General synthesis of the nitropyrrolin family of natural products via regioselective CO2-mediated alkyne hydration

Article abstract of DOI:10.1021/acs.orglett.7b02687

The total synthesis of the 2-nitropyrrole natural products nitropyrrolins A and B and the formal synthesis of nitropyrrolin D are reported. The key 2-nitro-4-alkylpyrrole core was efficiently assembled by Sonogashira cross-coupling, with complete control of regioselectivity. An unusual carboxylative cyclization, sulfonylcarbamate formation, and base-promoted cleavage sequence enabled access to the key hydroxy ketone without affecting the protected 2-nitropyrrole unit. The total synthesis provides a general approach for preparation of the bioactive nitropyrrolin family of natural products.

Full text of DOI:10.1021/acs.orglett.7b02687

Letter
pubs.acs.org/OrgLett
General Synthesis of the Nitropyrrolin Family of Natural Products via
Regioselective CO2‑Mediated Alkyne Hydration
Xiao-Bo Ding, Daniel P. Furkert,* and Margaret A. Brimble*
School of Chemical Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, 23 Symonds Street,
Auckland 1142, New Zealand
S
* Supporting Information
ABSTRACT: The total synthesis of the 2-nitropyrrole natural products nitropyrrolins A and B and the formal synthesis of
nitropyrrolin D are reported. The key 2-nitro-4-alkylpyrrole core was efficiently assembled by Sonogashira cross-coupling, with
complete control of regioselectivity. An unusual carboxylative cyclization, sulfonylcarbamate formation, and base-promoted
cleavage sequence enabled access to the key hydroxy ketone without affecting the protected 2-nitropyrrole unit. The total
synthesis provides a general approach for preparation of the bioactive nitropyrrolin family of natural products.
produced by Streptomyces sp. (CMB-M0423), these compounds
itropyrrolins A−E (1−5, Figure 1) were isolated from the
Nculture broth of the MAR4 strain CNQ-509 from a are the only natural products reported to date bearing the rare
2-nitro-4-alkyl pyrrole core.2a Nitropyrrolins A (1), B (2), and
marine sediment sample collected off La Jolla, California in
2010.1 Together with the heronapyrroles (e.g., 6−7, Figure 1)2
D (4) exhibit cytotoxic activity toward the human colon
carcinoma cell line HCT-116 (1 IC50 31.1 μM, 2 IC50 31.0 μM,
and 4 IC50 5.7 μM).1 Inspired by the unique structures,
promising biological activity and low abundance in nature,
several groups have shown interest in the syntheses of these
natural products.3 Stark et al.2b,4 and our group5 have reported
successful syntheses of heronapyrroles C and D in 2012 and
2014, respectively. We later reported a more efficient strategy
for regioselective preparation of the 2-nitro-4-alkyl pyrrole
framework, which enabled improved syntheses of heronapyr-
roles C and D.6 Recently, Morimoto and co-workers
accomplished syntheses of heronapyrroles A (6), B (7) and
nitropyrrolins A (1), B (2), D (4).7 In their syntheses of the
nitropyrrolins, nonselective nitration of an alkylated pyrrole was
employed as the key step to assemble the 2-nitro-4-farnesyl
pyrrole core which only afforded the desired product as the
minor regioisomer. At the outset of our studies, no synthesis of
members of the nitropyrrolin family had been reported. Given
our ongoing interest in 2-nitropyrrole containing natural
products, we were interested in investigating the syntheses of
nitropyrrolins A (1), B (2), and D (4), with the goal of
establishing efficient and general access to this biologically
active pharmacophore, to enable more thorough evaluation of
their potential as leads for drug discovery.
Received: August 28, 2017
Figure 1. 2-Nitro-4-alkyl pyrrole natural products.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02687
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Based on our previous studies toward the closely related
heronapyrroles,5,6 we envisaged that a palladium catalyzed
cross-coupling would enable efficient construction of the 2-
nitro-4-farnesyl pyrrole core with complete regiochemical
control. With this in mind, it was envisaged that nitropyrrolin
A (1) could be accessed by stereoselective reduction of a
suitably protected hydroxy ketone such as 8 (Scheme 1). We
prepared from 2-nitropyrrole following our previously opti-
mized procedures.5 Enantiomerically pure alkyne 11 was
prepared from commercially available farnesol in three steps
using literature methods.9 Sonogashira coupling of iodide 10
and terminal alkyne 11 then successfully assembled the 2-nitro-
4-farnesylpyrrole framework, affording alkyne 9 in 90% yield.
Initial attempts to effect direct CO2-promoted hydration of
alkyne 9 using reported conditions including AgOAc/DBU8b
and ionic liquid ([Bu4P][Im])8b in the presence of CO2 failed
to deliver the desired ketone 8 (Scheme 2), with only
decomposition and/or recovery of the starting material
observed. Extensive attempts to optimize the reaction
conditions did not improve the outcome.
Scheme 1. Retrosynthesis of the Nitropyrrolin Framework
With this setback, we revised our approach to initially
prepare the cyclic carbonate intermediate 12, which was
expected to then undergo hydrolysis to afford the desired
hydroxy ketone 8 in a separate step (Scheme 2). After
screening of reaction conditions, we were pleased to find that
mild conditions involving exposure to silver(I) carbonate and
carbon dioxide (generated from dry ice), with triphenyl
phosphine as cocatalyst, in dichloromethane, successfully
effected the carboxylative cyclization at room temperature,8e
affording the desired carbonate 12 in high yield. Unfortunately,
the subsequent hydrolysis step proved unexpectedly challeng-
ing. Examination of a wide range of acids and bases in various
solvents (see the Supporting Information for details) did not
reveal conditions for conversion of cyclic carbonate 12 to the
target ketone 8. Decomposition of the starting material was
observed in most cases, indicating that the limited stability of
the 2-nitropyrrole subunit under the reaction conditions
examined was potentially problematic.
expected that ketone 8 could in turn be obtained from the
propargylic alcohol 9 via regioselective hydration of the alkyne
functionality. Carbon dioxide mediated hydration of prop-
argylic alcohols has been reported for related transformations,8
although its application in natural product synthesis has not
been well established. The requisite propargylic alcohol 9
would be assembled by Sonogashira coupling of iodide 105 with
alkyne 11.9
Inspired by the cleavage mechanism of the tetramethyl-1,3-
oxazolidine-3-carbonyl (Cby) auxiliary (Scheme 3A),10 we
envisaged that conversion of the cyclic carbonate 12 to the
corresponding β-hydroxyethylcarbamate (e.g., 13) would
facilitate an intramolecular cyclization upon subsequent treat-
Our synthesis began with the preparation of the substrates
for the key Sonogashira coupling reaction (Scheme 2). N-
Benzyloxymethyl (N-Boz) protected iodide 10 was readily
Scheme 2. CO2-Mediated Regioselective Hydration of Alkyne 9
B
DOI: 10.1021/acs.orglett.7b02687
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Scheme 3. Literature Precedent for Investigations into the Two-Step Cleavage of Cyclic Carbonate 17
ment with a suitable base, releasing the desired hydroxy ketone
8. Accordingly, cyclic carbonate 12 was initially treated with N-
isopropyl ethanolamine; however, none of the desired
carbamate was isolated. The electrophilicity of carbonate 12
toward secondary amines was then examined by reaction with
pyrrolidine, resulting in quantitative formation of carbamate 14.
Encouraged by this result, use of the less hindered N-methyl-
ethanolamine as a nucleophile was also pursued affording
carbamate 15 in 90% yield. With the required carbamate 15 in
hand, investigations of the carbamate cleavage to yield the
required hydroxy ketone 8 were next undertaken. Disappoint-
ingly, however, examination of a wide range of previously
reported conditions including Ba(OH)2/MeOH,10a K3CO3/
MeOH,10c and NaH/THF11 failed to effect formation of ketone
8, with decomposition observed in most cases. Although use of
the carbamate formation and cleavage strategy failed to afford
the desired hydroxy ketone 8, these experiments revealed the
electrophilicity of carbonate 12 and laid a foundation for further
investigation using other nucleophiles.
Scheme 4. Final Synthesis of Nitropyrrolin A(1)
Table 1. Diastereoselective Reduction of Hydroxy Ketone 8
temp
(°C)
yield
a
entry
conditions
(%)
17a:17b
1
2
3
ZnCl2, NaBH4, THF
0
−10
−10
70
84
85
3:1
2:1
3:1
NaBH4, CeCl3·7H2O, MeOH
NaBH4, CeCl3·7H2O, EtOH/THF
(1:1)
Sulfonyl carbamates have recently been reported as effective
protecting groups for alcohols that are readily removed under
mildly basic conditions (Scheme 3B).12 It therefore seemed
plausible that nucleophilic opening of cyclic carbonate 12 with
p-toluenesulfonamide would afford the corresponding sulfonyl
carbamate 16, which would then release the desired hydroxy
ketone 8 upon cleavage of the sulfonylcarbamate using the
reported mild conditions. Accordingly, 12 was treated with the
anion of p-toluenesulfonamide, generated by treatment of p-
toluenesulfonamide with NaH in DMF. Pleasingly, the desired
sulfonylcarbamate 16 was obtained in 40% yield. After
optimization of the reaction conditions, sulfonylcarbamate 16
was finally obtained in a greatly improved yield of 92% by
stirring 12 with excess p-toluenesulfonamide in the presence of
potassium carbonate in DMF at elevated temperature. We next
set out to cleave the sulfonylcarbamate motif and were pleased
to discover that heating 16 under reflux in pyridine−MeOH
(2:1) finally afforded the desired hydroxy ketone 8, in 60%
yield.
With access to the target hydroxy ketone 8 secured,
investigations into the necessary diastereoselective reduction
of the ketone were next undertaken (Scheme 4). Borohydride
reduction of 8 in the presence of zinc chloride13 or cerium
chloride heptahydrate as chelating reagents afforded the
separable epimeric diols 17a and 17b in a 2:1 to 3:1 ratio, in
high yields (Table 1, entries 1−3). Zinc borohydride14 was
found to give an improved ratio of diastereomers (4.5:1) in
80% yield (Table 1, entry 4). Finally, Corey−Bakshi−Shibata
(CBS) reduction using (R)-2-methyl-CBS-oxazaborolidine and
a borane−dimethyl sulfide complex afforded diols 17a and 17b
in 75% yield, with a further improved d.r. of 6:1 (Table 1, entry
5).
4
5
Zn(BH4)2, THF
−20
−40
80
75
4.5:1
6:1
(R)-Me-CBS, BH3·DMS, THF
a
b
Isolated yield. Determined by NMR analysis.
The total synthesis of nitropyrrolin A (1) was finally achieved
in 92% yield by N-Boz deprotection of diol 17a, using aqueous
K2CO3 in methanol at 0 °C (Scheme 4). The spectroscopic
data and specific rotation of our synthetic sample were in good
agreement with the literature report and that reported by
Morimoto [this work [α]D +20.7; natural [α]D +8; Morimoto
[α]D +26.6].7b
With the synthesis of initial target nitropyrrolin A (1)
completed, the focus next turned to nitropyrrolin B (2). This
required the enantiomer of N-Boz hydroxy ketone 8 used for
nitropyrrolin A (1), which was prepared using the optimized
method (Scheme 5). Diastereoselective CBS reduction of ent-8
afforded ent-17a, which underwent successive mesylation and
one-pot epoxide formation, followed by N-Boz deprotection
under very mild conditions to afford nitropyrrolin B (2) in 60%
overall yield from ent-17a. The spectroscopic data and specific
rotation of our synthetic nitropyrrolin B (2) were in good
agreement with the literature report [this work [α]D +10.6;
natural [α]D +3; Morimoto [α]D +12.3].7b In addition, synthesis
of nitropyrrolin B (2) provides a formal synthesis of
nitropyrrolin D (4) which is available by regioselective epoxide
ring opening, as previously demonstrated by Morimoto and co-
workers.7b
In conclusion, we have achieved the total synthesis of the 2-
nitropyrrole natural products, nitropyrrolins A (1) and B (2),
and a formal synthesis of nitropyrrolin D. The synthetic route is
underpinned by a highly efficient Sonogashira coupling that
enables direct regioselective construction of the 2-nitro-4-
C
DOI: 10.1021/acs.orglett.7b02687
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Letter
Scheme 5. Completion of Nitropyrrolin B (2) and Formal
Synthesis of Nitropyrrolin D (4)
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02687.
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S
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: m.brimble@auckland.ac.nz.
*E-mail: d.furkert@auckland.ac.nz.
ORCID
Daniel P. Furkert: 0000-0001-6286-9105
Margaret A. Brimble: 0000-0002-7086-4096
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the NZ Ministry for Science and Innovation
(IIOF) for financial support.
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DOI: 10.1021/acs.orglett.7b02687
Org. Lett. XXXX, XXX, XXX−XXX