Improved synthetic route to C-ring ester-functionalized prodigiosenes

Article abstract of DOI:10.1055/s-0030-1258769

An efficient, optimized, and scalable process for the synthesis of C-ring ester-functionalized prodigiosenes has been developed by (i) exploiting a silylative Mukaiyama aldol strategy for the condensation of alkyl 5-formyl-2,4-dimethylpyrrole-3-carboxylate and 4-methoxy-3-pyrrolin-2-one to form the corresponding ester-functionalized dipyrrinone analogues, and (ii) developing a facile synthesis of stable bromodipyrrin analogues for the use in formal Suzuki coupling reactions. The process was applied to the synthesis of three C-ring ester-functionalized prodigiosenes in multigram scales (up to 6.5 g prodigiosene free-base) with useful yields (35-56% overall yields over three steps starting from the 2-formyl pyrroles). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258769

LETTER
2561
Improved Synthetic Route to C-Ring Ester-Functionalized Prodigiosenes
Synthetic Route to
C
-R
d
ing Ester-Fu
.
nctionalized
I
P
rodigio
m
senes am Uddin, Srinath Thirumalairajan, Sarah M. Crawford,* T. Stanley Cameron, Alison Thompson*
Department of Chemistry, Dalhousie University, Halifax, NS, B3H 4J3, Canada
Fax +1(902)4941310; E-mail: Sarah.Crawford@dal.ca; E-mail: Alison.Thompson@dal.ca
Received 18 August 2010
Path A suffered from low yields as the bipyrrolic unit was
consistently synthesized using a low yielding McFayen–
Stevens reduction.5 An alternative strategy to generate the
bipyrrolic unit was recently developed by Dairi et al. (path
Abstract: An efficient, optimized, and scalable process for the syn-
thesis of C-ring ester-functionalized prodigiosenes has been devel-
oped by (i) exploiting a silylative Mukaiyama aldol strategy for the
condensation of alkyl 5-formyl-2,4-dimethylpyrrole-3-carboxylate
and 4-methoxy-3-pyrrolin-2-one to form the corresponding ester- B, Scheme 1) and involves the synthesis of a 2-formyl bi-
functionalized dipyrrinone analogues, and (ii) developing a facile
pyrrole in a two-step route from 4-methoxy-3-pyrrolin-2-
one.8,9 Unfortunately, this process was not successful in
synthesis of stable bromodipyrrin analogues for the use in formal
Suzuki coupling reactions. The process was applied to the synthesis
our hands as the 2-formyl bipyrrole could only be isolated
of three C-ring ester-functionalized prodigiosenes in multigram
in low and irreproducible yields.
scales (up to 6.5 g prodigiosene free-base) with useful yields (35–
56% overall yields over three steps starting from the 2-formyl pyr-
roles).
Path C is relatively more convenient and has traditionally
relied on a base-promoted condensation of a 2-formyl pyr-
role with a pyrrolin-2-one to generate the dipyrrinone
unit, followed by formation of the triflated analogues and
then Suzuki coupling to the final pyrrolyl-dipyrrin skele-
tons.3 However, the base-promoted condensation step of
this process to generate the dipyrrinones suffers serious
limitations due to the equilibrium between the retro 2-
formyl pyrrole in the presence of strong base, as observed
by others during the synthesis of metacycloprodigiosin.10
Once synthesized, the dipyrrinone is converted into a tri-
flate analogue, which, depending on the substituent at R1,
has limited thermal stability. The low thermal stability of
these analogues renders purification of multigram quanti-
ties problematic.
Key words: prodigiosin, prodigiosene, bromodipyrrin, dipyrri-
none, bromination
Prodigiosenes belong to a family of tripyrrolic red pig-
ments with important biological properties.1 Thus several
investigations have been focused on the structure–activity
relationships in prodigiosenes.2 Recently, we have discov-
ered that C-ring functionalized prodigiosenes exhibit effi-
cient anticancer properties in effective doses.3,4 These
discoveries stimulated the development of an expedient
synthetic strategy to prepare novel analogues with potent
anticancer properties (Figure 1) and to prepare highly ac-
tive derivatives on a multigram scale.
As part of our studies towards mapping the SAR profile of
C-ring ester-functionalized prodigiosenes with optimized
immunosuppressive properties, we needed an improved
synthetic process with (i) a short reaction sequence, (ii) an
alternative condensation step to form the dipyrrinone unit,
and (iii) a stable analogue for use in the formal Suzuki di-
heteroaryl coupling reactions with BOC-protected pyrrole
2-boronic acid. We anticipate that addressing these issues
would result in a scalable synthetic process. Our investi-
gations in this regard are discussed herein.
C-ring
OMe
B-ring
O
RO
NH
HCl
N
HN
A-ring
1a R = Et
1b R = Bn
1c R = Me
Our synthetic strategy (Scheme 2) involved starting with
2-formyl pyrroles 4, synthesized by following a slight
modification of a reported protocol.11 Knorr pyrrole 5-
tert-butyl esters 2a,b were subjected to acid-promoted hy-
drolysis, decarboxylation to give 3a,b, then Vilsmeier
formylation to give 4a–c in almost quantitative overall
yields (Scheme 2). Based on the understanding that the
base-promoted condensation of 4a–c and 5 suffers several
drawbacks due to a reversible retro 2-formyl pyrrole gen-
eration in the presence of a strong base,10 we used an al-
ternative strategy involving dual Lewis acid–Lewis base
activation using a silylative Mukaiyama aldol strate-
gy.10,12 Acid-promoted elimination of the OTMS func-
tionality gave the dipyrrinone analogues 6a–c in moderate
to good yields (Scheme 2).
Figure 1 C-Ring ester-functionalized prodigiosenes
Two main synthetic strategies for the synthesis of the
tripyrrolic skeleton of prodigiosenes have been reported:
(i) the condensation of a bipyrrole unit with the C-ring
moiety (path A and path B, Scheme 1),5,6 and (ii) the cou-
pling of a dipyrrin unit with the A-ring (path C,
Scheme 1).7
SYNLETT 2010, No. 17, pp 2561–2564
x
x
.x
x
.2
0
1
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Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258769; Art ID: S05110ST
© Georg Thieme Verlag Stuttgart · New York

2562
Md. I. Uddin et al.
LETTER
path A
MeO
N
H
N
H
EtO2C
R1
OMe
O
N
N
H
N
H
path B
H
OMe
OMe
Br
R1
N
B(OH)2
N
NEt2
Boc
NH
HCl
N
path C
HN
OMe
OTf
OMe
O
R1
R1
NH
N
NH HN
B(OH)2
N
R2
R2
Boc
Scheme 1 Synthetic strategies for the synthesis of prodigiosenes
O
O
H
H
OMe
H
O
RO
RO
O
N
O
10 M HCl, EtOH
65 °C, 4 h
O
H
RO
N
RO
N
N
N
H
N
H
H
H
H
O
O
H
O
2a R = Et
2b R = Bn
3a R = Et (99%)
3b R = Bn (99%)
I
II
minor isomer
major isomer
POCl3,
DMF
MeO
Figure 2 NOESY correlations observed for the dipyrrinones I and
II
O
N
O
OMe
O
H
O
RO
5
RO
1) TMSOTf, Et3N
2) 10 M HCl, THF
NH HN
N
H
O
6a R = Et (78–93%)
6b R = Bn (71–97%)
6c R = Me (90%)
4a R = Et (99%)
4b R = Bn (97%)
4c R = Me (92%)a
Scheme 2 Preparation of ester-functionalized dipyrrinone ana-
logues. a4c was prepared using an esterification strategy (see Suppor-
ting Information for more details).
The dipyrrinones 6a–c were observed to form as a mixture
of distinguishable isomers I and II depending on the reac-
tion conditions, that is, acid concentration and dilution.
The structural assignment for the isomeric dipyrriones I
and II was executed using NOESY (Figure 2). In the
NOESY spectrum, the correlation between NH/NH of the
major isomer I indicated the Z-configuration at the dipyr-
rin moiety, and the correlation between NH/meso-H of the
minor isomer II indicated the E-configuration (Figure 2).
Figure 3 X-ray crystal structure of 6b
In our previous work with prodigiosenes, we noted that
several triflate analogues were thermally unstable.3 In one
case, a symmetrical dipyrrin byproduct was isolated from
the triflation reaction mixture. The generation of this sym-
metrical dipyrrin byproduct 813 (Figure 4) is probably due
to the hydrolysis of the dipyrrinone as its triflate in the
presence of even trace amounts of moisture, followed by
acid-catalyzed self-condensation.
The structure of the major isomer was further confirmed
by the isolation of the major isomer in pure form by alter-
ing the reaction conditions. The structure of benzyl ester
dipyrrinone 6b was confirmed by an X-ray crystal struc-
ture (Figure 3).
With the knowledge that triflate analogues had proven
problematic, our modified strategy for the synthesis of C-
ring ester-functionalized prodigiosenes focused on the
Synlett 2010, No. 17, 2561–2564 © Thieme Stuttgart · New York

LETTER
Synthetic Route to C-Ring Ester-Functionalized Prodigiosenes
2563
mixture was similarly unsuccessful, probably due to the
low stability of the carboxylic acid. As another alternative
method, direct transesterification of ethyl ester prodigi-
osene 1a was attempted. High-pressure microwave-pro-
moted reaction conditions were used for the
transesterification of ethyl ester prodigiosene 1a in at-
tempts to generate the methyl ester 1c, the n-butyl ester
1d, and the 2-propyl ester prodigiosene 1e. The results of
experiments towards these transformations are shown in
Scheme 4 with the investigated conditions listed in
Table 1.
O
O
O
N
HN
O
8
Figure 4 The symmetrical dipyrrin byproduct 8
analogous bromodipyrrin analogues 7a–c. Bromination of
the dipyrrinone using POBr3 was thought to be a viable al-
ternative based on the work of Dairi,8 who used POBr3 to
brominate pyrrolinones, and Rapoport,14 who used POCl3
to chlorinate pyrrolinones.
OMe
OMe
O
Regardless of isomeric ratios, when the dipyrrinones 6a–
c were treated with POBr3, isomers I and II react to gen-
erate a single isomer of the corresponding bromodipyrrins
(Scheme 3). The bromodipyrrins were obtained as HBr
salts, which, upon basic workup, gave free bases 7a–c in
good yields (up to 85%). These meso-unsubstituted bro-
modipyrrins are stable at room temperature under air and
can be used in bench-top operations, making them feasi-
ble intermediates for the large-scale production of prodi-
giosenes.
O
RO
NaOR, ROH
MW
N
HN
EtO
N
HN
HCl
HCl
1a
HN
HN
1c R = Me (75–87%)
1d R = n-Bu
1e R = i-Pr
Scheme 4 Microwave-promoted transesterification of prodigiosene
1a
Finally, the Suzuki coupling reaction of bromodipyrrins
7a–c with N-Boc-protected pyrrole-2-boronic acid
worked well as for the triflated analogues, and was used
effectively for the large-scale synthesis of prodigiosenes
1a–c (up to 6.5 g prodigiosene free base) in good yields
(35–56% overall yields over three steps starting from the
2-formyl pyrroles; Scheme 3).
Table 1 Conditions for the Microwave-Promoted Transesterifica-
tion of Prodigiosene 1a
R
Conditions
Results
Me
NaOMe (1.2 equiv), MeOH, 125 °C, 10 min 1a and 1c
NaOMe (1.5 equiv), MeOH, 125 °C, 20 min 1c 75–87%
NaOMe (1.5 equiv), MeOH, reflux,a 20 min
n-Bu NaOn-Bu (15 equiv), n-BuOH, 200 °C, 40 min 1a and 1d
i-Pr NaOi-Pr (125 equiv), i-PrOH, 140 °C, 40 min 1a and 1e
1a recovered
OMe
1. POBr3
CH2Cl2, reflux
OMe
O
O
RO
RO
2. aq NaHCO3
NH HN
NH
N
O
Br
a Without using microwave.
6a R = Et
6b R = Bn
6c R = Me
7a R = Et (80–85%)
7b R = Bn (77–85%)
7c R = Me (63%)
The ethyl ester prodigiosene 1a was successfully transes-
terified to give the methyl ester prodigiosene 1c, in high
yields, by treating it with 1.5 equivalents of sodium meth-
oxide and heating the reaction to 125 °C for 20 minutes in
methanol under microwave irradiation. When the same re-
action was carried out under reflux conditions, 1a was re-
covered quantitatively, thus identifying the microwave
promotion to be key for the transesterification to be suc-
cessful. When this method was adapted to n-butyl and 2-
propyl alkoxides, 1H NMR spectroscopic analysis showed
the presence of the desired product along with remaining
starting material, even though large excesses of the alkox-
ides were used. Re-subjection of these mixtures to the re-
action conditions did not noticeably improve the ratio of
starting material to product, and the mixtures of starting
material and product could not be adequately separated
using column chromatography. Although this method
produced the methyl ester derivative 1c in good yield, it
was not general for other esters and not a synthetically vi-
able method for synthesizing prodigiosene C-ring esters.
1. Pd(PPh3)4, Na2CO3,
LiCl, DME
OMe
O
B(OH)2
N
RO
NH
HCl
N
Boc
2. HCl in MeOH
HN
1a R = Et (89%)
1b R = Bn (87%)
1c R = Me (61%)
Scheme 3 Preparation of ester-functionalized prodigiosenes
In addition, we investigated a convergent hydrolysis/
esterification approach to a series of new prodigiosene
esters using 1a15 and 1b. Several attempts were made to
hydrolyze the ethyl ester of 1a and, although the required
crude carboxylic acid product was observed using mass
spectrometry, it was unstable and could not be isolated.
Hydrogenolysis of the benzyl-ester functional group of
1b followed by esterification of the crude acid reaction
Synlett 2010, No. 17, 2561–2564 © Thieme Stuttgart · New York

2564
Md. I. Uddin et al.
LETTER
Atlantic Region. S.M.C. thanks the Natural Sciences and Enginee-
ring Research Council of Canada (NSERC) for a graduate scholar-
ship. We offer our gratitude to Carlie Charlton for her help in this
research.
In conclusion, we have developed an efficient method for
the multigram synthesis of functionalized prodigiosenes
using a silylative Mukaiyama aldol strategy to generate
dipyrrinone intermediates and using stable bromodipyr-
rins in place of triflates in the final Suzuki coupling reac-
tion to generate the prodigiosene targets. The process was References
successfully applied to the total synthesis of three C-ring
ester-functionalized prodigiosenes.
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General Procedures and Representative Data
Compounds 2a,b,11 3a,b,11 4a,b,11 4c,16 and 6a–c10,12 were prepared
following modified literature procedures.
Procedure for the Synthesis of Bromodipyrrins (7)
To a stirred suspension of 6a (3.4 g, 11.7 mmol) in dry CH2Cl2 (250
mL) was added POBr3 (6.70 g, 23.37 mmol). The resulting solution
was heated at reflux temperature under nitrogen for 17 h. After the
reaction mixture was cooled to r.t., sat. NaHCO3 (500 mL) was add-
ed at 0 °C, and the organic layer was separated, washed with brine
and H2O, dried using anhyd Na2SO4, filtered, and the solvent was
evaporated in vacuo. The crude product was purified by passing a
solution in EtOAc through a pad of silica gel eluting with 20% hex-
ane in EtOAc to give the title compound 7a as bright orange yellow
solid (3.30 g, 80%).
1H NMR (500 MHz, CDCl3): d = 11.20 (1 H, br s), 6.94 (1 H, s),
5.59 (1 H, s), 4.29 (2 H, q, J = 7.0 Hz), 3.85 (3 H, s), 2.59 (3 H, s),
2.40 (3 H, s), 1.36 (3 H, t, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3):
d = 167.5, 165.4, 147.2, 144.1, 139.2, 134.1, 126.5, 115.9, 114.1,
100.2, 59.7, 58.7, 15.2, 14.6, 11.6. HRMS (ESI+): m/z calcd for
C15H18BrN2O3 [M+]: 353.0495; found: 353.0482.
Procedure for the Synthesis of Prodigiosenes (1)
(4) Sáez Díaz, R. I.; Bennett, S. M.; Thompson, A.
Compound 7a (3.20 g, 9.06 mmol), LiCl (1.16 g, 27.36 mmol), 1-
N-Boc-pyrrole-2-boronic acid (2.32 g, 10.99 mmol), and Pd(PPh3)4
(1.05 g, 0.91 mmol) were dissolved in 1,2-dimethoxyethane (180
mL), and the solution was purged by bubbling with nitrogen for 10
min. A solution of Na2CO3 (2 M, 18.2 mL, 36.4 mmol) was then
added, and the reaction mixture was stirred at 85 °C for 24 h. After
cooling to r.t. the reaction mixture was poured into H2O. Extraction
with EtOAc (3 × 100 mL), followed by washing of the combined
organic fractions with brine (150 mL), drying with anhyd Na2SO4,
filtration, and evaporation of the solvent in vacuo gave the crude
product that was purified using flash chromatography on neutral
aluminum oxide (grade III) using a gradient of EtOAc–hexane
(10:90 to 20:80) as eluent to give the prodigiosene free base (2.73
g, 89%). Then a solution of HCl in MeOH (0.75 M, 1.5 equiv) was
added to a solution of the free base in MeOH–CHCl3 (20:1) to give
1a as deep pink solid.
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1H NMR (500 MHz, CDCl3): d = 12.90 (1 H, br s), 12.69 (1 H, br
s), 12.64 (1 H, br s), 7.28 (1 H, s), 7.09 (1 H, s), 6.98 (1 H, s), 6.37
(1 H, s), 6.09 (1 H, s), 4.30 (2 H, d, J = 7.0 Hz), 4.04 (3 H, s), 2.80
(3 H, s), 2.50 (3 H, s), 1.37 (3 H, t, J = 7.0 Hz). 13C NMR (125 MHz,
CDCl3): d = 166.7, 164.7, 150.4, 150.1, 140.6, 128.5, 123.5, 122.5,
122.1, 119.1, 115.9, 113.0, 112.5, 93.5, 60.1, 59.2, 14.9, 14.5, 12.0.
UV/vis: lmax (CHCl3) = 528 (e = 108017), 500 (e = 51587). HRMS
(ESI+): m/z calcd for C19H22N3O3 [M + H]+: 340.1656; found:
340.1637.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
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Thompson, A.; Chen, X.; Okamoto, Y. J. Org. Chem. 2005,
70, 9967.
This work was supported by the Canadian Institutes for Health
Research (CIHR) and the Canadian Breast Cancer Foundation-
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