol (20 mL of a 1:1:2 v/v/v mixture) was treated with KOH (386
mg, 6.9 mmol) and the ensuing mixture stirred at 22 °C for 24 h then acidified, using HCl (2
M aqueous solution), to pH 2. The mixture thus obtained was diluted with brine (50 mL) and
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then extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed
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with brine (3 × 100 mL) before being dried (Na2SO4), filtered, and then concentrated under
reduced pressure. The residue thus obtained was subjected to flash chromatography (silica,
3:1 v/v hexane/acetone elution) to afford, after concentration of the appropriate fractions (Rf
= 0.6 in 1:1 v/v hexane/acetone), compound 16 (353 mg, 90%) as a lightꢀyellow oil. 1H NMR
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(400 MHz, CDCl3)
δ 9.71 (d, J = 7.5 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.71 (dd, J = 8.3 and
2.1 Hz, 1H), 7.45 (d, J = 16.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H),
6.91−6.84 (complex m, 4H), 6.75 (dd, J = 16.0 and 7.6 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H),
6.24 (s, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 3.46 (s, 3H), 3.41 (s, 3H), 2.29 (dd, J = 15.2 and 7.0
Hz, 1H), 2.19 (dd, J = 15.2 and 7.2 Hz, 1H), 1.66 (m, 1H), 0.85 (m, 6H) (signal due to
carboxylic acid group proton not observed); 13C NMR (100 MHz, CDCl3)
δ 193.4, 169.1,
156.3, 155.1, 150.1, 141.7, 133.6(3), 133.5(9), 132.5, 131.9, 131.8, 130.5, 130.2, 129.6,
129.0, 126.3, 122.3, 116.1, 115.9, 108.4, 94.7, 94.6, 56.2, 56.1, 36.4, 27.9, 22.7(2), 22.6(8);
IR νmax 2954, 1680, 1515, 1232, 1198, 1150, 1121, 1078, 999, 920, 837, 731 cm–1; MS (ESI,
+ve) m/z 570 [(M+H)+, 100%]; HRMS (ESI, +ve): (M+H)+ Calcd for C34H36NO7 570.2492;
Found 570.2496.
(E)-3-(3a-Isobutyl-1,2-bis(4-(methoxymethoxy)phenyl)-3,5-dioxo-3,3a-dihydro-5H-ben-
zo[d]pyrrole[2,1-b][1,3]oxazin-7-yl)acrylaldehyde (17). A magnetically stirred solution of
compound 16 (540 mg, 0.95 mmol) in dry methanol (25 mL) maintained under a nitrogen
atmosphere at 22 °C was treated with MoOPH (825 mg, 1.9 mmol). The ensuing yellowꢀ
colored reaction mixture was stirred, while being protected from light, at 22 °C for 16 h then
filtered through a pad of TLCꢀgrade silica. The filtrate was concentrated under reduced
pressure and the residue thus obtained subjected to flash chromatography (silica, 2:1 v/v
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hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions (Rf =
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6
1
0.3 in 2:1 v/v hexane/ethyl acetate), compound 17 (277 mg, 50%) as a lightꢀyellow oil. H
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8
9
NMR (400 MHz, CDCl3)
δ 9.69 (d, J = 7.5 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.50 (dd, J =
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8.8 and 2.2 Hz, 1H), 7.40 (d, J = 16.0 Hz, 1H), 7.19−7.06 (complex m, 6H), 6.88 (d, J = 8.8
Hz, 2H), 6.66 (dd, J = 16.0 and 7.5 Hz, 1H), 6.34 (d, J = 8.6 Hz, 1H), 5.26−5.21 (complex m,
2H), 5.14−5.09 (complex m, 2H), 3.53 (s, 3H), 3.44 (s, 3H), 2.35 (dd, J = 14.1 and 5.7 Hz,
1H), 1.97 (dd, J = 14.1 and 7.0 Hz, 1H), 1.83−1.71 (complex m, 1H), 0.94 (d, J = 6.7 Hz,
3H), 0.83 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 193.8, 193.2, 167.4, 161.3,
159.4, 156.5, 149.8, 139.1, 133.4, 131.7, 130.4, 130.2(9), 130.2(7), 129.3, 122.3, 122.1,
122.0, 118.4, 117.0, 116.4, 116.1, 94.6, 94.4, 91.2, 56.6, 56.2, 42.4, 24.1, 23.1; IR νmax 2959,
1740, 1702, 1679, 1607, 1498, 1389, 1237, 1152, 1121, 1079, 989 cm–1; MS (ESI, +ve) m/z
606 [(M+Na)+, 90%], 584 [(M+H)+, 100]; HRMS (ESI, +ve): (M+H)+ Calcd for
C34H33NO8Na 606.2104; Found 606.2107.
Potassium [1-(tert-Butoxycarbonyl)-1H-indol-3-yl]trifluoroborate (18). Following a
procedure reported by Aggarwal,16 a magnetically stirred mixture of 3ꢀBpinꢀNꢀBocꢀindole17
(9.60 g, 28 mmol) in methanol/THF (90 mL of a 7:2 v/v mixture) was treated, dropwise at 0
°C, with a solution of KHF2 (9.93 g, 126 mmol) in water (33 mL) and the ensuing white
suspension was stirred at 20 °C for 3 h then concentrated under reduced pressure. The residue
thus obtained was reꢀdissolved in methanol/water (50 mL of a 1:1 v/v mixture) and all the
volatile materials were again removed under reduced pressure. This evaporationꢀdissolution
cycle was repeated a further four times and the white solid thereby obtained was treated with
acetone (100 mL) and ensuing mixture then filtered (through filter paper) and the filtrate soꢀ
obtained concentrated under reduced pressure. The resulting solid was then dried over P2O5
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for 16 h to afford compound 1812 (8.99 g, 99%) as a colorless solid, m.p. = 168ꢀ176 °C. H
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4
5
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7
8
NMR (400 MHz, (CD3)2CO)
δ 8.03 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.33 (s,
1H), 7.11 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 1.64 (s, 9H); 13C NMR [100 MHz,
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(CD3)2CO]
δ
150.7, 137.0, 136.6, 127.7, 123.8, 122.9, 121.9, 114.8, 82.5, 28.2 (one signal
3.48; 19F NMR (376 MHz,
obscured or overlapping); 11B NMR (128 MHz, (CD3)2CO)
δ
(CD3)2CO)
δ −138.3; IR νmax 2984, 1724, 1706, 1455, 1370, 1250, 1161, 1127, 1084, 983,
928, 900, 754 cm–1; MS (ESI, +ve) m/z 362 [(M+K)+, 100%]; HRMS (ESI, +ve): (M+K)+
Calcd for C13H14BF3NO2K 362.0344; Found 362.0340.
tert-Butyl
3-((1R)-1-(3a-Isobutyl-1,2-bis(4-(methoxymethoxy)phenyl)-3,5-dioxo-3,3a-
dihydro-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-7-yl)-3-oxopropyl)-1H-indole-1-carboxyl
-ate (19). A magnetically stirred mixture of compound 17 (41 mg, 0.07 mmol), (R)ꢀ3,3’ꢀ
(C7F7)2ꢀBINOL (25 mg, 0.035 mmol), compound 18 (68 mg, 0.21 mmol) and molecular
sieves (200 mg of 4 Å powdered material) in dry toluene (3 mL) was heated at 80 °C in a
sealed tube for 48 h. The cooled reaction mixture was filtered through a pad of TLCꢀgrade
silica and the filtrate concentrated under reduced pressure. The residue thus obtained was
subjected to flash chromatography (silica, 2:1 v/v hexane/ethyl acetate elution) to afford,
after concentration of the appropriate fractions (Rf = 0.2 in 2:1 v/v hexane/ethyl acetate),
compound 19 (45 mg, 80%) as a 1:1 mixture of diastereoisomers and as a clear, lightꢀyellow
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oil, [α]D = +60 (c 0.3, CHCl3). H NMR (400 MHz, CDCl3)
δ 9.81 (s, 1H), 8.19−8.03
(complex m, 2H), 7.49 (s, 1H), 7.34−6.99 (complex m, 10H), 6.88 (m, 2H), 6.28 (m, 1H),
5.27−5.17 (complex m, 2H), 5.11 (m, 2H), 4.80 (m, 1H), 3.57−3.49 (complex m, 3H), 3.46
(m, 3H), 3.42−3.07 (complex m, 2H), 2.32 (m, 1H), 2.00−1.87 (complex m, 1H), 1.77−1.66
(complex m, 10H), 0.96−0.90 (complex 3H), 0.84−0.77 (complex m, 3H); 13C NMR (100
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MHz, CDCl3) δ 199.9, 199.8, 194.1(0), 194.0(7), 168.5(3), 168.5(1), 161.9, 161.8, 159.1,
156.2, 149.7, 139.4(2), 139.3(6), 136.2, 136.1, 135.9, 134.7, 134.5, 130.6, 130.3, 130.2,
130.1, 129.7(1), 129.6(5), 129.2(0), 129.1(5), 124.9, 122.9, 122.8(4), 122.7(8), 122.6(2),
122.6(0), 122.4, 122.3, 122.2, 122.0, 121.7, 121.6, 119.3(3), 119.2(7), 118.2, 118.1, 116.8,
116.7, 116.0, 115.6(0), 115.5(7), 115.2(8), 115.2(7), 94.5(4), 94.5(2), 94.4, 91.3, 91.2, 84.2,
56.5, 56.1, 49.0, 48.9, 42.1, 42.0, 35.9, 35.8, 29.8, 28.3, 24.0, 23.9, 23.1; MS (ESI, +ve) m/z
801 [(M+H)+, 100%]; HRMS (ESI, +ve): (M+H)+ Calcd for C47H49N2O10 801.3387; Found
801.3381.
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tert-Butyl 3-((1R,2S)-2,3-Dihydroxy-1-(3a-isobutyl-1,2-bis(4-(methoxymethoxy)phenyl)-
3,5-dioxo-3,3a-dihydro-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-7-yl)propyl)-1H-indole-1-
carboxylate (20). A magnetically stirred mixture of compound 19 (67 mg, 0.083 mmol) and
nitrosobenzene (8.9 mg, 0.083 mmol) in acetonitrile (0.5 mL) was cooled to 4 °C then treated
with Dꢀproline (2.9 mg, 0.025 mmol). The ensuing and initially greenꢀcolored mixture was
stirred at 4 °C for 6 h during which time the color of the mixture turned to yellow (and thus
marking the endꢀpoint of the αꢀaminoxylation reaction) and at which stage it was diluted
with 1,2ꢀdichloroethane (2 mL) and treated with NaBH(OAc)3 (145 mg, 0.66 mmol). The
resulting yellow suspension was stirred at 22 °C for 16 h then treated, successively, with
NaHCO3 (2 mL of a saturated aqueous solution) and water (10 mL) before being extracted
with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine (1 x 30
mL) then dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus
obtained was dissolved in dry dichloromethane (2 mL) and the resulting solution cooled to 4
°C before being treated with nitrosobenzene (17 mg, 0.16 mmol). The ensuing greenꢀcolored
was mixture was stirred at 4 °C for 4 h and then subjected to flash chromatography (silica,
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2:3 v/v hexane/ethyl acetate elution) to afford, after concentration of the appropriate fractions
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(Rf = 0.2 in 1:1 v/v hexane/ethyl acetate), compound 20 (24.7 mg, 36%) as a clear, yellow oil
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and a 1:1 mixture of diastereoisomers, [α]D = −29 (c 0.2, CHCl3). H NMR (600 MHz,
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CD3OD) 8.13 (d, J = 2.1 Hz, 0.5H), 8.11 (d, J = 2.1 Hz, 0.5H), 8.10 (m, 1H), 7.77 (s,
δ
0.5H), 7.75 (s, 0.5H), 7.51 (m, 0.5H), 7.49 (m, 0.5H), 7.38 (d, J = 7.9 Hz, 0.5H), 7.35 (d, J =
7.8 Hz, 0.5H), 7.26 (m, 1H), 7.19−7.12 (complex m, 3H), 7.08 (m, 1H), 7.05−7.01 (complex
m, 3H), 6.86 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.38 (d, J = 8.5 Hz, 0.5H), 6.36 (d,
J = 8.5 Hz, 0.5H), 5.23 (s, 1H), 5.19 (m, 1H), 5.11 (s, 2H), 4.42−4.36 (complex m, 2H),
3.52−3.45 (complex m, 2H), 3.48 (s, 1.5H), 3.44 (s, 1.5H), 3.40 (s, 3H), 2.22−2.14 (complex
m, 1H), 2.04−1.93 (complex m, 1H), 1.80−1.71 (complex m, 1H), 1.69 (s, 4.5H), 1.68 (s,
4.5H), 0.93 (d, J = 6.7 Hz, 1.5H), 0.92 (d, J = 6.7 Hz, 1.5H), 0.82 (d, J = 6.7 Hz, 1.5H), 0.81
13
(d, J = 6.7 Hz, 1.5H) (signals due to hydroxyl group protons not observed); C NMR (150
MHz, CD3OD)
δ 196.3(1), 196.2(9), 172.1(0), 172.0(9), 163.5, 163.4, 160.7, 160.6, 157.7,
151.1, 139.6(2), 139.5(7), 137.6, 137.5, 137.0, 132.5, 132.4, 131.6, 131.5, 131.4, 131.2,
125.6, 124.3, 124.1, 123.5(9), 123.5(7), 123.4(2), 123.3(8), 123.1, 122.9, 122.8, 122.7, 120.4,
120.3, 118.8(2), 118.7(9), 117.7(1), 117.6(7), 116.9, 116.2(0), 116.1(8), 116.1(5), 116.1,
95.5(0), 95.4(7), 95.4, 92.7, 92.6, 85.0, 74.4, 74.2, 65.6, 65.5, 56.5(9), 56.5(6), 56.2, 45.0,
43.0, 42.9, 28.4(3), 28.4(2), 25.2, 25.1, 24.2(1), 24.1(7), 23.5(1), 23.4(9); IR νmax 3449, 2925,
1735, 1611, 1499, 1453, 1371, 1240, 1155, 1080, 996 cm–1; MS (ESI, +ve) m/z 841
[(M+Na)+, 100%]; HRMS (ESI, +ve): (M+Na)+ Calcd for C47H50N2O11Na 841.3312; Found
841.3312.
7-((1R,2S)-2,3-Dihydroxy-1-(1H-indol-3-yl)propyl)-1,2-bis(4-hydroxyphenyl)-3a-isobut-
yl-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazine-3,5(3aH)-dione (Discoipyrrole D, 4).
A
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magnetically stirred solution of compound 20 (24.5 mg, 0.03 mmol) in dichloromethane (2
mL) was treated with trifluoroacetic acid (460 ꢀL, 6 mmol) and the ensuing brownꢀcolored
reaction mixture was stirred at 22 °C for 2 h before being treated, successively, with
NaHCO3 (1 × 2 mL of a saturated aqueous solution) and water (1 × 10 mL) and then
extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with
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brine (1 × 30 mL) then dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue thus obtained was dissolved in THF (2 mL), the resulting solution treated with
HCl (2 mL of a 4.0 M aqueous solution) and the mixture thus obtained stirred at 22 °C for 3
h before being diluted with NaHCO3 (2 mL of a saturated aqueous solution) and water (10
mL) then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were
washed with brine (1 × 30 mL) then dried (Na2SO4), filtered and concentrated under reduced
pressure. The yellow oil thus obtained was subjected to flash chromatography (silica, 12:1
v/v ethyl acetate/isopropanol elution) and thus affording, after concentration of the
appropriate fractions (Rf = 0.6), compound 4 (11 mg, 60%) as a clear, lightꢀyellow oil and a
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1:1 mixture of diastereoisomers, [α]D = +25 (c 0.2, MeOH). For the purposes of
spectroscopic analysis, a portion of this material was subjected to further purification by
reversed phase HPLC using 3:7 v/v acetonitrile/water as the eluting solvent at a flow rate of 1
1
mL/min. H NMR (800 MHz, CD3OD)
δ 8.13 (d, J = 2.1 Hz, 0.5H), 8.10 (d, J = 2.1 Hz,
0.5H), 7.52 (td, J = 8.8 and 2.1 Hz, 1H), 7.42 (d, J = 8.0 Hz, 0.5H), 7.40 (d, J = 8.0 Hz,
0.5H), 7.33 (d, J = 8.1 Hz, 0.5H), 7.32 (d, J = 8.1 Hz, 0.5H), 7.31 (s, 0.5H), 7.30 (s, 0.5H),
7.07 (m, 1H), 7.05⎯7.02 (complex m, 2H), 6.97⎯6.90 (complex m, 3H), 6.82 (d, J = 8.9 Hz,
1H), 6.80 (d, J = 8.8 Hz, 1H), 6.62 (dm, J = 8.8 Hz, 1H), 6.61 (dm, J = 8.8 Hz, 1H), 6.39 (d,
J = 8.5 Hz, 0.5H), 6.38 (d, J = 8.5 Hz, 0.5H), 4.43⎯4.40 (complex m, 1H), 4.36 (d, J = 8.1
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Hz, 0.5H), 4.35 (d, J = 8.1 Hz, 0.5H), 3.56 (m, 1H), 3.45 (complex m, 1H), 2.15 (m, 1H),
1.99 (m, 0.5 H), 1.95 (m, 0.5 H), 1.73 (m, 1H), 0.91 (t, J = 6.4 Hz, 3H), 0.80 (d, J = 6.7 Hz,
3H) (signals due to OH and NH group protons not observed); 13C NMR (200 MHz, CD3OD)
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δ
196.6, 196.5, 172.4(4), 172.4(2), 163.8, 161.0(6), 161.0(5), 157.6, 141.8(4), 141.8(1),
137.9(8), 137.9(6), 137.3, 137.2, 136.5, 132.0, 131.9, 131.6, 131.4, 128.0, 123.3(2), 123.3(1),
122.9(2), 122.8(7), 122.5(9), 122.5(8), 121.8, 121.0(6), 121.0(5), 119.8(3), 119.8(2),
119.5(4), 119.5(0), 118.6, 118.5, 116.8(8), 116.8(6), 116.7(4), 116.6(7), 116.1, 116.0, 115.9,
112.4, 112.3, 92.6(4), 92.6(2), 75.3, 75.1, 66.1, 66.0, 46.1(2), 46.0(9), 42.9(6), 42.9(5), 25.2,
24.2(2), 24.1(9), 23.4(2), 23.4(0) (seventeen signals obscured or overlapping); IR νmax 3364,
2959, 2927, 1720, 1612, 1498, 1387, 1273, 1240, 1172, 1070, 1042 cm–1; MS (ESI, +ve) m/z
653 [(M+Na)+, 40%], 631 [(M+H)+, 100]; HRMS (ESI, +ve): (M+H)+ Calcd for C38H35N2O7
631.2444; Found 631.2441.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.XXXXXXX. Tabular comparison of the 13C NMR data reported for
discoipyrrole D with those recorded on the synthetically derived compound 4. H and 13C
1
NMR spectra of compounds 7ꢀ9, 11ꢀ20 and 4 (PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: Martin.Banwell@anu.edu.au.
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
We thank the Australian Research Council for financial support. Y.Z. is the grateful recipient
of a PhD Scholarship provided by the China Scholarship Council of the People’s Republic of
China. Dr Hideki Onagi is thanked for his expert assistance with HPLC purifications and
analyses.
REFERENCES
1. Hu, Y.; Potts, M. B.; Colosimo, D.; HerreraꢀHerrera, M. L.; Legako, A. G.;
Yousufuddin, M.; White, M. A.; MacMillan, J. B. J. Am. Chem. Soc. 2013, 135,
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9. Banwell, M. G.; Zhang, Y. Modular Synthesis of Discoipyrrole Type Alkaloids and
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