A formal approach to the cyanobacterial sunscreen indole, prenostodione

Article abstract of DOI:10.24820/ark.5550190.p010.464

The synthesis of the indole sunscreen pigment prenostodione was attempted via an LDA-initiated condensation of N-carbamate indole-2-methyl ester 22 with 4-[(t-butyldimethylsilyl)oxy]benzaldehyde (14) and a late-stage Vilsmeier-Haack formylation. Difficulties with the ensuing oxidation required installation of a C-3 carboxylic acid necessitating the use of a recently reported protocol and thus a formal synthesis of the natural product was realized from 2-aminobenzyl alcohol (17) in nine steps.

Full text of DOI:10.24820/ark.5550190.p010.464

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Organic Chemistry
Arkivoc 2018, part iv, 183-194
A formal approach to the cyanobacterial sunscreen indole, prenostodione
Ilene L. Green, Jason J. Jordan, and Jeanese C. Badenock*
Department of Biological and Chemical Sciences, University of the West Indies, Cave Hill, Barbados
Email: jeanese.badenock@cavehill.uwi.edu
Dedicated to Dr. Gordon W. Gribble in recognition of his outstanding contributions to the field of indole
chemistry
Received 12-31-2017
Accepted 03-15-2018
Published on line 04-07-2018
Abstract
The synthesis of the indole sunscreen pigment prenostodione was attempted via an LDA-initiated
condensation of N-carbamate indole-2-methyl ester 22 with 4-[(t-butyldimethylsilyl)oxy]benzaldehyde (14)
and a late-stage Vilsmeier–Haack formylation. Difficulties with the ensuing oxidation required installation of a
C-3 carboxylic acid necessitating the use of a recently reported protocol and thus a formal synthesis of the
natural product was realized from 2-aminobenzyl alcohol (17) in nine steps.
Keywords: Prenostodione, isoprenostodione, scytonemin, cyanobacteria, Pinnick–Lindgren oxidation
DOI: https://doi.org/10.24820/ark.5550190.p010.464
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Introduction
The ubiquitous indole skeleton continues to feature prominently in alkaloids isolated from diverse terrestrial
and marine sources.1-2 One such source of novel, and in many cases bioactive, indole-based isolates is
cyanobacteria.3-5 These oxygenic photoautotrophic prokaryotes, commonly referred to as blue-green algae,
date back as far as 3.5 billion years6 and adopt filamentous, unicellular, or aggregated morphologies generally
reflective of the habitats to which they have adapted.7-8
From those alkaloids reported in the last few decades, members of the classes of hapalindoles,9-21
fischerindoles,9,17-18,22 ambiguines,23,36-37 and welwitindolinones9,18,22,25-29 have received significant attention
from the synthetic community, with over 10 groups rendering total or formal protocols – many with
enantioselective precision – since their first isolation in 1984.30 The sunscreen indole pigments scytonemin
(1),31 nostodione A (2),32-34 and prenostodione (3),33 isolated from a variety of cyanobacterial species including
Scytonema sp., Nostoc sp., and Scytonema hofmanni, however, have not garnered the same level of interest.
While a few total syntheses of these three species are available,35-39 the focus has been on the exploration of
their bioactivity and their enzymatically determined biosynthetic pathways.40-48 More interestingly, the
syntheses of four recently isolated and structurally-related derivatives – scytonine (4), dimethoxyscytonemin
(5), tetramethoxyscytonemin (6),49 and scytonemin-3a-imine (7)50 – remain unreported (Figure 1).
OH
O
CO2H
CO2Me
CO2Me
N
HN
O
O
N
H
N
H
O
H
MeO2C
O
N
H
N
HO
H
HO
OH
HO
1
2
3
4
OH
HO
HO
OMe
OMe
MeO
O
N
N
MeO
O
N
O
O
O
O
N
N
H
N
OMe
MeO
HN
HO
OH
HO
5
6
7
Figure 1. Cyanobacterial alkaloids of interest.
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Driven by our desire to access scytonemin (1) we sought an initial approach to prenostodione (3),
proposed by Pluotno and Carmeli33 to be the precursor of both nostodione A (2) and scytonemin (1). This
indole-3-carboxylic acid derivative is substituted with a p-hydroxybenzylidene group appended at the C-2
position of the indole and was determined to have E-geometry around the exocyclic double bond. We herein
outline our endeavors towards this target compound along with the interesting detours which resulted in a
synthesis of an isomer of the natural product, dubbed isoprenostodione (13).51
Results and Discussion
A previous account described our initial strategy, which was centered on the installation of the vinyl
appendage at the methylene position of an indole diester, and revealed a correlation between the choice of
ester and the geometry observed in the coupling.52 The indole methyl diester 10, accessed via a Fischer indole
synthesis, was therefore smoothly converted into vinyl indole 12 after reaction with 4-[(TBS)oxy]benzaldehyde
(14) in the presence of base – LDA then CaH2. A final selective hydrolysis, though not without precedent,53
proved problematic in this system and regrettably dimethyl ester 12 underwent cleavage at the C-2 position
rather than at the intended C-3 site (Scheme 1).
O
Me
CO2Me
CO2Me
O
ii, iii
i
.
CO2Me
NH2 HCl
O
N
N
Bn
Bn
8
9
10
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2H
iv
v
N
N
H
N
H
Boc
H
H
TBSO
HO
11
12
13
Scheme 1. Reagents and Conditions: i. MeOH, , 12 h (57%); ii. AlCl3, PhH, , 0.5 h (85%); iii. Boc2O, DMAP,
THF, rt (100%); iv. n-BuLi, ((CH3)2CH)2NH, 4-TBSOC6H4CHO (14), -78 °C; CaH2, , 1 h (46%); v. KOH, MeOH, ,
4 h (23%).
This disappointing result caused us to consider a new approach which was aimed at introducing the C-3
acid in the terminal stages of the synthesis. Furthermore, it was envisioned that, when used in tandem with
the base-catalyzed coupling protocol54 used in our previous attempt at prenostodione (3),51 a late-stage
Vilsmier–Haack formylation55 could introduce an oxidizable C-3 formyl group (Scheme 2).
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Green, I. L. et al.
CO2H
CO2Me
CHO
CO2Me
CO2Me
N
H
N
H
N
H
TBSO
HO
3
15
16
Scheme 2. Revised retrosynthetic strategy to prenostodione (3).
Consequently, treatment of 2-aminobenzyltriphenylphosphonium bromide (18), obtained from reaction of
commercially obtained 2-aminobenzyl alcohol (17) and triphenylphosphonium hydrogen bromide, with methyl
malonyl chloride, resulted in the isolation of 1,3-dicarbonyl intermediate 19 as a white powder in 79% yield.56
Construction of the indole ring was realized when 19 was treated with slightly more than stoichiometric
amounts of potassium tert-butoxide resulting in indole ester 16 – the product of an intramolecular Wittig
condensation (Scheme 3).57
PPh3Br
i.
PPh3Br
NH2
O
O
OH
NH2
ii.
iii.
CO2Me
N
H
OMe
N
H
16
17
18
19
Scheme 3. Reagents and Conditions: i. PPh3•HBr, CH3CN (88%); ii. MeO2CCH2COCl, CH2Cl2, 3 h (79%); iii. 1.1 eq.
KOt-Bu, PhMe, , 6 h (74%).
With sights firmly set on accessing vinyl indole 15, a Vilsmeier Haack formylation of indole 16 resulted in 3-
formylindole derivative 20 but suffered from low yields after purification. Resultantly, and notwithstanding the
successful conversion of 20 to the N-Boc-indole 21, the order of the installation of the functional groups was
re-engineered with a view to improving the product yields. Accordingly, coupling of t-butoxycarbamate 22,
obtained by protection of indole 16 in almost quantitative yield, with 4-[(TBS)oxy]benzaldehyde (14), in the
presence of LDA and NaH, led to the isolation of alkene 23 as a yellow solid in 44% yield as outlined in Scheme
4. Although alkene 23 was observed to undergo rapid decomposition in deuterated chloroform, we were able
to confirm its identity using NMR spectroscopy. Moreover, 2D NOESY and 1D NOE experiments, conducted on
23, did not reveal any correlation between the NH proton (8.41) and the vinyl proton at7.85 and
consequently gave support to the assignment of an E-geometry at the exocyclic double bond.58
The introduction of the C-3 aldehyde via Vilsmeier–Haack formylation, this time in the absence of an alkali
in the hydrolysis step,59 also resulted in the cleavage of the silyl ether functional group and therefore
completion of the strategy would have only required oxidation of the aldehyde to a carboxylic acid (Scheme
5). Unfortunately, a carboxylic acid did not result from reaction under Pinnick–Lindgren oxidation
conditions,60,61 nor upon using other oxidants such as AgNO3, KMnO4, and DDQ. During the ensuing lull in
progression, we were fatefully made aware of a recent paper by Biswas et al. which outlined the conversion of
methyl 2-(3-formyl-1H-indole-2-yl)acetate into prenostodione (3).37 Their approach, while synthetically
unmatched, was strikingly similar to our proposed route and involved the coupling of methyl ester aldehyde
20 with p-hydroxybenzaldehyde, in the presence of the catalyst L-proline, to generate aldehyde 24. There was
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Green, I. L. et al.
also a notable absence of a direct oxidation protocol which was indicative of the incompatibility of the indole
NH and/or the phenol OH with oxidation conditions.
CHO
CO2Me
CHO
CO2Me
ii.
i.
N
N
H
Boc
20
21
CO2Me
N
H
iii.
16
iv.
CO2Me
CO2Me
N
N
H
Boc
TBSO
22
23
Scheme 4. Reagents and Conditions: i. POCl3, DMF, 0 °C, 1 h; NaHCO3, NaOH (33%); ii. Boc2O, DMAP, THF, rt
(65%); iii. Boc2O, DMAP, THF, rt (96%); iv. LDA, 4-TBSOC6H4CHO (14), THF -78 °C, 1 h; NaH, , 2 h (44%).
Given this regretful turn of events, we decided to complete a formal synthesis of prenostodione (3) using
this reported protocol37 and reprotected both the -NH and -OH functional groups, by stirring aldehyde 24 with
2.5 equivalents of Boc2O in the presence of catalytic amounts of DMAP at room temperature for 4 hours
(Scheme 5). The ensuing Pinnick–Lindgren oxidation required the sequential addition of sodium chlorite and
monosodium phosphate to the heterogeneous mixture of aldehyde 25 and sulfamic acid in t-BuOH/H2O, and
afforded di-Boc-acid 26 as a pale yellow solid in 87% yield (over 2 steps). The identity of 26 was confirmed by
1
the disappearance of the aldehyde signals found at  9.81 and  186.7 in H- and 13C-NMR spectra,
respectively. In a final effort to secure the coveted natural product prenostodione (3), diBoc-acid 26 was
treated with TFA in CH2Cl2 at 0 °C to facilitate deprotection and the natural product was obtained as a yellow
oil, albeit in a modest 24% yield. The NMR spectra of the synthetic product were comparable to literature
values for the natural product but revealed minor deviations from those of isoprenostodione (13) previously
reported (Table 1).33
CHO
CO2Me
CHO
CO2Me
i.
ii.
CO2Me
N
H
N
H
N
Boc
TBSO
BocO
HO
23
24
25
CO2H
CO2Me
CO2H
iii.
iv.
CO2Me
N
H
N
Boc
HO
BocO
3
26
Scheme 5. Reagents and Conditions: i. POCl3, DMF, ∆, 1 h (79%); ii. Boc2O, DMAP, CH2Cl2, rt (100%); iii.
NH2SO3H, NaClO2, NaH2PO4, t-BuOH/H2O (3:1), rt, 8 h (87%); iv. TFA, CH2Cl2, 0 °C, 8 h (24%).
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Green, I. L. et al.
1
Table 1. Comparison of H- and 13C-NMR data for the naturally occurring prenostodione (3) (N.P.), synthetic
prenostodione (S.P.) and isoprenostodione (13) (I.P)33,51
8
8
7
4
7
4
CO2H
CO2Me
7a
7b
7a
7b
6
5
6
5
1
1
2a
2a
3
3
CO2Me
CO2H
3a
3a
N
N
2
9
2
15 H
15 H
9
14
14
10
11
10
11
13
13
HO
HO
12
12
3
13
Position
N.P. (C)a
166.9
52.1
S.P. (C)b
166.8
52.0
I.P. (C)a
167.8
50.8
N.P. (H)a
S.P. (H)b
I.P. (H)a
1
1-OMe
2
3.63 s
3.64 s
11.84
3.69 s
120.4
139.3
120.3
139.2
120.5
140.9
2a
3
11.82 s
11.93 s
3a
135.8
112.1
135.7
112.0
135.8
112.2
7.37 d
(8.8 Hz)
7.37-7.38 d 7.38 -7.41
(6.7 Hz)
4
m
5
6
122.5
121.2
122.4
121.1
122.8
121.1
7.20 m
7.18 m
7.18-7.20 7.22-7.18 d
(8.0 Hz)
m
8.03 d
(8.7 Hz)
8.04-8.05 d 8.03-8.00 d
7
121.2
121.1
121.6
(6.7 Hz)
(8.7 Hz)
7a
7b
8
127.1
105.8
165.8
142.3
124.8
127.0
105.7
165.7
142.1
124.7
126.7
104.8
165.0
141.9
125.1
9
7.78 s
7.79 s
7.77 s
10
6.84 d
(8.7 Hz)
6.58 d
6.84-6.85 6.84-6.81 d
d (8.3 Hz) (8.6 Hz)
6.58-6.59 d 6.60-6.57 d
11, 15
12, 14
132.3
132.2
132.2
115.8
159.6
115.6
159.4
115.8
159.4
(8.7 Hz)
(8.3 Hz)
(8.6 Hz)
13
13-O
9.99 s
10.05 s
10.04 s
a NMR experiments conducted in DMSO-d6; b NMR experiments conducted in CDCl3
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Conclusions
We have completed a formal synthesis of prenostodione (3) in nine steps from commercially available 2-
aminobenzyl alcohol. Efforts geared towards improving the yield of the hydrolysis step and developing
synthesis of other similar indole pigments continue in our laboratory.
Experimental Section
General. Melting points were determined on a Sanyo Gallenkamp capillary melting point apparatus, in open
capillaries and are uncorrected. Thin layer chromatography (TLC) was performed on Whatman brand 20 x 20
cm aluminum backed silica plates with fluorescent indicator. Plates were visualized by 254 nm UV light. Flash
chromatography was carried out using Silicycle ultra-pure silica gel 60 Å (230 - 400 mesh). Preparative TLC
1
(PTLC) was performed with Merck precoated TLC plates silica gel 60 F254. 1H (300 MHz), H (600 MHz), 13C (75
MHz), 13C (150 MHz) NMR spectra were recorded on Bruker-300 and -600 Fourier transform spectrometers.
The chemical shifts are reported in  (ppm) using the  7.26 signal of CDCl3 (1H-NMR) and the  77.16 signal of
CDCl3 (13C-NMR), the  2.50 signal of (CD3)2SO (1H-NMR) and the  39.50 signal of (CD3)2SO (13C-NMR).
Ultraviolet (UV) spectra were recorded on a Hewlett-Packard 8451A Diode Array UV spectrophotometer and
are reported in nanometers. Infrared spectra (IR) were recorded on a Shimadzu IR Affinity-1 FTIR
spectrophotometer and are referenced to the 1601 cm-1 band of polystyrene. IR spectra were obtained using
solid potassium bromide pellets (KBr) and are reported in reciprocal centimeters.
[2-(Methoxycarbonylacetamido)benzyl]triphenylphosphonium bromide (19). Methyl malonyl chloride (1.02
mL, 1.29 g, 9.48 mmol, 1 eq.) was added to a stirring solution of 2-aminobenzyltriphenylphosphonium
bromide (18) (4.12 g, 9.48 mmol, 1 eq.) in CH2Cl2 (20 mL). After 3 h, the solvent was removed and the residue
was recrystallized from hot MeOH to give phosphonium bromide 19 (4.10 g, 79%) as a white solid; mp 235 °C
1
(dec) (lit.62 mp 238-239 °C); H-NMR (300 MHz, CDCl3)  10.44 (s, 1H), 7.60-7.80 (m, 17H), 6.81-6.86 (m, 1H),
6.70-6.74 (m, 1H), 5.46-5.51 (d, J 14.4 Hz, 2H), 3.65 (s, 3H), 3.52 (s, 2H); 13C-NMR (75 MHz, CDCl3)  168.6,
165.5, 138.0, 135.2, 134.4, 131.6, 130.3, 129.3, 127.2, 125.3, 120.1, 118.4, 117.3, 52.1, 43.4. IR  (KBr) 3433,
3101, 1744, 1682, 1435, 1242, 1157, 1111, 748 cm-1; UV max (MeOH) 204, 241, 292 nm.
Methyl 2-(1H-indol-2-yl)acetate (16). Potassium tert-butoxide (835 mg, 7.44 mmol, 1.1 eq.) was added to a
stirring suspension of phosphonium bromide 19 (3.71 g, 6.77 mmol, 1 eq.) in toluene (17 mL) at reflux. After 6
h, the reaction was poured onto H2O and stirred for a further 10 min. The mixture was extracted with CH2Cl2
(3 x 30 mL) and the organic extracts were combined, washed with brine (1 x 30 mL), dried (MgSO4) and
concentrated in vacuo. Purification by flash chromatography (2:1 hexanes : EtOAc) gave the desired indole 16
(947 mg, 74%) as a pale yellow solid: mp 65-67 °C (lit.62 mp 68-69 °C); 1H-NMR (300 MHz, CDCl3)  8.64 (s, 1H),
7.54-7.56 (d, 1H, J 7.74 Hz), 7.34-7.37 (d, 1H, J 7.98 Hz), 7.06-7.19 (m, 2H), 6.36 (s, 1H), 3.85 (s, 2H), 3.76 (s,
3H); 13C-NMR (75 MHz, CDCl3)  171.1, 136.5, 130.5, 128.3, 121.9, 120.3, 120.0, 110.9, 102.0, 52.5, 33.9; IR 
(KBr) 3356, 2847, 1728, 1543, 748 cm-1; UV max (MeOH) 219, 271, 290, 389 nm.
tert-Butyl 2-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (22). To a solution of indole 16 (499 mg, 2.63
mmol, 1 eq.) in dry THF (17 mL) was added DMAP (14.9 mg, 0.122 mmol, 0.05 eq.) and di-tert-butyl
dicarbonate (637 mg, 2.92 mmol, 1.1 eq.) with stirring. The reaction was allowed to stir at rt overnight before
being poured onto ice H2O (20 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL) and the organics were
combined, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (1:2 hexanes :
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1
EtOAc) gave the protected indole 22 (0.735 g, 96%) as a pale yellow solid: mp 52-55 °C; H-NMR (300 MHz,
CDCl3)  8.07-8.10 (d, J 7.8 Hz, 1H), 7.46-7.49 (m, 1H), 7.16-7.29 (m, 2H), 6.45 (s, 1H), 4.03 (s, 2H), 3.69 (s, 3H),
1.64 (s, 9H); 13C-NMR (75 MHz, CDCl3)  170.9, 150.6, 136.7, 133.3, 128.9, 124.1, 122.9, 120.4, 115.8, 110.5,
84.4, 52.1, 36.3, 28.2; IR  (KBr) 3449, 1736, 1381, 1327, 748 cm-1; UV max (MeOH) 259, 282 nm.
(E)-Methyl 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-(1H-indol-2-yl)acrylate (23). To a stirred solution of
LDA (0.74 mL, 1.50 mmol, 1.5 eq., 2.0 M in hexanes) in dry THF (4 mL) at -75 °C was added a solution of ester
22 (286 mg, 0.99 mmol, 1 eq.) in dry THF (4 mL). The mixture stirred for 45 min before adding a solution of
siloxy benzaldehyde 14 (260 mg, 1.10 mmol, 1.1 eq.) in dry THF (2 mL) and further stirred for 1 h at -75 °C
before allowing the mixture to warm to rt slowly. NaH (27.8 mg, 1.2 mmol, 1.2 eq.) was added and the
reaction mixture was stirred at reflux for 1 h. The solution was allowed to cool and poured onto H2O (25 mL)
with stirring. The aqueous mixture was extracted with CH2Cl2 (3 x 25 mL), and the combined organic extracts
were washed with brine (1 x 25 mL), dried (MgSO4) and concentrated in vacuo. Column chromatography (5:1
hexanes : EtOAc) gave the desired alkene 23 (177 mg, 44%) as a yellow oil. Further purification by PTLC (5:1
1
hexanes : EtOAc) afforded a amorphous solid which was analyzed by HRMS: mp 68-70 °C; H-NMR (600 MHz,
CDCl3)  8.41 (s, 1H), 7.86 (s, 1H), 7.58-7.60 (m, 1H), 7.33-7.34 (m, 1H), 7.18-7.20 (m, 1H), 7.14-7.15 (d, 2H, J
8.66 Hz) 7.10-7.13 (m, 1H), 6.68-6.70 (d, 2H, J 8.66 Hz) 6.56-6.57 (m, 1H) 3.84 (s, 3H), 0.96 (s, 9H), 0.19 (s, 6H);
13C-NMR (150 MHz, CDCl3)  168.1, 157.4, 142.2, 136.2, 132.0, 131.3, 128.5, 127.6, 122.4, 121.4, 121.0, 120.3,
120.0, 111.2, 104.7, 52.6, 25.7, 18.3, -4.3; IR  (KBr) 3441, 1636, 1250, 1142, 902 cm-1; UV max (MeOH) 350,
300, 288 nm. HRMS calcd for C24H29NO3Si (M+ +H) 408.1995. Found 408.2008.
(E)-methyl 2-(3-formyl-1H-indol-2-yl)-3-(4-hydroxyphenyl)acrylate (24). POCl3 (0.109 g, 0.07 mL, 0.712 mmol,
1.2 equiv.) was added to DMF (0.052 g, 0.05 mL, 0.71 mmol, 1.2 equiv.) and after stirring for 15 min, alkene 23
(0.242 g, 0.595 mmol, 1 equiv.) in 1,2-dichloroethane (7 mL) was added. The reaction was heated to reflux for
1 h before it was poured onto an aqueous solution (1 mL) of NaOAc (0.464 g, 5.64 mmol, 9.5 equiv.) under ice-
cooling and stirred overnight. The reaction mixture was diluted with H2O (15 mL), the aqueous mixture was
extracted by CH2Cl2 (3 x 15 mL) and the combined organic extracts were dried (MgSO4) and concentrated in
vacuo. Flash column chromatography (1:1 hexanes : EtOAc) gave the desired product 24 (0.151 g, 79%) as
1
yellow solid; mp 203 °C (dec); H-NMR (600 MHz, DMSO-d6)  12.27 (s, 1H), 10.19 (s, 1H), 9.70 (s, 1H), 8.10-
8.12 (m, 2H), 7.48-7.50 (d, 1H, J 7.9 Hz), 7.26-7.29 (m, 2H), 6.93-6.95 (d, 2H, J 8.8 Hz), 6.60-6.62 (d, 2H, J 8.8
Hz), 3.72 (s, 3H); 13C-NMR (150 MHz, DMSO-d6) 184.5, 166.3, 160.1, 146.2, 144.0, 136.3, 132.6, 125.0, 123.9,
123.6, 122.4., 120.9, 116.4, 115.8, 113.9, 112.3, 52.4; IR  (KBr) 3310, 2847, 1690, 1636, 1204, 748 cm-1; UV

max (MeOH) 213, 245, 268, 303 nm.
(E)-tert-butyl-2-(1-(4-((tert-butoxycarbonyl)oxy)phenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-3-formyl-1H-indole
-1-carboxylate (25). To a stirred solution of compound 24 (61 mg 0.168 mmol, 1 equiv.) and DMAP (2.3 mg,
0.019 mmol, 0.1 equiv.) at 0 °C in CH2Cl2 (5 mL) was added Boc2O (102.5 mg, 0.47 mmol, 2.5 equiv.). The
stirring continued for 4 h at rt before the reaction mixture was extracted with CH2Cl2 (3 x 10 mL), quenched
with dilute HCl and washed with H2O. Evaporation of solvent afforded 25 as a crude white solid (98 mg, 100%)
that was used without further purification: mp 102-105 °C; 1H-NMR (600 MHz, CDCl3)  9.81 (s, 1H), 8.31-8.32
(d, 1H, J 7.8 Hz), 8.27-8.28 (d, 1H, J 8.3 Hz) 8.14 (s, 1H), 7.44-7.46 (m, 1H), 7.38-7.40 (m, 1H), 7.13-7.15 (d, 2H, J
8.6 Hz), 7.04-7.05 (d, 2H, J 8.6 Hz), 3.78 (s, 3H), 1.57 (s, 9H), 1.50 (s, 9H); 13C-NMR (150 MHz, CDCl3)  186.7,
166.2, 152.5, 151.2, 149.2, 143.5, 143.4, 136.5, 131.5, 130.7, 126.2, 125.8, 124.9, 122.4, 122.0, 121.9, 118.2,
115.6, 86.4, 84.2, 52.8, 27.9, 27.1; IR  (KBr) 2947, 2847, 1751, 1667, 1543, 1373, 756 cm-1; UV max (MeOH)
218, 314 nm.
(E)-1-(tert-butoxycarbonyl)-2-(1-(4-((tert-butoxycarbonyl)oxy)phenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-1H-
indole-3-carboxylic acid (26). To a heterogeneous mixture of aldehyde 25 (100 mg, 0.19 mmol, 1 equiv.) and
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sulfamic acid (75 mg, 0.77 mmol, 4 equiv.) in t-BuOH:H2O (3:1 = 4 mL) were added NaH2PO4 (69 mg, 0.58
mmol, 3 equiv.) and NaClO2 (80%, 73 mg, 0.81 mmol, 3 equiv.), sequentially at room temperature. The
reaction mixture was allowed to stir for 8 h then poured onto H2O (10 mL) and extracted with EtOAc (3 x 10
mL). The combined organic extracts were concentrated in vacuo and purified by flash column chromatography
1
(1:1 hexanes : EtOAc) to furnish acid 26 as a white solid (89 mg, 87%): mp 144-146 °C; H-NMR (600 MHz,
CDCl3)  8.23-8.27 (m, 2H), 7.95 (s, 1H), 7.38-7.44 (m, 2H), 6.97-7.01 (m, 4H), 3.76 (s, 3H), 1.49 (s, 9H), 1.48 (s,
9H); 13C-NMR (150 MHz, CDCl3)  168.7, 166.6, 152.1, 151.3, 149.0, 141.6, 139.9, 136.2, 131.6, 130.9, 127.3,
125.6, 124.4, 124.1, 122.4, 121.7, 115.6, 111.3, 85.9, 84.0, 52.6, 27.9, 27.7; IR  (KBr) 2978, 2932, 1751, 1674,
1373, 1150 cm-1; UV max (MeOH) 271, 272, 282 nm.
(E)-2-(1-(4-hydroxyphenyl)-3-methoxy-3-oxoprop-1-en-2-yl)-1H-indole-3-carboxylic acid (3). To a solution of
di-Boc acid 26 (49.7 mg, 0.925 mmol, 1 equiv.) in CH2Cl2 (2 mL) at 0 °C was added TFA (0.55 mL). The mixture
was allowed to stir for 8 h before being concentrated by rotary evaporation to give the crude product.
1
Purification by PTLC (1:2 hexanes : EtOAc) afforded the pure compound 3 as a yellow oil (7.6 mg, 24%): H-
NMR (600 MHz, DMSO-d6)  11.84 (s, 1H), 10.05 (s, 1H), 8.04-8.05 (d, 1H, J 6.7 Hz), 7.79 (s, 1H), 7.37-7.38 (d,
1H, J 6.7 Hz), 7.18-7.20 (m, 2H), 6.84-6.85 (d, 2H, J 8.3 Hz), 6.58-6.59 (d, 2H, J 8.3 Hz), 3.64 (s, 3H); 13C-NMR
(150 MHz, DMSO-d6)  166.8, 165.7, 159.4 142.1, 139.2, 135.7, 132.2, 127.0, 124.7, 122.4, 121.1, 121.1, 120.3,
115.6, 112.0, 105.7, 52.0; IR (KBr) 3549, 2924, 2855, 1643, 1574, 1512, 1443 cm-1; UV max (MeOH) 231, 286,
321 nm.
Acknowledgements
This work was supported by the School of Graduate Studies and Research, University of the West Indies, Cave
Hill, and the Government of Barbados. The authors thank Prof. Gordon Gribble for his continued support,
encouragement and mentorship.
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