Reactivity of 2-Nitropyrrole Systems: Development of Improved Synthetic Approaches to Nitropyrrole Natural Products

Article abstract of DOI:10.1021/acs.joc.8b01692

Fundamental study of the reactivity of 2-nitropyrrole systems has enabled the identification of effective methods for incorporation of this unusual motif into advanced natural product frameworks. The presence of electron-rich pyrrole N-protecting groups (BOM, Boz) was demonstrated to enable a variety of previously unsuccessful palladium-mediated cross-couplings to be carried out in high yield. Based on this foundation, a series of regio- and stereoselective synthetic routes toward the nitropyrrolin and heronapyrrole families of natural products was developed by our group (G1-3). A full account of the strategic evolution of these approaches is reported here, highlighting the details of the setbacks encountered and eventual successes achieved en route, including the total synthesis of heronapyrrole B. The fundamental studies and completed total syntheses provide general access to the bioactive 2-nitropyrrole natural product manifold and also establish practical and efficient methods for preparation and elaboration of the medicinally relevant 2-nitropyrrole motif.

Full text of DOI:10.1021/acs.joc.8b01692

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Article
Reactivity of 2-Nitropyrrole Systems: Development of Improved
Synthetic Approaches to Nitropyrrole Natural Products
Xiao-Bo Ding, Margaret A. Brimble, and Daniel P. Furkert
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01692 • Publication Date (Web): 01 Oct 2018
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Reactivity of 2-Nitropyrrole Systems: Development of Improved Synthetic Approaches to
Nitropyrrole Natural Products
XiaoꢀBo Ding,a Margaret A. Brimblea,b* and Daniel P. Furkerta,b*
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aSchool of Chemical Sciences and bMaurice Wilkins Centre for Molecular Biodiscovery, The
University of Auckland, Symonds Street, Auckland 1010, New Zealand
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Eꢀmail: d.furkert@auckland.ac.nz; m.brimble@auckland.ac.nz
Abstract
Fundamental study of the reactivity of 2ꢀnitropyrrole systems has enabled the identification of
effective methods for incorporation of this unusual motif into advanced natural product frameworks.
The presence of electronꢀrich pyrrole Nꢀprotecting groups (BOM, Boz) was demonstrated to enable a
variety of previously unsuccessful palladiumꢀmediated crossꢀcouplings to be carried out in high yield.
Based on this foundation, a series of regioꢀ and stereoselective synthetic routes towards the
nitropyrrolin and heronapyrrole families of natural products have been developed by our group (G1ꢀ3).
A full account of the strategic evolution of these approaches is reported here, highlighting the details
of the setbacks encountered and eventual successes achieved en route, including the total synthesis of
heronapyrrole B. The fundamental studies and completed total syntheses provide general access to the
bioactive 2ꢀnitropyrrole natural product manifold and also establish practical and efficient methods
for preparation and elaboration of the medicinally relevant 2ꢀnitropyrrole motif.
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Introduction
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The nitropyrrolins AꢀE 1ꢀ5 (Figure 1) and heronapyrroles AꢀD 6ꢀ9 are structurally related
pyrroloterpene natural products sharing an unusual 2ꢀnitroꢀ4ꢀalkylpyrrole core.1 Nitropyrrolins AꢀE 1ꢀ
5 were isolated from the culture broth of the MAR4 strain CNQꢀ509, obtained from a marine
sediment sample collected off La Jolla, California by Fenical et al. in 2010.1a The simultaneously
reported heronapyrroles AꢀC 6ꢀ8 were produced by a Streptomyces sp. (CMBꢀM0423) isolated from a
beach sand sample off Heron Island, Australia by Capon et al.1b Heronapyrrole D 9 was also produced
by Streptomyces sp. (CMBꢀM0423) and later reported by Capon and Stark in 2014.2 Nitropyrrolins A
1, B 2, and D 4 exhibit cytotoxic activity toward human colon carcinoma cell line HCTꢀ116 (1;
IC50 31.1 ꢀM, 2; IC50 31.0 ꢀM, and 4; IC50 5.7 ꢀM).1a Heronapyrroles AꢀD 6ꢀ9 were found to display
promising activity against Gramꢀpositive bacteria Staphylococcus aureus ATCC 9144 (IC50 0.6–1.1
ꢀM) and Bacillus subtilis ATCC 6633 (IC50 1.1–6.5 ꢀM), without exhibiting cytotoxicity toward
mammalian cell lines.1b
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Figure 1. Natural products featuring the 2ꢀnitropyrrole motif.
The novel molecular architecture, promising biological activities, and unconfirmed stereochemical
assignments make these natural products attractive synthetic targets. In 2012, Stark et al. reported the
first synthesis of the enantiomer of heronapyrrole C 8 and proposed the absolute stererochemisty of
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the natural product.3 Morimoto et al. later reported the syntheses of heronapyrroles A 6, B 7 and
nitropyrrolins A 1, B 2, D 4.4 The Stark and Morimoto syntheses of this family of natural products
demonstrated that the desired nitration of alkylpyrrole 10 was a challenging task, featuring low yields
and regioselectivity in favour of the undesired nitropyrrole 11 (Scheme 1). In order to fully control the
regioselectivity, our synthetic program introduced the nitro group at the start of the synthesis and
achieved a first generation synthesis of heronapyrrole C using a key JuliaꢀKocienski olefination of
aldehyde 13 and sulfone 14 (Scheme 1, G1).5 This strategy provided completely regioselective access
to the required nitropyrrole unit, but the yield and E/Z selectivity of the olefination (42%, E/Z ca. 1:1)
were not satisfactory. We later reported an improved second generation synthesis (Scheme 1, G2) that
hinged on a robust crossꢀcoupling of iodide 15 and vinyl stannane 16 for construction of the 4ꢀalkylꢀ
2ꢀnitropyrrole framework, enabling access to heronapyrroles C 8 and D 9.6
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Encouraged by this improved synthesis of heronapyrroles C and D, in this work we aimed to further
apply our successful crossꢀcoupling strategy to the synthesis of other members of the 2ꢀnitropyrrole
natural product manifold, in particular nitropyrrolin A 1 and heronapyrrole B 7, that feature a C7,8
anti diol motif. The Stille coupling strategy successfully provided access to the 4ꢀalkylꢀ2ꢀnitropyrrole
framework, but further elaboration towards the final natural products proved surprisingly problematic.
We report here the development of effective new crossꢀcoupling protocols for 4ꢀiodoꢀ2ꢀnitropyrroles
17, that had previously been unsuccessfully investigated by other groups, and the subsequent
successful total syntheses of natural products 1 and 7 (Scheme 1, G3).7
Scheme 1. Synthetic strategies investigated for access to 2ꢀnitropyrrole natural products.
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We had initially envisaged that synthesis of both nitropyrrolin A 1 and heronapyrrole B 7 could be
achieved from common intermediate sulfone 20 via an additional regioselective C15,16
dihydroxylation for heronapyrrole B (Scheme 2). Sulfone 20 in turn would be obtained by alkylation
of sulfone 21 with epoxy iodide 22 that could be prepared via Stille coupling of iodide 23 and vinyl
stannane 24.
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Scheme 2. Initial retrosynthetic analysis.
Synthetic studies based on this initial retrosynthetic analysis commenced with the Stille coupling of
iodide 23 and vinyl stannane 24, to afford allylic alcohol 25 (Scheme 3).6 Sharpless asymmetric
epoxidation of alcohol 25 using (ꢀ)ꢀDIPT, selected by application of the Sharpless mnemonic,8
followed by iodination afforded iodide 22 in excellent overall yield. The stereochemistry of iodide 22
was later confirmed by comparison of synthetic and isolated natural product spectral data. With iodide
22 in hand, the key alkylation of sulfone 21 was next investigated. Despite abundant literature
precedent9 however, and the examination of a wide range of additional conditions, it did not prove
possible to achieve the desired alkylation to effect the union of 21 and 22. Decomposition of the
starting material was observed in most cases, likely due to the sensitive nature of the 2ꢀnitropyrrole
motif in 22.
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Scheme 3. Unsuccessful attempted alkylation of sulfone 21.
To avoid exposure of labile 2ꢀnitropyrrole fragments to harsh alkylation conditions it was decided to
install this fragment at a later stage. Accordingly, the revised plan aimed to synthesise heronapyrrole
B 7 from diene 26 via regioselective C7,8 dihydroxylation followed by desulfonylation (Scheme 4).
Diene 26 would be constructed by Stille coupling of iodide 23 and advanced stannane 27, which in
turn would be available from allyl bromide 28 and sulfone 29. This approach would still guarantee the
ability to control the regioselectivity of the necessary alkene epoxidation and dihydroxylations, while
performing the sulfone alkylation on substrates not containing a 2ꢀnitropyrrole unit.
Scheme 4. Revised retrosynthesis via Stille coupling of advanced stannane 27.
Synthetic investigations applying this revised approach commenced with Sharpless asymmetric
dihydroxylation of sulfone 21 (Scheme 5) using the ligand (DHQ)2PHAL as prescribed by the
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standard Sharpless mnemonic.10 Protection of the resulting diol with 2,2ꢀdimethoxypropane (DMP)
afforded acetonide 29, which underwent alkylation on treatment with KOtBu and bromide 28,
circumventing the previously encountered problems with this step, to afford iodide 30 in 75% yield.
Subsequent palladiumꢀmediated stannylation of 30 with hexamethylditin afforded stannane 27 in 68%
yield. Stille coupling of 27 and iodide 23 then gave diene 26 in 76% yield. Regioselective Sharpless
asymmetric dihydroxylation of diene 26 followed by protection of the resulting diol, again with 2,2ꢀ
dimethoxypropane, afforded sulfone 31. With sulfone 31 in hand, desulfonylation was next
investigated, however despite investigation of a wide range of conditions for palladiumꢀcatalyzed
reductive desulfonylation,11 [e.g. PdCl2(dppp), Pd(OAc)2/dppp, Pd(PPh)4) with boron hydrides (e.g.
KBH4, NaHB(OAc)3, NaBH4 or LiHBEt3) in various solvents] access to 32 was not able to be secured.
Decomposition was observed in most cases.
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This approach had demonstrated the utility of our previously established sp3ꢀsp2 Stille coupling
strategy for construction of the 4ꢀalkylꢀ2ꢀnitropyrrole framework, after reꢀordering of the synthetic
sequence to accommodate the sulfone, and enable the necessary asymmetric regioselective
dihydroxylations en route to diene 31. The difficulties encountered in the problematic desulfonylation
however, forced us to seek an alternative strategy to access the natural product framework.
Scheme 5. Revised approach halted by problematic desulfonylation of 31.
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Table 1. NꢀSubstituent Dependent CrossꢀCoupling of 4ꢀIodoꢀ2ꢀNitropyrrole Systems.
Conditionsa
Yield (%)b
Entry
Substrate
R1-M
Product
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a Conditions: (A) Various catalytic systems; (B) Pd(dppf)Cl2, Cs2CO3, DMF, 90°C; (C) Pd(dppf)Cl2, DMF, 80°C; (D)
Pd(PPh3)2Cl2, CuI, Et3N, DMF, rt. b Isolated yield.
During our previous studies into the synthesis of heronapyrrole C 8, we had initially attempted to
construct the 4ꢀallylꢀ2ꢀnitropyrrole framework via cross coupling of iodide 33a and a number of
organometallic species (Table 1, Entry 1ꢀ4). Various allylic organometallic reagents were investigated,
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however none of them had afforded the corresponding nitropyrrole derivatives. Stark and coꢀworkers
had also earlier reported investigations into the coupling reactivity of the 2ꢀnitropyrrole system using
NꢀBoc protected 4ꢀiodoꢀ2ꢀnitropyrrole 33a, however efforts to achieve coupling reactions using aryl
boronic acids or pinacolborane were abandoned after failing to deliver the expected products.12
Despite these setbacks, and the unproductive literature precedent, we carried out further investigations
into the soughtꢀafter crossꢀcoupling step using the 2ꢀnitropyrroles 33b and 33c.
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2ꢀNitropyrroles 33b and 33c, incorporating an electron donating protecting group (NꢀBOM, NꢀBoz)
on the pyrrole nucleus were revealed to be highly competent crossꢀcoupling partners, in marked
contrast to the NꢀBoc series earlier probed by Stark. SuzukiꢀMiyaura coupling reactions using aryl
boronic acids with different electronic properties afforded the expected biaryl products in good yields
(Table 1, Entries 5 and 6). Stille coupling using vinyl tributyltin, catalysed by Pd(dppf)Cl2 in DMF
successfully afforded vinyl 2ꢀnitropyrroles in 90% and 86% yield (Table 1, Entries 7 and 8). Finally,
Sonogashira coupling using 3ꢀbutynꢀ1ꢀol generated the desired alkyne in 92% yield (Table 1, Entry 9).
The results in Table 1, taken together with the earlier work reported by ourselves and others, it
appears clear that the electronic effect of the Nꢀprotecting group has a considerable influence on the
coupling reactivity of the 2ꢀnitropyrrole system; an electron donating protecting group is critical for
productive crossꢀcoupling. This successful coupling strategy now provided us with a reliable platform
to prepare novel 4ꢀsubstitutedꢀ2ꢀnitropyrrole derivatives for further investigation of the 2ꢀnitropyrrole
pharmacophore and total synthesis.
Based on the robust success of the crossꢀcoupling reactivity study, it now appeared feasible to
assemble nitropyrrolin A 1 and heronapyrrole B 7 from the common intermediate hydroxyketone 39,
in turn derived from propargylic alcohol 19 (Scheme 6). Advanced alcohol 19 would be assembled
via Sonogashira coupling of NꢀBoz protected 4ꢀiodoꢀ2ꢀnitropyrrole 33c and terminal alkyne 18.7,13
Scheme 6. Retrosynthesis of 1 and 7 via Sonogashira coupling and alkyne hydration.
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As expected based on our crossꢀcoupling study, Sonogashira coupling of 4ꢀiodoꢀ2ꢀnitropyrrole 33b
and terminal alkyne 1813 successfully afforded propargylic alcohol 19 in 90% yield (Scheme 7). As
the regioselective hydration of internal propargylic alcohols has been reported to be a challenging
task,14 three strategies were devised for parallel investigation to effect the desired conversion of 19
into 39; (1) introduction of a neighbouring acetate group (e.g. 40) to assist regioselective hydration;15
(2) ketone assisted indirect hydration via a ketal intermediate (e.g. 41);16 and (3) CO2–promoted direct
or indirect hydration via a cyclic carbonate intermediate (e.g. 42).17
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Accordingly, alcohol 19 was initially converted into the corresponding acetate 40 in 75% yield, with
expectation that the neighbouring acetate group would assist the desired regioselective alkyne
hydration (Scheme 7).15 Unfortunately, attempted hydration of alkyne 40 using mercury sulfate
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(HgSO4),18 or other catalysts (NaAuCl4 and PdCl2(CH3CN)220) under various conditions only led to
decomposition, or recovery of starting material. Alternatively, treatment of propargylic alcohol 19
with trifluoroacetophenone in presence of silver nitrate and DBU successfully afforded ketal 41 as a
mixture of two diastereomers (d.r. 1:1) in 85% yield.16 However, the subsequent hydrolysis of ketal
41 turned out to be challenging; even strong acid such as aqueous HCl (1M) in THF was not able to
hydrolyse the ketal at room temperature and use of elevated temperatures only led to decomposition.
Scheme 7. Attempted approaches for elaboration of propargylic alcohol 19 towards the natural
product framework, and the succesful route7 using pꢀtoluenesulfonamide as nucleophile.
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Finally, as reported previously,7 CO2ꢀpromoted hydration of alkyne 19 was successfully achieved,
giving carbonate 42 in high yield that was then converted to 43 by an unusual carbonate opening with
pꢀtoluenesulfonamide. Despite the limited stability of the 2ꢀnitropyrrole to a range of acidic or basic
conditions, final access to 39 was eventually effected by treatment with pyridine in methanol.21
Diastereoselective ketone reduction could then be carried out with good diastereoselectivity (d.r. ~6:1)
using (R)ꢀ2ꢀmethylꢀCBSꢀoxazaborolidine.22 The major product 44a was presumed to bear the required
7R stereogenic center based on examples of typical CBS reductions. This was later confirmed by
comparison of spectral data for the synthetic and isolated natural products.
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Scheme 8. Synthesis of nitropyrrolin A (1) and heronapyrrole B (7).
Nitropyrrolin A 1 was readily prepared by highꢀyielding NꢀBoz deprotection of 44a (Scheme 8).
Alternatively, access to heronapyrrole B 7 was achieved through Sharpless asymmetric
dihydroxylation of diol 44a using ADꢀmixꢀα, affording tetrol 45 in 40% yield, along with small
amount of the 11,12ꢀdihydroxy regioisomer. The stereochemistry of the newly introduced C15
stereogenic center was expected to be R by application of the standard mnemonic.10 Mild deprotection
of the NꢀBoz pyrrole masking group then afforded heronapyrrole B 7 in 90% yield. The spectroscopic
data and specific rotation of our synthetic heronapyrrole B were in good agreement with earlier
synthetic data (this work [α]D +10.6; Morimoto [α]D +9.95; natural [α]D +33.3) although the
magnitude of the rotation in the original isolation report was somewhat greater.1b, 4a
Conclusion
In conclusion, the strategic evolution of synthetic approaches to the 2ꢀnitropyrrole natural products
nitropyrrolin A 1 and heronapyrrole B 7 is described. Initially, an unusual sp2ꢀsp3 Stille coupling
enabled successful synthesis of advanced epoxy iodide 22, however subsequent alkylation proved
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challenging, due to the sensitive nitropyrrole subunit. A revised strategy based on Stille coupling of
iodide 23 and vinyl stannane 27 successfully established the framework of heronapyrrole B 7, leading
to the final stages of the total synthesis, however a challenging desulfonylation step defeated this
approach. Crucially, fundamental study of the palladiumꢀmediated crossꢀcoupling of the 4ꢀiodoꢀ2ꢀ
nitropyrrole system revealed a critical dependence on the use of an electronꢀdonating Nꢀsubstituent for
success. Based on this work, construction of the required 2ꢀnitroꢀ4ꢀalkylpyrrole framework was
achieved using a highly efficient Sonogashira coupling. Regioselective hydration of a propargylic
alcohol in presence of the sensitive 2ꢀnitropyrrole subunit then enabled the total synthesis of
nitropyrrolin A 1 and heronapyrrole B 7.
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The specific reactivity pattern of 2ꢀnitroꢀ4ꢀiodopyrrole systems revealed in this work provide reliable
and efficient methods to prepare 4ꢀsubstitutedꢀ2ꢀnitropyrrole derivatives to support investigation of
the littleꢀexplored 2ꢀnitropyrrole pharmacophore. The synthetic strategies reported here provide
efficient preparative access to 2ꢀnitropyrrole natural products and will facilitate material supply for
ongoing biological evaluation of the natural products and derivative libraries.
Experimental Section
General. Unless otherwise noted, all reactions were performed under an oxygenꢀfree atmosphere of
nitrogen using standard techniques. Tetrahydrofuran (THF), dichloromethane (CH2Cl2),
dimethylformamide (DMF) and acetonitrile (MeCN) were dried by passage through a column of
activated alumina under N2 using an LC Technology solvent purification system. All other reagents
were used as received unless otherwise noted. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reactions were
monitored by thinꢀlayer chromatography (TLC) carried out on silica gel plates using UV light as the
visualizing agent and an ethanolic solution of vanillin and ammonium molybdate and heat as
developing agents. Silica gel (60, 230−400 mesh) was used for flash column chromatography. NMR
spectra were recorded at room temperature in CDCl3 or CD3OD solution on a spectrometer operating
on a Bruker 400 MHz instrument. Chemical shifts are reported in parts per million on the δ scale, and
coupling constants, J, are in Hertz. Multiplicities are reported as “s” (singlet), “br s” (broad singlet),
“d” (doublet), “dd” (doublet of doublets), “ddd” (doublet of doublets of doublets), “t” (triplet), and “m”
(multiplet). Where distinct from those due to the major diastereomer, resonances due to minor
1
diastereomers are denoted by an asterisk. H and 13C NMR resonances were assigned using a
combination of DEPT 135, COSY, HSQC, HMBC, and NOESY spectra. Resonances due to the
presence of a diastereoisomer are denoted with an asterisk ‘*’. Infrared (IR) spectra were recorded
using a thin film on a composite of zinc selenide and diamond crystal on an FTꢀIR system transform
spectrometer. Melting points are uncorrected. Highresolution mass spectrometry (HRMS) was
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performed using a spectrometer operating at a nominal accelerating voltage of 70 eV or a TOFꢀQ
mass spectrometer.
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Allylic alcohol 25. To a degassed solution of iodide 23 (70 mg, 0.21 mmol) and vinyl tributyltin 24
(76 mg, 0.24 mmol) in DMF (1 mL) was added Pd2(dba)3 (10 mg, 5 mol%). The mixture was heated
to 80 °C and stirred for 2 h. Then the resulting mixture was diluted with diethyl ether (15 mL),
washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was
purified by flash chromatography (hexanes/EtOAc 10:1) to afford allylic alcohol 25 (50 mg, 85%) as
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a light yellow oil; IR νmax (neat)/cm–1: 1H NMR (300 MHz, CDCl3):
6.92 (d, J = 2.3 Hz, 1H), 5.58–5.51 (m, 1H), 4.06 (s, 2H), 3.19 (d, J = 7.4 Hz, 2H), 1.73 (s, 3H), 1.56
(s, 9H); 13C NMR (75 MHz, CDCl3):
147.1, 137.1, 123.9, 121.8, 117.3 (2C), 86.7, 68.2, 27.5 (3C),
δ 7.05–7.01 (d, J = 2.3 Hz, 1 H),
δ
24.7, 13.7, CNO2 was not observed; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C14H20N2NaO5
319.1264; Found: 319.1267.
Epoxy iodide 22. To a suspension of powdered, activated molecular sieves (4 Å ) in CH2Cl2 (10 mL)
was added Ti(OiPr)4 (457 mg, 1.61 mmol), Lꢀ(+)ꢀdiethyl tartrate (351 mg, 1.70 mmol) and tertꢀbutyl
hydroperoxide (1.08 mL, 5.0 M solution in decane, 5.40 mmol) at −20 °C. After 25 min, allylic
alcohol 25 (800 mg, 2.70 mmol) in CH2Cl2 (5 mL) was added dropwise over 30 min. The mixture was
stirred at −20 °C for 1 h and then slowly warmed up to 0 °C over 1h. The reaction was quenched with
H2O (1.0 mL) and allowed to warm to rt. After 30 min of vigorous stirring, the solution was filtered
through Celite® and concentrated in vacuo. The residue was purified by flash chromatography
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(hexanes/EtOAc 3:1) to afford the epoxy alcohol (775 mg, 92%) as a yellow oil: [α]D = +18.8 (c
2.21, CHCl3); IR νmax (neat)/cm–1: 3420, 2982, 1761, 1521, 1472, 1387, 1372, 1328, 1284, 1253, 1149,
1086, 1036, 840, 809, 769; 1H NMR (CDCl3, 400 MHz):
3.72–3.60 (m, 2H), 3.23 (t, J = 6.4 Hz, 1H), 2.71 (d, J = 6.3 Hz, 2H), 1.57 (s, 9H), 1.37 (s, 3H); 13C
NMR (CDCl3, 100 MHz): 146.8, 124.4, 120.5, 117.1, 87.0, 65.0, 61.3, 58.9, 27.5 (3C), 25.8, 14.3,
δ 7.15–7.14 (m, 1H), 7.00 (d, J =2.2 Hz, 1H),
δ
CNO2 was not observed; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C14H20N2NaO6 335.1214; Found
335.1210.
To a stirred solution of the above epoxy alcohol (360 mg, 1.15 mmol) in CH2Cl2 (8 mL) was added
imidazole (230 mg, 3.38 mmol) at 0°C. When the imidazole was totally dissolved, PPh3 (600 mg, 2.29
mmol) was added in one portion followed by addition of I2 beads (590 mg, 2.32 mmol) portionꢀwise.
The solution was stirred vigorously at 0 °C for 1 h and then concentrated in vacuo. The residue was
dissolved in EtOAc (20 mL) and washed with saturated aqueous Na2S2O3. The organic phase was
dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 10:1) to afford epoxy iodide 22 (417 mg, 86%) as a yellow oil:
[α]D20 = −11.8 (c 1.56, CHCl3); IR νmax (neat)/cm–1: 2981, 1760, 1520, 1472, 1371, 1327, 1283, 1252,
1
1148, 1087, 840, 809, 768; H NMR (CDCl3, 400 MHz):
δ
7.19–7.18 (m, 1H), 7.01 (d, J = 2.2 Hz,
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1H), 3.26 (d, J = 9.9 Hz, 1H), 3.10 (d, J = 9.9 Hz, 1H), 3.05 (t, J = 6.3 Hz, 1H), 2.68 (d, J = 6.3 Hz,
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2H), 1.56 (s, 9H), 1.54 (s, 3H); 13C NMR (CDCl3, 100 MHz):
δ 146.7, 138.4 (weak, CNO2), 124.4,
119.8, 117.0, 87.0, 65.1, 60.5, 27.5 (3C), 26.6, 16.1, 12.8; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for
C14H19IN2NaO5 445.0231; Found 445.0219.
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Sulfone 21. To a stirred solution of geraniol (3.08 g, 20.0 mmol) and Ph3P (7.86 g, 30.0 mmol) in
THF (100 mL) was added NBS (5.34 g, 30.0 mmol) in small portions at −20 °C over 20 min. The
mixture was warmed up to 0 °C over 30 min, then PhSO2Na (6.56 g, 40.0 mmol) and Bu4NI (0.73 g,
2.0 mmol) were added portionꢀwise over 10 min. The mixture was stirred overnight and then
concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and washed with saturated
aqueous Na2S2O3 (50 mL). The layers were separated and the aqueous phase was extracted with
EtOAc (2 × 50 mL). The combined organic extracts were successively washed with water and brine,
dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 5:1) to afford sulfone 21 (5.00 g, 90%) as a colourless oil: 1H NMR
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(CDCl3, 300 MHz):
1H), 5.05–4.99 (m, 1H), 3.80 (d, J = 7.9 Hz, 2H), 2.00–1.98 (m, 4H), 1.68 (s, 3H), 1.58 (s, 3H), 1.31
(s, 3H); 13C NMR (CDCl3, 75 MHz):
146.3, 138.7, 138.5, 132.1, 128.9 (2C), 128.6 (2C), 123.4,
δ 7.88–7.84 (m, 2H), 7.66–7.60 (m, 1H), 7.55–7.49 (m, 2H), 5.18 (t, J = 7.9 Hz,
δ
110.3, 56.1, 39.6, 26.2, 25.7, 17.6, 16.1; Spectroscopic data were in good agreement with those
previously reported.23
Acetonide 29. To a suspension of K3Fe(CN)6 (3.73 g, 11.3 mmol), K2CO3 (1.56 g, 11.3 mmol) and
(DHQ)PHAL (29.4 mg, 0.38 mmol) in tꢀBuOH (20 mL) and H2O (20 mL) was added OsO4 (0.20 mL,
40 mg/mL in tertꢀbutanol, 0.015 mmol) at 0 °C. After 10 min, methanesulfonamide (359 mg, 3.78
mmol) was added, followed by sulfone 21 (1.05 g, 3.78 mmol). The reaction mixture was stirred for
24 h at 0 ⁰C, then quenched with saturated aqueous sodium sulfite (5 mL), warmed to room
temperature and stirred for another 1 h. The mixture was extracted with ethyl acetate (3 × 30 mL) and
the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc 1:2) to afford the
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expected diol (1.08 g, 92%) as a colourless oil: [α]D = +5.6 (c 1.86, CHCl3); IR νmax (neat)/cm–1:
3480, 2977, 2518, 1447, 1304, 1146, 1083, 732, 687; 1H NMR (CDCl3, 400 MHz):
δ 7.87 –7.81 (m,
2H), 7.64–7.59 (m, 1H), 7.55–7.48 (m, 2H), 5.25–5.16 (m, 1H), 3.81 (d, J = 9.6 Hz, 2H), 3.26 (dd, J
= 10.7, 1.5 Hz, 1H), 2.46 (brs, 1 H, OH), 2.45 (brs, 1 H, OH), 2.29–2.19 (m, 1H), 2.11–2.01 (m, 1H),
1.53–1.42 (m, 1H), 1.44–1.38 (m, 1H), 1.35 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H); 13C NMR (CDCl3, 100
MHz):
δ 146.5, 138.8, 133.7, 129.1 (2C), 128.4 (2C), 110.6, 77.8, 73.2, 56.1, 36.7, 29.3, 26.4, 23.2,
16.2; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C16H24NaO4S 335.1288; Found 335.1290.
The above diol (312 mg, 1.00 mmol) was stirred together with camphorsulfonic acid (12 mg, 0.05
mmol) and 2,2ꢀdimethoxypropane (520 mg, 5.00 mmol) in CH2Cl2 (5 mL) at room temperature for 3
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h. The resulting mixture was then diluted with saturated aqueous NaHCO3 (15 mL) extracted with
dichloromethane (3 × 15 mL). The combined organics were washed with brine, dried over Na2SO4
and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc
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5:1) to afford acetonide 29 (334 mg, 95%) as a colourless oil: [α]D = +9.7 (c 1.21, CHCl3); IR νmax
(neat)/cm–1: 2976, 2934, 1447, 1447, 1302, 1146, 1083, 738, 688; 1H NMR (CDCl3, 400 MHz):
δ 7.89
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–7.85 (m, 2H), 7.66–7.61 (m, 1H), 7.56–7.50 (m, 2H), 5.22–4.28 (m, 1H), 3.81 (d, J = 8.1 Hz, 2H),
3.61 (dd, J = 9.7, 3.5 Hz, 1H), 2.29–2.19 (m, 1H), 2.09–2.00 (m, 1H), 1.58–1.49 (m, 1H), 1.44–1.38
(m, 4H), 1.36 (d, J = 1.0 Hz, 3H), 1.32 (s, 3H), 1.23 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100
MHz):
δ 145.9, 138.8, 133.6, 129.0 (2C), 128.5 (2C), 110.6, 106.7, 82.7, 80.1, 56.1, 36.9, 28.6, 27.5,
26.9, 26.1, 22.9, 16.3; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C19H28NaO4S 375.1601; Found
375.1590.
Bromide 28. To a solution of (Z)ꢀ3ꢀiodoꢀ2ꢀmethylpropꢀ2ꢀenꢀ1ꢀol (198 mg, 1.00 mmol) and Ph3P (340
mg, 1.30 mmol) in CH2Cl2 (5 mL) was added NBS (267 mg, 1.50 mmol) at −20 °C. After 1 h, the
reaction mixture was diluted with pentane (20 mL), filtered through a silica plug and concentrated in
vacuo to afford bromide 28 (200 mg, 77%), which was immediately used in the next step due to its
instability: 1H NMR (CDCl3, 400 MHz):
δ
6.20 (s, 1H), 4.08 (s, 2H), 2.06 (s, 3H); 13C NMR (CDCl3,
100 MHz): 143.3, 79.9, 37.4, 22.1. Spectroscopic data were in good agreement with those
δ
previously reported.24
Iodide 30. A solution of sulfone 29 (352 mg, 1.0 mmol) and bromide 28 (312 mg, 1.20 mmol) in THF
(5 mL) was cooled to −45 °C. A solution of tꢀBuOK (134 mg, 1.2 mmol) in THF (2.0 mL) was added
dropwise over 15 min. The resulting mixture was stirred at −45°C for 1 h, quenched with saturated
aqueous NH4Cl (1.0 mL) and warmed up to room temperature. The mixture was diluted with H2O (20
mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 5:1) to afford iodide 30 (399 mg, 75%) as a colourless oil: IR νmax
1
(neat)/cm–1: 3488, 2974, 1447, 1303, 1266, 1143, 1082, 734, 688; H NMR (CDCl3, 400 MHz):
δ
7.92–7.84 (m, 2H), 7.69–7.61 (m, 1H), 7.60–7.53 (m, 2H), 5.99–5.96 (m, 1H), 5.14–5.06 (m, 1H),
4.15–4.06 (m, 1H), 3.66–5.59 (m, 1H), 2.92–2.77 (m, 1H), 2.76–2.67 (m, 1H,), 2.06–1.94 (m, 1H),
1.82 (s, 1.5 H), 1.83* (s, 1.5 H), 1.58–1.45 (m, 1H), 1.47ꢀ1.43 (m, 1H), 1.41 (s, 3H), 1.40–1.35 (m,
1H), 1.33 (s, 3H), 1.31 (d, J = 1.2 Hz, 1.5H), 1.26* (d, J = 1.2 Hz, 1.5 H), 1.24 (s, 3H), 1.08 (s, 3H);
13C NMR (CDCl3, 100 MHz):
δ 145.6, 145.5*, 142.9, 142.8*, 137.8, 133.6, 129.3 (2C), 128.9 (2C),
116.1, 116.0*, 106.7, 82.9, 82.8*, 80.1, 77.9, 77.8*, 62.6, 36.7, 36.8*, 36.6, 28.6, 27.6, 27.5*, 26.9,
26.2, 26.1*, 24.5, 24.4*, 23.0, 16.8, 16.7*; *donates minor isomer. HRMS (ESIꢀTOF) m/z: [M+Na]+
Calcd for C23H33NaIO4S 555.1037; Found 555.1040.
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Stannane 27. A mixture of iodide 30 (53 mg, 0.10 mmol), DIPEA (4 mg, 0.03 mmol), (Me3Sn)2 (50
mg, 0.15 mmol) and (Ph3P)4Pd (11.5 mg, 0.01 mmol) in degassed toluene (1 mL) was stirred at 70 °C
for 30 min. The resulting mixture was concentrated in vacuo. The residue was subjected to flash
chromatography (hexanes/EtOAc 10:1) to afford stannane 27 (39 mg, 68%) as a colourless oil: IR νmax
(neat)/cm–1: 3488, 2974, 1447, 1303, 1266, 1143, 1082, 734, 688; 1H NMR (CDCl3, 400 MHz):
δ 7.86
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–7.82 (m, 2H), 7.66–7.61 (m, 1H), 7.55–7.49 (m, 2H), 5.56 (s, 1H), 4.92–4.85 (m, 1H), 4.05–3.93 (m,
1H), 3.65–3.55 (m, 1H), 3.00–2.90 (m, 1H), 2.40–2.28 (m, 1H,), 2.25–2.14 (m, 1H), 2.05–1.92 (m,
1H ), 1.75 (s, 3H), 1.55–1.44 (m, 1H), 1.40 (s, 3H), 1.40–1.33 (m, 1H), 1.33 (s, 3H), 1.30 (d, J = 1.2
Hz, 1.5H), 1.28* (d, J = 1.2 Hz, 1.5H), 1.24 (s, 1.5H), 1.22* (s, 1.5H), 1.08 (s, 1.5H), 1.07* (s, 1.5H),
0.12 (s, 9H); 13C NMR (CDCl3, 100 MHz):
δ 149.3, 149.2*, 145.2, 145.0*, 137.8, 137.7*, 133.5,
129.4*, 129.37, 129.3 (2C), 128.8 (2C), 116.91*, 116.87, 106.7, 82.7*, 82.1, 80.1, 63.53, 63.50*, 37.8,
37.6*, 36.8*, 36.7, 28.6, 27.7, 27.4*, 27.0*, 26.9, 26.2, 26.1*, 25.7, 25.6*, 22.98*, 22.95, 16.7, 16.5*;
−8.5 (3C); *donates minor isomer. HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C26H42NaO4SSn
593.1722; Found 593.1726.
Diene 26. To a degassed solution of iodide 23 (70 mg, 0.20 mmol) and stannane 27 (136 mg, 0.24
mmol) in DMF (1 mL) was added Pd2(dba)3 (10 mg, 5 mol%) and the mixture was stirred at 80 °C for
2 h. The mixture was diluted with diethyl ether (15 mL), washed with H2O/brine (1:1), dried over
sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography
(hexanes/ EtOAc 6:1) to afford diene 26 (96 mg, 76%) as a light yellow oil: IR νmax (neat)/cm–1: 2925,
1652, 1620, 1603, 1449, 1339, 1188, 1098, 980, 766, 697; 1H NMR (CDCl3, 400 MHz):
δ 7.86 –7.82
(m, 2H), 7.66–7.60 (m, 1H), 7.55–7.49 (m, 2H), 7.04–6.96 (m, 1H), 6.91–6.85 (m, 1H), 5.39–5.31 (m,
1H), 5.05–4.97 (m, 1H), 3.95–3.80 (m, 1H), 3.65–3.55 (m, 1H), 3.24–3.04 (m, 2H), 2.94–2.81 (m,
1H), 2.59–2.49 (m, 1H), 2.24–2.09 (m, 1H), 1.99–1.87 (m, 1H), 1.68 (s, 3H), 1.57 (s, 9H), 1.47–1.37
(m, 4H), 1.35–1.28 (m, 4H), 1.22 (s, 3H), 1.20 (d, J = 1.4 Hz, 1.5H), 1.13* (d, J = 1.4 Hz, 1.5H), 1.06
(s, 3H); 13C NMR (CDCl3, 100 MHz):
δ 147.0, 145.3, 145.1*, 138.9 (weak, CNO2), 137.9, 137.8*,
113.6, 113.5*, 133.0, 129.2 (2C), 129.1*, 129.08*, 129.05, 128.9 (2C), 128.8*, 124.8, 124.0*, 123.9,
117.2*, 117.1, 117.09*, 117.07, 106.7, 86.7, 82.8*, 82.7, 80.0, 63.4, 36.9, 36.8*, 29.8, 29.5*, 28.6,
27.7, 27.6*, 27.5 (3C), 26.9, 26.1, 25.0, 23.62*, 23.60, 22.9, 22.8*, 16.4, 16.1*; *donates minor
isomer. HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C33H46N2NaO8S 653.2867; Found 653.2859.
Sulfone 31. To a suspension of K3Fe(CN)6 (373 mg, 1.10 mmol), K2CO3 (156 mg, 1.10 mmol) and
(DHQ)PHAL (2.9 mg, 0.038 mmol) in tꢀBuOH (2 mL) and H2O (2 mL) was added OsO4 (20 ꢁL, 40
mg/mL in tꢀBuOH, 0.015 mmol) at 0 °C. After 10 min, methanesulfonamide (19 mg, 0.20 mmol) was
added, followed by diene 26 (96 mg, 0.15 mmol). The reaction mixture was stirred for 24 h at 0 ⁰C,
then quenched with saturated aqueous sodium sulfite (1 mL), warmed to room temperature and stirred
for 1 h. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The
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combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by column chromatography (hexanes/EtOAc 1:2) to afford the
diol (90 mg, 90%) as a colourless oil: IR νmax (neat)/cm–1: 3493, 2926, 1718, 1447, 1370, 1297, 1143,
6
1082, 734, 688; 1H NMR (CDCl3, 400 MHz):
δ 7.86–7.80 (m, 2H), 7.66–7.60 (m, 1H), 7.55–7.49 (m,
7
8
2H), 7.19–7.10 (d, J = 2.2, 1H), 7.03–7.00 (m, 1H), 5.14 (d, J = 9.8 Hz. 1H), 4.30–4.14 (m, 1H),
3.64–3.49 (m, 2H), 2.76–2.59 (m, 2H), 2.51–2.34 (m, 2H), 2.23–2.11 (m, 1H), 2.05–1.92 (m, 1H),
1.76–1.63 (m, 1H), 1.56 (s, 9H), 1.46–1.36 (m, 4H), 1.30 (s, 3H), 1.26–1.20 (m, 6H), 1.14 (s, 3H),
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1.07(s, 1.5H), 1.05* (s, 1.5H). 13C NMR (CDCl3, 100 MHz):
δ 146.9, 144.8, 144.2*, 138.3 (weak,
CNO2), 137.3, 137.2*, 133.7, 133.6*, 129.35*, 129.29 (2C), 128.85 (2C), 128.81*, 125.1*, 125.0,
122.1, 122.0*, 119.4*, 118.8, 117.7, 106.8, 106.7*, 86.8, 83.2, 82.8*, 80.08, 80.05*, 78.5, 77.7*, 73.7,
73.5*, 60.9, 60.6*, 37.1, 36.8*, 35.1, 34.3*, 29.7*, 28.6, 28.5, 28.4, 27.3*, 27.5(3C), 26.9, 26.1, 26.0*,
23.7, 23.5*, 23.0, 22.9*, 16.4, 16.3*; *donates minor isomer. HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd
for C33H48N2NaO10S 687.2922; Found 687.2905.
The above diol (90 mg, 0.14 mmol) was stirred together with camphorsulfonic acid (2.3 mg, 0.01
mmol) and 2,2ꢀdimethoxypropane (52 mg, 0.50 mmol) in CH2Cl2 (1 mL) at room temperature for 3 h.
The resulting mixture was diluted with saturated aqueous NaHCO3 (15 mL) and extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate
and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc
3:1) to afford sulfone 31 (94 mg, 95%) as a light yellow oil: IR νmax (neat)/cm–1: 2926, 1718, 1447,
1370, 1297, 1143, 1082, 734, 688; 1H NMR (CDCl3, 400 MHz):
δ 7.86–7.80 (m, 2H), 7.66–7.60 (m,
1H), 7.55–7.49 (m, 2H), 7.20–7.13 (m, 1H), 7.05–7.00 (m, 1H), 5.11 (d, J = 9.8 Hz, 1H), 4.17 (t, J
=10.3 Hz, 0.5 H), 3.95* (t, J = 9.3 Hz, 0.5 H), 3.91 (dd, J = 10.3, 3.1, 0.5 H), 3.82* (dd, J = 10.3, 2.6,
0.5 H), 3.63–3.56 (m, 1H), 2.78–2.48 (m, 2H), 2.26–2.10 (m, 2H), 2.0–1.87 (m, 2H), 1.57 (s, 9H),
1.51–1.43 (m, 2H), 1.41* (s, 1.5H), 1.40 (s, 1.5H), 1.32 (s, 3H), 1.30* (s, 3H), 1.28 (s, 3H), 1.27* (s,
3H), 1.23 (s, 1.5H), 1.22* (s, 1.5H), 1.17 (s, 1.5H), 1.16* (s, 1.5H), 1.09 (s, 1.5H), 1.08* (s, 1.5H);
13C NMR (CDCl3, 100 MHz):
δ 146.9, 144.5, 142.5*, 138.2 (weak, CNO2), 137.9, 137.8*, 133.5,
133.4*, 129.3*, 129.2 (2C), 128.7 (2C), 124.6, 121.4, 121.3*, 119.8*, 119.7, 117.5, 108.2*, 107.8,
106.7, 106.6*, 86.8, 84.7, 83.7*, 83.0, 82.8*, 80.9, 80.5*, 80.0, 601.1, 60.9*, 36.9, 36.8*, 33.0, 31.9*,
28.5, 28.0, 27.8*, 27.6, 27.4 (3C), 27.3*, 26.9, 26.8, 26.7*, 26.1, 26.07*, 26.0, 25.7*, 23.7*, 23.3,
22.9, 16.48, 16.2*; *donates minor isomer. HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for
C36H52N2NaO10S 727.3235; Found 727.3238.
NꢀBOMꢀ4ꢀ(2ꢀMethoxyphenyl)ꢀ2ꢀnitropyrrole 34. To a degassed solution of iodide 33b (36 mg, 0.10
mmol) in DMF (1 mL) was added Pd(dppf)Cl2 (2.5 mg, 5 mol%), (2ꢀmethoxyphenyl)boronic acid (23
mg, 0.15 mmol) and Cs2CO3 (65 mg, 0.20 mmol). The mixture was stirred at 90 °C overnight then
diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by
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flash chromatography (hexanes/EtOAc 9:1) to afford 34 (27 mg, 82%) as a yellow oil: IR νmax
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(neat)/cm–1: 2935, 1465, 1358, 1304, 1203, 925, 736, 697; 1H NMR (CDCl3, 400 MHz):
= 1.9 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.51–7.45 (m, 1H), 7.26–7.36 (m, 6H), 6.98–7.04 (m, 2H),
5.82 (s, 2H), 4.61 (s, 2H), 3.92 (s, 3H); 13C NMR (CDCl3, 100 MHz):
156.4, 137.2, 136.5, 128.7
δ 7.63 (d, J
δ
8
9
(2C), 128.6, 128.5, 128.2, 127.9 (2C), 127.8, 121.1, 121.0, 114.4, 111.3, 77.8, 71.0, 55.4, CNO2 was
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not observed; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C19H18N2NaO4 361.1159; Found 361.1163.
NꢀBOMꢀ4ꢀ(pꢀTolyl)ꢀ2ꢀnitropyrrole 35. To a solution of iodide 33b (36 mg, 0.10 mmol) in degassed
DMF (1 mL) was added Pd(dppf)Cl2 (2.5 mg, 5 mol%), (4ꢀmethylphenyl)boronic acid (20 mg, 0.15
mmol) and CsCO3 (65 mg, 0.20 mmol). The mixture was stirred at 90 °C overnight then diluted with
H2O (10 mL) extracted with ethyl acetate (3× 10 mL). The combined organic layers were washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash
chromatography (hexanes/EtOAc 10:1) to afford 35 (25 mg, 78%): IR νmax (neat)/cm–1: 3104, 2918,
1446, 1372, 1353, 1292, 1202, 1073, 1043, 812, 695, 734; 1H NMR (CDCl3, 400 MHz):
1.9 Hz, 1H), 7.27–7.3 (m, 7H), 7.20–7.24 (m, 3H), 5.82 (s, 2H), 4.62 (s, 2H), 2.38 (s, 3H); 13C NMR
(CDCl3, 100 MHz): 137.3, 136.4, 129.7 (2C), 129.6, 128.6 (2C), 128.3, 127.8 (2C), 125.3 (2C),
δ 7.39 (d, J =
δ
125.1, 124.8, 112.4, 78.0, 71.3, 21.2, CNO2 was not observed; HRMS (ESIꢀTOF) m/z: [M+Na]+
Calcd for C19H18N2NaO3 345.1215; Found 345.1218.
NꢀBOMꢀ4ꢀ(Vinyl)ꢀ2ꢀnitropyrrole 36. A mixture of iodide 33b (395 mg, 1.10 mmol), vinyltributyltin
(385 mg, 1.20 mmol), Pd(dppf)Cl2 (8.0 mg, 0.01 mmol) in degassed DMF (2 mL) was stirred at 90 °C
overnight. The mixture was directly subjected to flash chromatography (hexanes/EtOAc 10:1) to
afford 36 (250 mg, 90%) as a yellow oil: IR vmax (neat)/cm–1: 3121, 3031, 2898, 1459, 1342, 1289,
1
1087, 1075, 904, 836, 734, 696. H NMR (CDCl3, 400 MHz):
δ 7.33–7.25 (m, 6H), 6.99 (d, J = 2.2
Hz, 1H); 6.50–6.43 (dd, J = 17.5, 10.9 Hz, 1H), 5.74 (s, 2H), 5.55–5.51 (dd, J = 17.4, 1.0 Hz, 1H),
5.19–5.16 (dd, J = 10.9, 1.0 Hz, 1H), 4.56 (s, 2H); 13C NMR (CDCl3, 100 MHz):
137.5 (weak,
δ
CNO2), 136.3, 128.6 (2C), 128.2, 127.8 (2C), 127.5, 126.4, 123.0, 114.0, 111.9, 77.8, 71.2; HRMS
(ESIꢀTOF) m/z: [M+Na]+ Calcd for C14H14N2NaO3 281.0897; Found 281.0901.
NꢀBozꢀ4ꢀ(Vinyl)ꢀ2ꢀnitropyrrole 37. A mixture of iodide 33c (930 mg, 2.50 mmol), vinyltributyltin
(950 mg, 3.00 mmol), Pd(dppf)Cl2 (8 mg, 0.01mmol) in degassed DMF (2.5 mL) was stirred at 90 °C
for 3 h. The mixture was directly subjected to flash chromatography (hexanes/EtOAc 10:1) to afford
37 (571 mg, 84%) as a yellow solid: mp 101.3–103.9 °C; IR vmax (neat)/cm–1: 3125, 1724, 1468, 1352,
1258, 1084, 1066, 709; 1H NMR (CDCl3, 400 MHz):
7.47 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 6.42–6.49 (m, 1H), 6.46 (s, 2H), 5.55
(d, J = 17.4 Hz, 1H), 5.19 (dd, J = 11.0, 1.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
165.7, 133.9,
δ 8.02–8.04 (m, 2H), 7.56–7.61 (m, 1H), 7.41–
δ
130.1 (2C), 128.6 (2C), 128.1, 127.2, 123.2, 121.7, 114.5, 112.2, 69.9, CNO2 was not observed;
HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C14H12N2NaO4 295.0690; Found 295.0693.
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NꢀBOMꢀ4ꢀ(4′ꢀAlkynyl)ꢀ2ꢀnitropyrrole 38. To a solution of iodide 33b (90 mg, 0.25 mmol) in
degassed DMF (0.5 mL) and Et3N (0.5 mL) was added Pd(PPh3)2Cl2 (9 mg, 5 mol%) and CuI (1 mg,
2.5 mol%). After 15 min, 4ꢀpentyneꢀ1ꢀol (32 mg, 0.38 mmol) was added and the mixture was stirred
at room temperature for 2 h. The mixture was diluted with Et2O (20 mL), filtered through a Celite®
plug, washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The crude
product was purified by flash chromatography (hexanes/EtOAc 7:1) to afford compound 38 (56 mg,
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72%) as a yellow oil: IR νmax (neat)/cm–1: 3303, 2920, 1432, 1322, 1276, 1033, 843, 665; H NMR
(CDCl3, 400 MHz):
2H), 4.56 (s, 2H), 3.79 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 6.0 Hz, 2H), 1.87–1.80 (m, 2H); 13C NMR
(CDCl3, 100 MHz): 136.1, 130.6 (2C), 128.7, 128.3, 127.8 (2C), 117.5, 106.2, 90.2, 78.0, 72.7, 71.3,
δ 7.38–7.27 (m, 5H), 7.21 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 5.73 (s,
δ
61.7, 31.3, 15.9, CNO2 was not observed; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C17H18N2NaO4
337.1159; Found: 337.1167.
Alkyne 19. Iodide 33c (148 mg, 0.40 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol), CuI (7.6 mg, 0.04
mmol) were added successively to degassed triethylamine/DMF (2:1, 3 mL) and stirred for 10 min at
room temperature. Alkyne 18 (105 mg, 0.48 mmol) in trimethylamine (0.5 mL) was slowly added
over 30 min and the mixture was stirred for a further 2 h. The reaction mixture was added slowly to a
1:1 mixture of cooled aqueous HCl (1M) and brine (30 mL) and extracted with diethyl ether (3 × 30
mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo.
Purification by flash chromatography (hexanes/ EtOAc 3:1 to 2:1) afforded alkyne 19 (168 mg, 90%)
as a yellow oil. [α]D = −15.7 (c 2.30, CHCl3); IR νmax (neat)/cm–1: 3525, 2915, 1730, 1474, 1380,
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1313, 1261, 1083, 1065, 1025, 839, 708; 1H NMR (CDCl3, 400 MHz) δ 8.05ꢀ8.00 (m, 2H), 7.63ꢀ7.57
(m, 1H), 7.48ꢀ7.41 (m, 2H), 7.33 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.46 (s, 2H), 5.24ꢀ5.17
(m, 1H), 5.11ꢀ5.05 (m, 1H), 2.39ꢀ2.27 (m, 1H), 2.26ꢀ2.15 (m, 1H), 2.11ꢀ2.03 (m, 2H), 2.03ꢀ1.96 (m,
2H), 1.79ꢀ1.73 (m, 2H), 1.68 (d, J = 0.8 Hz, 3H), 1.66 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 165.6, 136.3, 134.0, 132.8, 131.5, 130.1, 128.6 (2C), 128.4 (2C), 124.1, 123.5,
117.6, 105.6, 93.9, 75.0, 69.8, 68.9, 43.3, 39.7, 29.8, 26.6, 25.7, 23.7, 17.7, 16.1, (NO2C not observed);
HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C27H32N2NaO5 487.2203; Found 487.2220.
Acetate 40. A mixture of propargylic alcohol 19 (46 mg, 0.10 mmol), DMAP (3.6 mg, 0.03 mmol),
Et3N (30.3 mg, 0.30 mmol) and Ac2O (51 mg, 0.50 mmol) in CH2Cl2 (1 mL) was stirred overnight at
room temperature. The mixture was concentrate in vacuo and the residue was purified by flash
chromatography (hexanes/EtOAc 8:1) to afford acetate 40 (38 mg, 75%) as a yellow oil: [α]D18 = −7.4
(c 2.00, CHCl3); IR νmax (neat)/cm–1: 2918, 1731, 1475, 1382, 1246, 2083, 1065, 1025, 837, 708; H
1
NMR (CDCl3, 400 MHz)
δ 8.05–8.00 (m, 2H), 7.63–7.57 (m, 1H), 7.48–7.41 (m, 2H), 7.35 (d, J =
2.06, 1H), 7.28 (d, J = 2.06, 1H), 6.45 (s, 2H), 5.19–5.12 (m, 1H), 5.12–5.05 (m, 1H), 2.26–2.12 (m,
2H), 2.11–1.95 (m, 8H), 1.91–1.82 (m, 1H), 1.71 (s, 3H), 1.68 (s, 3H), 1.62 (s, 3H), 1.59 (d, J = 1.79,
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3H); 13C NMR (CDCl3, 400 MHz)
δ 169.3, 165.6, 136.4, 135.9, 134.0, 133.0, 131.4, 130.1 (2C),
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128.6 (2C), 128.4, 124.2, 123.0, 117.8, 105.4, 90.5, 75.3, 69.8, 41.4, 39.6, 26.7, 26.4, 25.7, 22.9, 21.9,
17.7, 16.0, CNO2 not observed; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C29H34N2NaO6 529.2309;
Found 529.2300.
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Cyclic ketal 41. To a solution of propargylic alcohol 19 (46 mg, 0.10 mmol) and trifluoromethyl
acetophenone (22.8 mg, 0.12 mmol) in toluene (1.0 ml) was added AgNO3 (1.7 mg, 0.01 mmol) and
DBU (1.5 mg, 0.01 mmol). The mixture was stirred at room temperature overnight. The mixture was
concentrated in vacuo and the residue was purified by flash chromatography (hexanes/EtOAc, 10:1)
to afford cyclic ketal 41 as a 1:1 mixture of two diasteteomers (54 mg, 85%) as a yellow oil: IR νmax
(neat)/cm–1: 2917, 1728, 1470, 1379, 1314, 1260, 1185, 1083, 1065, 1025, 955, 720, 707, 696; 1H
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NMR (CDCl3, 400 MHz):
7H), 6.54 (s, 2H), 5.20–4.83 (m, 3H), 2.41–1.63 (m, 8H), 1.68* (s, 2H), 1.62 (s, 4H), 1.60 (s, 2H),
1.53*(s, 1H), 1.32* (s, 1H), 1.21(s, 2H); 13C NMR (CDCl3, 400 MHz)
165.7.3, 156.1*, 155.9, 136.9,
δ 8.11–8.01 (m, 2H), 7.74–7.63 (m, 2H), 7.61–7.54 (m, 1H), 7.50–7.37 (m,
δ
136.1, 135.9*, 134.5, 134.0*, 133.8, 131.4, 131.3*, 130.1, 130.0 (4C), 128.7, 128.6 (4C), 128.2 (2C),
126.9, 126.6*, 124.2, 124.1*, 123.1, 122.6*, 118.89, 118.87*, 114.4, 88.7*, 88.4, 87.6*, 86.8, 70.1,
41.9*, 40.2, 39.6, 39.5*, 27.2, 26.7, 26.5*, 25.7, 25.6*, 22.6*, 22.2, 17.7, 17.6*, 15.9, 15.7*; HRMS
(ESIꢀTOF) m/z: [M+Na]+ Calcd for C35H37F3N2NaO6 661.2496; Found 661.2500.
Cyclic carbonate 42. To a solution of 2ꢀnitropyrrole 19 (600 mg, 1.3 mmol) in dichloromethane (0.5
mL) in a 45 mL sealed tube was added PPh3 (85 mg, 0.32 mmol) and AgCO3 (36 mg, 0.13 mmol).
The mixture was stirred for 5 min before dry ice (600 mg) was quickly sealed inside to create a CO2
atmosphere. The mixture was stirred at room temperature overnight and then directly subjected to
flash chromatography (hexanes/ EtOAc 5:1 to 3:1) to afford cyclic carbonate 42 (594 mg, 90%) as a
yellow liquid. [α]D18 = +0.7 (c 1.60, CHCl3); IR νmax (neat)/cm–1: 1829, 1728, 1474, 1384, 1305, 1263,
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1085, 709; H NMR (CDCl3, 400 MHz) δ 8.08ꢀ7.98 (m, 2H), 7.63ꢀ7.53 (m, 1H), 7.50ꢀ7.37 (m, 4H),
6.48 (s, 2H), 5.35 (s, 1H), 5.11ꢀ5.00 (m, 2H), 2.39ꢀ2.27 (m, 2H), 2.26ꢀ1.89 (m, 5H), 1.83ꢀ1.73 (m,
1H), 1.66 (s, 3H), 1.63 (s, 3H), 1.57 (s, 3H), 1.56 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.7, 151.0,
150.4, 137.2, 134.0, 131.6, 130.1, 129.1, 128.7 (2C), 128.6 (2C), 124.1, 121.6, 116.6, 114.5, 93.2,
87.7, 70.2, 40.5, 39.6, 26.6 (2C), 25.7, 22.0, 17.7, 16.1, (NO2C not observed); HRMS (ESIꢀTOF) m/z:
[M+Na]+ Calcd for C28H32N2NaO7 531.2102; Found 531.2097.
Toluenesulfonyl carbamate 43. A mixture of cyclic carbonate 42 (112 mg, 0.2 mmol) , pꢀ
toluenesulfonylamide (137 mg, 0.8 mmol) and K2CO3 (55 mg, 0.4 mmol) in DMF (1 mL) was stirred
at 80 °C for 3 h. The resulting mixture was diluted with brine (25 mL) and extracted with diethyl ether
(3 × 25 mL). The combined organic extracts were dried over sodium sulfate and concentrated in
vacuo. Purification by flash chromatography (hexanes/ EtOAc 1:1) afforded toluenesulfonyl
carbamate 43 (111 mg, 90%) as a light yellow oil. [α]D20 = –12.6 (c 5.10, CHCl3); IR νmax (neat)/cm–1:
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1924, 1727, 1468, 1451, 1376, 1262, 1156, 1085, 1066, 735, 710, 662; 1H NMR (CDCl3, 400 MHz) δ
8.01 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.62ꢀ7.54 (m, 1H), 7.46ꢀ7.39 (m, 2H), 7.37ꢀ7.30 (m,
2H), 7.10 (s, 1H), 7.02 (s, 1H), 6.42 (s, 2H), 5.13ꢀ4.90 (m, 2H), 3.41 (s, 2H), 2.41 (s, 3H), 2.09ꢀ1.78
(m, 8H), 1.67 (s, 3H), 1.58 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 204.2,
181.4, 165.7, 149.4, 145.4, 136.8, 136.6, 135.4, 133.8, 131.6, 130.0, 129.7 (2C), 128.6 (2C), 128.5
(2C), 128.3 (2C), 124.0, 122.0, 116.4, 116.1, 39.6, 36.4, 34.7, 33.5, 26.5, 25.7, 21.6 (2C), 20.2, 17.7,
15.9, NO2C not observed; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C35H41N3NaO9S 702.2456;
Found 702.2452.
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Hydroxyketone 39. A solution of toluene sulfonyl carbomate 43 (111 mg, 0.16 mmol) in
pyridine/methanol (2:1, 3 mL) was stirred at 70 °C overnight. The resulting mixture was concentrated
in vacuo and purified by flash chromatography (hexanes/ EtOAc 2:1) to afford hydroxyketone 39 (47
mg, 60%) as a light yellow oil. [α]D20 = +9.0 (c 2.60, CHCl3); IR νmax (neat)/cm–1: 3496, 2851, 1722,
1452, 1375, 1308, 1065, 1025, 710; 1H NMR (CDCl3, 400 MHz) δ 8.03 (br d, J = 8.0 Hz, 2H), 7.59
(br t, J =7.1 Hz, 1H), 7.44 (br t, J =8.0 Hz, 2H), 7.20 (br s, 1H), 7.18 (br s, 1H), 6.46 (s, 2H), 5.12ꢀ
5.01 (m, 2H), 3.71 (s, 2H), 2.16ꢀ1.98 (m, 3H), 1.98ꢀ1.90 (m, 2H), 1.86ꢀ1.75 (m, 3H), 1.67 (s, 3H),
1.59 (s, 3H), 1.55 (s, 3H), 1.40 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.7, 165.7, 136.8, 136.5,
133.9, 131.5, 130.0, 129.7, 128.6 (2C), 128.5 (2C), 124.1, 122.9, 116.2, 115.9, 97.1, 69.9, 39.6. 39.5,
33.7, 26.5, 25.7, 25.6, 22.2, 17.7, 16.0; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C27H34N2NaO6
505.2309; Found 505.2293.
Diols 44a and 44b. A solution of (R)ꢀCBS (1 M solution in toluene, 0.3 mL, 0.3 mmol) in THF (5 mL)
was treated with the dropwise addition of BH3·DMS (22 mg, 0.3 mmol) in THF (0.3 mL). The
resulting mixture was stirred at room temperature for 20 min and then cooled to −40 °C. A solution of
hydroxyketone 39 (57 mg, 0.12 mmol) in THF (0.5 mL) was added dropwise and the reaction mixture
was stirred at −40 °C for 3 h. The reaction was quenched with MeOH (0.1 mL) and concentrated in
vacuo. Purification of the crude residue by flash column chromatography (hexanes/EtOAc 2:1 to 1:1)
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afforded diols 44a (35 mg, 60%) and 44b (6 mg, 11%) as yellow oils. 44a: [α]D = +8.7 (c 0.90,
CHCl3); IR νmax (neat)/cm–1: 351, 2923, 1726, 1465, 1451, 1375, 1310, 1260, 1084, 711; 1H NMR
(CDCl3, 400 MHz) δ 8.06ꢀ8.00 (m, 2H), 7.61ꢀ7.56 (m, 1H), 7.47ꢀ7.40 (m, 2H), 7.21 (d, J = 2.58, 1H),
7.14 (d, J = 2.58, 1H), 6.45 (s, 2H), 5.20ꢀ5.12 (m, 1H), 5.11ꢀ5.04 (m, 1H), 3.55 (dd, J = 10.8, 2.2 Hz,
1H), 2.77 (dd, J = 14.7, 2.1 Hz, 1H), 2.49 (dd, J = 14.7, 10.7 Hz, 1H), 2.24ꢀ2.00 (m, 6H), 1.76ꢀ1.68
(m, 1H), 1.68 (d, J =1.0 Hz, 3H), 1.64 (s, 3H), 1.60 (s, 3H), 1.41ꢀ1.51 (m, 1H), 1.24 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 165.7, 136.0, 133.8, 131.5, 130.0, 129.5, 128.7 (2C), 128.6 (2C), 124.1 (2C),
122.1, 116.1, 78.1, 74.5, 69.9, 39.7, 36.2, 28.5, 26.6, 25.7, 23.4, 22.0, 17.7, 16.1 (NO2C not observed);
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HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C27H36N2NaO6 507.2466; Found 507.2466. 44b: [α]D
=
+4.7 (c 1.20, CHCl3); IR νmax (neat)/cm–1:351, 2923, 1725, 1465, 1451, 1373, 1311, 1260, 1084, 711;
1H NMR (CDCl3, 400 MHz) δ 8.06ꢀ8.00 (m, 2H), 7.61ꢀ7.56 (m, 1H), 7.47ꢀ7.40 (m, 2H), 7.21 (d, J =
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2.6 Hz, 1H), 7.14 (d, J = 2.58, 1H), 6.44 (s, 2H), 5.20ꢀ5.12 (m, 1H), 5.11ꢀ5.04 (m, 1H), 3.58 (dd, J =
10.7, 2.2 Hz, 1H), 2.62 (dd, J = 14.7, 2.1 Hz, 1H), 2.47 ( dd, J = 14.7, 10.7 Hz, 1H), 2.20ꢀ2.00 (m,
6H), 1.69 (d, J =1.0 Hz, 3H), 1.64ꢀ1.52 (m, 2H), 1.63 (s, 3H), 1.60 (s, 3H), 1.19 (s, 3H);13C NMR
(CDCl3, 100 MHz) δ 165.8, 136.1, 133.9, 131.6, 130.0, 129.5, 128.7 (2C), 128.6 (2C), 124.1, 123.9,
122.0, 116.2, 76.9, 74.7, 69.9, 39.7, 38.8, 28.7, 26.6, 25.7, 22.1, 21.2, 17.7, 16.1 (NO2C not observed);
HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C27H36N2NaO6 507.2466; Found 507.2466.
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Nitropyrrolin A 1. To a solution of diol 44a (37 mg, 0.076 mmol) in methanol (0.5 mL) was added
aqueous K2CO3 (1M, 0.1 mL) dropwise at 0°C. The mixtue was stirred at 0°C for 30 min, then diluted
with H2O (10 mL) and extracted with diethyl ether (3 × 15 mL). The combined organic extracts were
washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by
flash chromatography (hexanes/ EtOAc 1:1) afforded nitropyrrolin A (1) (24 mg, 92%) as a light
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yellow oil. [α]D20 = +20.7 (c 0.15, CH2Cl2), [natural, [α]D24 = +8 (c 0.05, CH2Cl2);1a Morimoto, [α]D
= +26.6 (c 0.05, CH2Cl2)4b]; 1H NMR (CDCl3, 400 MHz) δ 9.40 (br s, 1H), 7.05 (d, J = 1.7, 1H), 6.89
(d, J = 1.7 Hz, 1H), 5.18 (m, 1H), 5.09 (m, 1H), 3.57 (dd, J = 10.5, 2.0 Hz, 1H), 2.73 (dd, J = 14.8,
2.0 Hz, 1H), 2.53 (dd, J = 14.8, 10.5 Hz, 1H), 2.23ꢀ2.00 (m, 8H), 1.69 (d, J = 1.0 Hz, 3H), 1.72 (ddd,
J = 14.0, 10.3, 6.0 Hz, 1H), 1.66 (s, 3H), 1.61 (s, 3H), 1.49 (ddd, J = 14.0,10.3, 6.0 Hz, 1H), 1.27 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 137.5, 136.0, 131.6, 124.4, 124.2, 124.1, 122.0, 111.2, 78.3, 74.6,
39.7, 36.2, 28.8, 26.6, 25.7, 23.4, 22.0, 17.7, 16.1; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for
C19H31N2O4 351.2284; Found 351.2280. The spectroscopic data were in agreement with those
reported in the literature. 1a, 4b
Tetraol 45. To a suspension of K3Fe(CN)6 (329 mg, 1.00 mmol), K2CO3 (138 mg, 1.00 mmol) and
(DHQ)PHAL (3.0 mg, 0.04 mmol) in tertꢀbutanol (2 mL) and H2O (2 mL) was added OsO4 (20 ꢁL,
40 mg/mL in tertꢀbutanol, 0.015 mmol) at 0 °C. After 10 min, methanesulfonamide (19 mg, 0.20
mmol) was added followed by diol 44a (96 mg, 0.20 mmol). After 24 h at 0 ⁰C, the reaction mixture
was quenched with saturated sodium sulfite (1 mL), warmed to room temperature and stirred for
another 1 h. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The
combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by column chromatography (hexanes/EtOAc 1:2) to afford
tetraol 45 (41 mg, 40%) as a light yellow oil: [α]D20 = +6.1 (c 1.90, CHCl3); IR νmax (neat)/cm–1: 3510,
2923, 1726, 1465, 1451, 1375, 1310, 1260, 1084, 711;1H NMR (CDCl3, 400 MHz):
δ 8.06–8.00 (m,
2H), 7.61–7.56 (m, 1H), 7.47–7.40 (m, 2H), 7.21 (d, J = 2.5, 1H), 7.16 (d, J = 2.5 Hz, 1H), 6.42 (s,
2H), 5.14–5.07 (m, 1H), 3.56 (dd, J = 10.8, 2.2 Hz, 1H), 3.42 (dd, J = 10.1, 1.7 Hz, 1H), 2.65 (dd, J =
14.7, 2.1 Hz, 1H), 2.45 (dd, J = 14.7, 10.7 Hz, 1H), 2.13–2.04 (m, 2H), 1.96–1.81 (m, 2H), 1.68 (s,
3H), 1.61 (s, 3H), 1.58–1.44 (m, 4H), 1.19 (s, 3H), 1.12 (s, 3H); 13C NMR (CDCl3, 100 MHz):
δ
165.8, 136.7, 133.8, 132.2, 130.0, 129.6, 128.7 (2C), 128.5 (2C), 124.1, 122.3, 116.2, 78.4, 78.0, 75.1,
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74.0, 69.9, 38.8, 33.3, 28.5, 25.7, 24.6, 23.1, 22.0, 20.8, 17.7; HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd
for C27H38N2NaO8 541.2521; Found 541.2520.
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Heronapyrrole B 7. To a solution of tetrol 45 (41 mg, 0.08 mmol) in methanol (0.5 mL) was added
aqueous K2CO3 (1M, 0.1 mL) dropwise at 0°C. The mixtue was stirred at 0°C for 30 min, then diluted
with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were
washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash
chromatography (hexanes/EtOAc 1:1) afforded heronapyrrole B (7) (27 mg, 90%) as a light yellow oil:
[α]D20 = +10.6 (c 0.50, MeOH); [Morimoto [α]D +9.95 (c 0.42, MeOH);4a natural [α]D +33.3 (c 0.05,
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MeOH)1b] 1H NMR (600 MHz, CD3OD)
δ 7.02 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 1.8 Hz, 1H), 5.21 (t, J
= 6.7 Hz, 1H), 3.46 (dd, J = 10.6, 1.7 Hz, 1H), 3.23 (dd, J = 10.5, 1.5 Hz, 1H), 2.85 (dd, J = 14.7, 1.3
Hz, 1H), 2.43 (dd, J = 14.7, 10.6 Hz, 1H), 2.28–2.20 (m, 1H), 2.21–2.04 (m, 2H), 2.01 (ddd, J = 13.5,
8.8, 7.4 Hz, 1H), 1.74–1.67 (m, 1H), 1.65 (s, 3H), 1.66–1.49 (m, 2H), 1.40–1.25 (m, 1H), 1.17 (s, 3H),
1.15 (s, 3H), 1.12 (s, 3H); 13C NMR (150 MHz, CD3OD):
δ 138.6, 136.0, 126.3, 126.1, 124.6, 112.3,
79.3, 79.0, 75.3, 73.8, 39.9, 37.9, 30.8, 29.5, 25.6, 24.9, 22.8, 21.5, 16.1; The spectroscopic data were
in agreement with those reported in the literature.1b, 4a
Supporting Information
Spectral data for all new compounds
Acknowledgements
The authors thank the NZ Ministry for Science and Innovation for financial support (IIOF Grant).
References
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