One-pot activation-alkynylation-cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

Article abstract of DOI:10.3762/bjoc.15.136

A consecutive three-component activation-alkynylation-cyclization reaction of (hetero)aryl glyoxylic acids, oxalyl chloride, arylacetylenes, and hydrazides efficiently forms 1,5-diacyl-5-hydroxypyrazolines in moderate to good yields. The structures were unambiguously corroborated by comprehensive NMR spectroscopy and X-ray structure analyses of selected derivatives.

Full text of DOI:10.3762/bjoc.15.136

One-pot activation–alkynylation–cyclization synthesis of
1,5-diacyl-5-hydroxypyrazolines in a consecutive
three-component fashion
Christina Görgen1, Katharina Boden1, Guido J. Reiss2, Walter Frank2
and Thomas J. J. Müller*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1360–1370.
1Heinrich-Heine Universität Düsseldorf, Institut für Organische
Chemie und Makromolekulare Chemie, Universitätsstraße 1, D-40225
Düsseldorf, Germany and 2Heinrich-Heine Universität Düsseldorf,
Institut für Anorganische Chemie und Makromolekulare Chemie,
Universitätsstraße 1, D-40225 Düsseldorf, Germany
doi:10.3762/bjoc.15.136
Received: 29 March 2019
Accepted: 28 May 2019
Published: 19 June 2019
Email:
This article is part of the thematic issue "Multicomponent reactions III" and
is dedicated to Prof. Dr. Dr. h.c. mult. Peter Langer on the occasion of his
50th birthday.
Thomas J. J. Müller* - ThomasJJ.Mueller@uni-duesseldorf.de
* Corresponding author
Associate Editor: D. Spring
Keywords:
activation; alkynylation; C–C coupling; copper; cyclization;
multicomponent reactions
© 2019 Görgen et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A consecutive three-component activation–alkynylation–cyclization reaction of (hetero)aryl glyoxylic acids, oxalyl chloride, aryl-
acetylenes, and hydrazides efficiently forms 1,5-diacyl-5-hydroxypyrazolines in moderate to good yields. The structures were un-
ambiguously corroborated by comprehensive NMR spectroscopy and X-ray structure analyses of selected derivatives.
Introduction
Pyrazoles [1,2] and pyrazolines [3-5] are privileged 1,2-diazole sive [20] agents. Especially, 1-acylpyrazolines have shown
derivatives in a broad range of application, both in life and ma- nanomolar in vitro activities against chloroquine-sensitive and
terials sciences. While the former are fully conjugated and can resistant strains of Plasmodium falciparum and can therefore be
be considered as heteroaromatic 6π-systems with interesting considered for the treatment of malaria [21]. Furthermore, simi-
properties as crop-protecting agents [6,7], as pharmaceutically lar derivatives have shown micromolar and submicromolar ac-
active ingredients [8-11], as ligands [12,13], and as chro- tivity against 60 selected cancer cell lines, presumably by inhi-
mophores [14-16], the partially unsaturated 2H-pyrazolines bition of microtubuli formation in cancer cells [22]. More
have particularly attracted attention for instance as antibacterial specifically, a series of 60 1,3-diaryl-1-acylpyrazolines was
[17], anti-inflammatory [18], antidiabetic [19], and antidepres- tested as xanthine oxygenase inhibitors that can be efficacious
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Figure 1: Selected anticancer active 3,5-diaryl-1-acylpyrazoline (left) and xanthine oxygenase inhibitors (center and right).
against articular gout, cancer, and inflammation, with IC50 published employing a cyclizing addition of an acylhydrazone
values of four derivatives in the range of 5.3–15.2 μM to the carbonyl group as a ring-forming reaction [32-40], their
(Figure 1) [23].
diversity-oriented one-pot synthesis in a multicomponent ap-
proach has remained unexplored to date. In the course of our
1-Acyl-5-hydroxypyrazolines have been shown to be anal- program directed to develop multicomponent syntheses of
gesics with a slightly improved pain-relieving efficacy than heterocycles by transition-metal catalysis [41,42] we conceptu-
Aspirin® [24,25], and 5-nitro-2-furyl-substituted derivatives are alized catalytic entries to alkynones and alkynediones as suit-
active antibacterials against the strains S. aureus, A. aerogenes, able intermediates in addition–cyclocondensation syntheses of
E. coli and B. subtilis (Figure 2) [26,27].
numerous heterocycles, which can indeed be prepared by
consecutive multicomponent reactions [43-47]. Particularly
interesting are alkynediones, because, as densely functionalized
trielectrophiles, the alkyne, ynone and dicarbonyl functionali-
ties can be selectively addressed. We have established two
complementary one-pot pathways to alkynediones, a glyoxyla-
tion–alkynylation (GA) [48] and an activation–alkynylation
(AA) [49] sequence, which both take advantage of a copper-cat-
alyzed alkynylation of the intermediary formed (hetero)arylgly-
oxyl chloride (Scheme 1). The alkynediones can be subse-
quently transformed, still in the same reaction vessel, to quinox-
alines [48,50-52], pyrimidines [48,49], and 5-acylpyrazoles
[48,49]. The latter 5-acylpyrazole arose after work-up from the
three-component AA–cyclocondensation synthesis employing
Boc-hydrazine as a binucleophilic hydrazide substrate. Based
on our attempts to isolate potential 1,5-diacylpyrazole precur-
sors we discovered that 1,5-diacyl-5-hydroxypyrazolines are the
Figure 2: Selected 1-acyl-5-hydroxypyrazolines with analgesic (left,
center) and antibacterial activity (center and right).
In addition, 1-acyl-5-hydroxypyrazolines are bidentate ligands intermediary products. Here, we report on the novel three-com-
for zinc complexes and by virtue of being ring tautomers of ponent AA–condensation–cyclization synthesis of 1,5-diacyl-5-
β-enolhydrazones they can also act as tridentate ligands for hydroxypyrazolines.
nickel [28] and tin [29,30] complexes. In contrast, dimethylzinc
forms dimeric complexes where the 1-acyl-5-hydroxypyrazo- Results and Discussion
line acts as a bidentate ligand [31]. Upon treatment with In our initial study [49], the three-component AA–cycloconden-
TMEDA mononuclear complexes with concomitant ring sation synthesis, starting from phenylglyoxylic acid (1a),
opening to give a seven-membered bidentate chelate are gener- phenylacetylene (2a), and Boc-hydrazide (4a) through the for-
ated.
mation of 1,4-diphenylbut-3-yne-1,2-dione (3a), with subse-
quent N-deacylation as the consequence of basic work-up
Although numerous syntheses of pyrazolines [3-5] in general (Scheme 2), furnished 5-benzoyl-3-phenyl-1H-pyrazole (6a) in
and 1-acyl-5-hydroxypyrazolines [24-26] specifically have been 41% isolated yield.
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Scheme 1: Glyoxylation–alkynylation (GA) and activation–alkynylation (AA) synthesis of alkynediones in a one-pot fashion.
Scheme 2: Consecutive three-component synthesis to give 5-benzoyl-3-phenyl-1H-pyrazole (6a) after alkaline deacylation of intermediate 5a.
In addition to spectroscopic assignment the structure of 6a has
now been corroborated by an X-ray structure analysis showing
infinite chains of molecules 6a formed by intermolecular hydro-
gen bonding between the pyrazole N1 and the carbonyl O1
(Figure 3) [53].
The first assumption was that the tentative intermediate 5a
could be a 1,5-diacylpyrazole. However, upon performing the
terminal cyclization step starting from 1,4-diphenylbut-3-yne-
1,2-dione (3a) and Boc-hydrazine (4a) under identical condi-
tions 1-Boc-5-benzoyl-5-hydroxypyrazoline was isolated in
83% yield (Scheme 3).
The molecular structure was additionally corroborated by
X-ray structure analysis showing that the assignment of inter-
mediate 5a was not a fully unsaturated pyrazole (Figure 4) [53].
Figure 3: ORTEP plot of 5-benzoyl-3-phenyl-1H-pyrazole (6a) (ther-
mal ellipsoids at 30% probability); the direction of intermolecular
N−H···O hydrogen bonding is indicated by dashed lines.
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ditioning (Na/benzophenone dried) led to a reduction of the
reaction time t1 from 24 to 15 h (see Supporting Information
File 1, Table S1). In addition, the concentration could be
doubled and the obtained yield of diphenylbut-3-yne-1,2-dione
(3a) increased from 63 to 76%.
Scheme 3: Cyclization of 1,4-diphenylbut-3-yne-1,2-dione (3a) and
Boc-hydrazine (4a) to give intermediate 5a.
The terminal cyclization step, consisting of a Michael addition
of benzoyl hydrazide (4b) to diphenylbut-3-yne-1,2-dione (3a)
followed by a cyclizing addition of the central hydrazide
nitrogen atom to the carbonyl group, was monitored by GC–MS
and optimized with respect to temperature T, reaction time t2,
and the alcohol additive (Table 1).
A ratio of 1.2 equiv of hydrazide 4b to 1.0 equiv of 3a turned to
be optimal for achieving full conversion (Table 1, entries 7–16)
and at a reaction temperature of 175 °C the reaction time of
5 min was identified to achieve full conversion with very good
to excellent yields of isolated 1,5-diacyl-5-hydroxypyrazoline
5b (Table 1, entries 12–16). Although ethylene glycol as a
cosolvent (Table 1, entry 13) gave slightly higher yields and
ethanol furnished slightly lower yields (Table 1, entry 14),
2-methoxyethanol not only gave high yields of 5b, but also
proved to be practical with respect to work-up. Upon compari-
son between dielectric and conductive heating the reaction in
Figure 4: Ellipsoid plot of 1-Boc-5-benzoyl-5-hydroxypyrazoline 5a.
Therefore, we set out to optimize the one-pot synthesis of 1,5- the microwave cavity gave no detectable difference in reaction
diacyl-5-hydroxypyrazolines by choosing the model reaction of time and yield. All these optimized conditions were therefore
phenylglyoxylic acid (1a), phenylacetylene (2a), and benzoyl directly employed in the consecutive one-pot sequence. Howev-
hydrazide (4b) giving 1,5-diacyl-5-hydroxypyrazoline 5b, er, some adjustments in the final step were necessary because
where the reaction times t1 and t2, as well as the conditions of an increase of pressure was detected under dielectric heating.
the cyclization step needed to be optimized (Scheme 4).
Therefore, the consecutive process was optimized with respect
to the terminal step (Table 2).
A quick optimization screening of the activation–alkynylation
synthesis of 1,4-diphenylbut-3-yne-1,2-dione (3a) revealed that In the sequence dielectric heating gave considerably lower
the use of KOH dried triethylamine instead of the initial precon- yields (Table 2, entries 1–3) than in the separated process
Scheme 4: Model reaction for optimizing the activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazoline 5b.
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Beilstein J. Org. Chem. 2019, 15, 1360–1370.
Table 1: Optimization of the cyclization step of 1,5-diacyl-5-hydroxypyrazoline 5b.a
entry
ROH [mL]
T [°C]
t2 [min]
1,5-diacyl-5-hydroxypyrazoline 5b (%)b
1c,d
2c,d
3d,f
4d,g
5d,h
6d,i
7d,h
8d,h
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
ethylene glycol (0.2)
100
150
150
150
150
150
150
150
150
100
125
175
175
175
175
175
60
60
60
60
60
60
30
15
5
10
10
5
5
5
incomplete conversione (n.i.)
incomplete conversione (n.i.)
complete conversione (n.i.)
complete conversione (n.i.)
complete conversione (n.i.)
incomplete conversione (n.i.)
complete conversione (n.i.)
complete conversione (n.i.)
incomplete conversione (n.i.)
incomplete conversione (n.i.)
incomplete conversione (n.i.)
full conversione (94)
9d,h
10d,h
11d,h
12d,h,j
13d,h,j
14d,h,j
15k
full conversione (96)
full conversione (87)
full conversione (90)
full conversione (93)
ethanol (0.2)
2-methoxyethanol (0.2)
2-methoxyethanol (0.2)
5
5
16h,l,j
ac0(3a) = 0.17 M; 1,4-dioxane (1.0 mL). bIsolated yield (n.i. = not isolated). cc0(4b) = 0.17 M. dDielectric heating in a microwave cavity (T is the set
temperature and t2 is the hold time). eAs monitored by GC–MS. fc0(4b) = 0.25 M. gc0(4b) = 0.21 M. hc0(4b) = 0.20 M. ic0(4b) = 0.18 M. jOn a
1.00 mmol scale (3a). kOn a 1.00 mmol scale (3a), c0(3a) = 0.34 M; c0(4b) = 0.40 M. 1,4-Dioxane (1.0 mL). lConductive heating in an oil bath at
preheated temperature T.
Table 2: Optimization of the consecutive three-component synthesis of 1,5-diacyl-5-hydroxypyrazoline 5b.
entry
c0(1a)
t2 [min]
1,5-diacyl-5-hydroxypyrazoline 5b, yield [%]a
1b
2b
3b
4c
5e,f
6e
7e
8e
9e
0.4 M
0.25 M
0.25 M
0.4 M
0.4 M
0.4 M
0.4 M
0.4 M
0.4 M
5
5
37
32
35
10
10
5
10
20
30
45
no product formationd
no product formationd
64
69
78
79
aIsolated yield. bDielectric heating in a microwave cavity (T is set to 175 °C and t2 is the hold time). cDielectric heating in a microwave cavity (T is set
to 150 °C and t2 is the hold time). dAs monitored by GC–MS. eConductive heating in an oil bath at preheated temperature T = 175 °C. f2.00 equiv of
NEt3 were added.
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(Table 1, entries 12–15). However, conductive heating, which With the optimized conditions of the consecutive three-compo-
already gave comparable results in the terminal cyclization step nent synthesis in hand (hetero)arylglyoxylic acids 1, oxalyl
(Table 1, entry 16), is obviously better suited to achieve full chloride, arylacetylenes 2, and hydrazides 4 were reacted in 1,4-
conversion and, ultimately, slightly longer heating also gives dioxane and in the presence of catalytic amounts of copper(I)
rise to good yields (Table 2, entries 6–9).
iodide in a one-pot activation–alkynylation–cyclization se-
quence to give 1,5-diacyl-5-hydroxypyrazoline 5 after flash
Taking into account the combined yield of 71% for both indi- chromatography on silica gel in moderate to good yields
vidually performed steps (ynedione formation with 76% and (Scheme 5, Table 3).
cyclization with 94%) is slightly lower than that of the one-pot
sequence with 78% (Table 2, entry 8), the consecutive three- The structures of the 1,5-diacyl-5-hydroxypyrazolines 5 were
component process clearly is superior. With four bond-forming unambiguously assigned by 1H and 13C NMR spectroscopy, in
steps (activation, alkynylation, Michael addition, and cycliza- selected cases by NOESY, HSQC, and HMBC experiments, as
tion) the average yield per bond-forming step accounts to 94%. well as by EI mass spectrometry and the elemental composition
Scheme 5: One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines 5.
Table 3: Consecutive three-component synthesis of 1,5-diacyl-5-hydroxypyrazolines 5.
entry
glyoxylic acid
R1COCO2H 1
alkyne
R2C≡CH 2
hydrazide
R3CONHNH2 4
1,5-diacyl-5-hydroxypyrazoline 5
yield
1
R1 = Ph (1a)
R2 = Ph (2a)
R3 = Ph (4b)
5b (78%)
5c (55%)
5d (41%)
2a
1a
2a
R3 = p-MeC6H4 (4c)
3
1a
2a
R3 = p-BrC6H4 (4d)
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Table 3: Consecutive three-component synthesis of 1,5-diacyl-5-hydroxypyrazolines 5. (continued)
4
5
1a
1a
2a
2a
R3 = 2-thienyl (4e)
5e (67%)
R3 = 2-furyl (4f)
5f (67%)
6
7
1a
1a
2a
2a
R3 = PhCH2 (4g)
5g (59%)
5h (66%)
R3 = iPr (4h)
8
1a
2a
R3 = cyclopropyl (4i)
5i (69%)
5j (58%)
5k (33%)
9
1a
1a
1a
2a
R3 = t-Bu (4j)
R3 = n-Pr (4k)
4b
10
11
2a
R2 = p-MeOC6H4 (2b)
5l (55%)
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Table 3: Consecutive three-component synthesis of 1,5-diacyl-5-hydroxypyrazolines 5. (continued)
12
13
14
1a
1a
1a
R2 = p-t-BuC6H4 (2c)
R2 = p-FC6H4 (2d)
R2 = p-NCC6H4 (2e)
4b
4b
4b
5m (69%)
5n (66%)
5o (29%)
15
16
R1 = 2,4,6-Me3C6H2 (1b)
2a
2a
4b
4b
5p (47%)
5q (73%)
R1 = 2-thienyl (1c)
17
1b
2b
4e
5r (38%)
aReaction time t2 = 20 min.
was confirmed by combustion analyses. Additionally, the struc- withdrawing substituents R2 (Table 3, entries 1, 11–14), howev-
ture was corroborated by an X-ray structure analysis of com- er, for the electron-poor cyano substituent a somewhat lower
pound 5r showing dimers held together by inter- and intramo- yield of the title compound is obtained (Table 3, entry 14).
lecular hydrogen bonding (Figure 5) [53].
Finally, the substituents R1 of the glyoxylic acids 1 can be aro-
matic, heteroaromatic and even sterically demanding (Table 3,
The three-component synthesis allows addressing three points entries 1, 15–17).
of diversity and especially for the hydrazide substrate 4 all dif-
ferent types of (hetero)aromatic, aliphatic, and alicyclic substit- All attempts to dehydrate 1,5-diacyl-5-hydroxypyrazoline 5b
uents R3 are well tolerated in the sequence (Table 3, entries under alkaline or Brønsted acidic conditions were accompanied
1–10). The alkynes 2 can bear electron-donating and electron- by simultaneous deacylation of substituent R3 finally furnishing
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Beilstein J. Org. Chem. 2019, 15, 1360–1370.
Figure 5: ORTEP plot and dimer of compound 5r (thermal ellipsoids at 30% probability).
5-(hetero)aroyl-3-(hetero)aryl-1H-pyrazole 6a (for attempted 4 h. After the mixture had cooled to room temperature, CuI
dehydrative aromatization, see Supporting Information File 1, (10 mg, 0.05 mmol), phenylacetylene (2a, 0.11 mL,
Table S5), as already reported for alkaline deprotection–aroma- 1.00 mmol), and dry triethylamine (0.42 mL, 3.00 mmol) were
tization [49]. However, compound 5b is stable against water successively added. Stirring at room temperature (external
and weakly basic conditions. This indicates that 1,5-diacyl-5- water bath) was continued for 15 h. Then, phenylhydrazide (3b,
hydroxypyrazolines might act as acyl transferring agents under 163 mg, 1.20 mmol) and 2-methoxyethanol (1.0 mL) were
certain conditions.
added and the reaction mixture was stirred at 175 °C (preheated
oil bath) for 30 min. After cooling to room temperature de-
ionized water (5 mL) was added and the mixture was extracted
Conclusion
In summary we could elucidate that the consecutive three-com- with dichloromethane (4 × 5 mL). The combined organic
ponent activation–alkynylation–cyclization sequence of phases were dried with anhydrous sodium sulfate and the sol-
(hetero)arylglyoxylic acids, oxalyl chloride, arylacetylenes, and vents were removed in vacuo. The crude product was adsorbed
hydrazides does not form aromatic pyrazoles, but rather 1,5- on celite© and purified by flash chromatography on silica gel
diacyl-5-hydroxypyrazolines, i.e., the aromatizing elimination (petroleum ether 40–60 °C/ethyl acetate 5:1) to give analytical-
of water does not occur under these neutral conditions. This ly pure 1,5-dibenzoyl-5-hydroxy-3-phenylpyrazoline (5b,
novel one-pot synthesis of 1,5-diacyl-5-hydroxypyrazolines is 291 mg, 78%) as colorless solid. Rf = 0.15 (petroleum ether/
concise, highly efficient and diversity-oriented. The deacy- ethyl acetate 5:1, detected with a hand-held UV lamp at 254 and
lating aromatization of the title compounds under weakly alka- 365 nm). Mp 152 °C; 1H NMR (CDCl3, 300 MHz) δ 3.54 (d,
line or acidic conditions indicates acyl-transfer ability. Further- J = 18.5 Hz, 1H), 3.76 (d, J = 18.5 Hz, 1H), 5.60–6.08 (br, 1H),
more, the peculiar reactivity of the ynedione intermediate calls 7.36–7.62 (m, 9H), 7.72–7.83 (m, 2H), 7.90–8.05 (m, 4H);
for more sophisticated cyclizing processes, eventually in a one- 13C NMR (CDCl3, 75 MHz) δ 45.6 (CH2), 92.2 (Cquat), 126.9
pot fashion. Further studies exploring the dense electrophilic re- (CH), 127.8 (CH), 128.9 (CH)*, 129.0 (CH), 130.2 (CH), 130.7
activity of ynediones in consecutive multicomponent reactions (Cquat), 130.9 (CH), 131.7 (CH), 131.8 (Cquat), 132.9 (Cquat),
are still underway.
133.9 (CH), 153.1 (Cquat), 166.7 (Cquat), 193.4 (Cquat); *broad-
ened signal; EIMS (m/z): 352 ([M − H2O])+, 2), 266 (11), 265
([M − PhCO]+, 59), 248 ([M − PhCO − H2O]+, 20), 105
Experimental
Typical procedure for the three-component synthesis of (PhCO+, 100), 77 (C6H5+, 34); IR (ATR), [cm−1]: 3333 (w),
compound 5b: In an oven-dried Schlenk flask equipped with a 1697 (m), 1626 (m), 1612 (m), 1566 (w), 1450 (m), 1427 (m),
magnetic stirring bar and screw cap were placed glyoxylic acid 1339 (m), 1315 (w), 1254 (w), 1202 (m), 1180 (m), 1113 (m),
1a (150 mg, 1.00 mmol) and dry 1,4-dioxane (2.5 mL) under 1057 (w), 1028 (w), 922 (w), 895 (w), 866 (m), 845 (w), 791
argon. Then, oxalyl chloride (0.09 mL, 1.00 mmol) was added (w), 762 (m), 708 (s), 689 (s), 669 (m), 627 (w); anal. calcd for
dropwise at room temperature (external water bath) and the C23H18N2O3 (370.4): C, 74.58; H, 4.90; N, 7.56; found: C,
reaction mixture was stirred at 50 °C (preheated oil bath) for 74.67; H, 5.07; N, 7.79.
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Supporting Information
For experimental details of the optimization studies on
intermediate 3a, on the cyclization step of 3a and 4b
(compound 5b), on the consecutive three-component
synthesis of compound 5b, experimental details of general
procedure of the consecutive three-component synthesis
and analytical data of 1,5-diacyl-5-hydroxypyrazolines 5,
experimental details on the attempted dehydrative
aromatization of compound 5b, and NMR spectra of the
compounds 5, and for summaries on the crystal structure
analyses of 5a, 5r, and 6a see Supporting Information
File 1.
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Supporting Information File 1
Experimental details, copies of NMR spectra and
crystallographic data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-136-S1.pdf]
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The support of this work by the Fonds der Chemischen Indus-
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Statement
The reported results have been summarized in the inaugural
dissertation "Diversitätsorientierte katalytische Ein-Topf-
Synthesen von ausgewählten Azolderivaten" by Dr. Christina
Boersch, Heinrich Heine University Düsseldorf, 2014. Dr.
Christina Görgen (née Boersch) is the first author of this article.
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Rhee, S. D.; Yang, S.-D.; Cheon, H. G.; Kim, S. S.
Bioorg. Med. Chem. Lett. 2004, 14, 4461–4465.
ORCID® iDs
Thomas J. J. Müller - https://orcid.org/0000-0001-9809-724X
doi:10.1016/j.bmcl.2004.06.046
20.Rajendra Prasad, Y.; Lakshmana Rao, A.; Prasoona, L.; Murali, K.;
Ravi Kumar, P. Bioorg. Med. Chem. Lett. 2005, 15, 5030–5034.
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