Proline Derived Bicyclic Derivatives through Metal Catalysed Cyclisations of Allenes: Synthesis of Longamide B, Stylisine D and their Derivatives

Article abstract of DOI:10.1002/ejoc.201901554

Annulations of allene-substituted proline derivatives promoted by transition metals have been investigated as a general way to access bicyclic structures with a bridgehead nitrogen. Two processes, Pd- and Ag-catalysed cyclisations, have been employed comp

Full text of DOI:10.1002/ejoc.201901554

A Journal of
Accepted Article
Title: Proline derived bicyclic derivatives via metal catalysed
cyclisations of allenes. Synthesis of longamide B, stylisine D and
their derivatives
Authors: Milos Jovanovic, Milos Petkovic, Predrag Jovanovic, Milena
Simic, Gordana Tasic, Slavica Eric, and Vladimir Savic
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901554
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10.1002/ejoc.201901554
European Journal of Organic Chemistry
Proline derived bicyclic derivatives via metal catalysed
cyclisations of allenes. Synthesis of longamide B, stylisine D
and their derivatives
Milos Jovanovic, [a] Milos Petkovic, [a]* Predrag Jovanovic, [a] Milena Simic, [a] Gordana Tasic, [a]
Slavica Eric, [b] Vladimir Savic [a]*
[a] University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450,
Belgrade, Serbia;
[b] University of Belgrade, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Vojvode
Stepe 450, Belgrade
Corresponding authors: Milos Petkovic, mpetkovic@pharmacy.bg.ac.rs;
Vladimir Savic, vladimir.savic@pharmacy.bg.ac.rs
Abstract: Annulations of allene-substituted proline derivatives promoted by transition metals have been investigated as a general
way to access bicyclic structures with a bridgehead nitrogen. Two processes, Pd- and Ag-catalysed cyclisations, have been
employed complementary to control the substitution pattern of the product. The investigated methodologies afforded the bicyclic
derivatives in comparable yields, while Ag-catalysis showed higher level of diastereoselectivity. Both processes have been utilized in
the synthesis of naturally occurring pyrroles longamide B, stylisine D and their derivatives.
Introduction
Pyrrolidine derived bicyclic skeleton, in particular one which possesses bridgehead nitrogen, is structural architecture found
in many natural products and biologically active compounds.1-6 Variations of this scaffold are numerous as indicated by large
classes of pyrrolizidine and indolizidine alkaloids.7-10 Further structural alternative, also found in naturally occurring
substances, is denoted by pyrrole ring in place of pyrrolidine moiety.11-16 Synthetic approaches to these bicyclic structures
are usually based on the annulation of pyrrolidine ring, which can be accomplished by a range of methodologies (Scheme
1a).17-25 As pyrrolidine ring can be transformed into pyrrole via oxidative processes, this approach is also valuable for the
synthesis of related pyrrole derivatives, as demonstrated by the recent preparation of agelastatin.14 Important alkaloids
containing aforementioned structural motif are bromopyrroles, a large group of secondary metabolites produced by marine
organisms.26 This diverse family of alkaloids includes more than 140 members among which a number of potently bioactive
molecules has been uncovered such as antagonists of serotonergic receptors, kinase inhibitors, and anticancer agents
(scheme 1a).27–29 Particularly remarkable is the antitumor activity of Agelastatin A against blood cancer cell lines.
Antiprotozoal and antibacterial properties have been reported for longamide B, displaying a potent activity against African
trypanosome (IC50 1.53 µg/mL) and moderate activity against Bacillus subtilis and Staphylococcus aureus with minimal
inhibitory concentrations of 45 µg/mL and 55 µg/mL respectively.30,31 An ethyl ester of longamide B, Hanishin, displays
cytotoxic activity against NSCLC-N6 human non-small-cell-lung carcinoma.32 The structural diversity coupled with potent
biological activities have sparked interest of synthetic chemists and in the last decades numerous syntheses of bromopyrrole
alkaloids have been accomplished.13,29,33–41 Bicyclic core, pyrroloketopiperazine, represents a common structural motif of a
large number of bromopyrrole alkaloids and can be accesed by some of the abovementioned methods.
1
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European Journal of Organic Chemistry
Scheme 1. a. Selected bioactive bromopyrrole alkaloids b. Annulations of pyrrolidine ring c. Our strategy for the synthesis of
pyrroloketopiperazine skeleton
Our interest in the annulation of proline derivatives was initiated as potential approach to the synthesis of bromopyrrole
alkaloids such as cyclooroidin and longamide B and stylisine D (Scheme 1b). Our envisaged strategy was based on the
hypothesis that the piperazinone core of bromopyrroles could be accessed via intramolecular nucleophilic addition to allene
moiety catalyzed by transition metals as outlined in Scheme 1c. In this type of cyclization processes Pd, Au and Ag have
been heavily utilized.42-44 While Pd-catalyzed reactions proceed via π-allylpalladium intermediate, Au and Ag can, due to
their Lewis acidic character, coordinate to either allenic double bond allowing for an easier nucleophilic attack on this
moiety.45-47 The outcomes in regioselectivity depend on the substrate itself and oftentimes result in formation of the exocyclic
double bond that can be utilized in further transformations. In case of our proposed synthesis of longamide B the secondary
amine functionality of the proline ring is ideally positioned for the metal promoted cyclization onto the proximal allenyl
substituent (Scheme 1c). In addition, the chirality of proline, which would be eventually sacrificed due to its oxidation to
pyrrole, might promote stereoselectivity in the cyclization step, which creates a novel chiral carbon.
2
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Results and Discussion
Our initial work regarding the exploration of annulation of proline ring required a synthesis of suitable allene derivative. This
was shown to be a straightforward task initiated with propargylation of the protected benzylamine followed by several routine
transformations to afford the key cyclization precursor proline derivative 6 (Scheme 2).48-50
a.(i) Boc2O, NaOH, THF/H2O, 0 oC to rt (ii) propargylbromide, NaH, DMF, 0 oC to rt, 79% b. (CH2O)n, iPr2NH, CuBr, dioxane, 110 oC, 72% c. TFA,
CH2Cl2, rt, 96% d. Boc-L-Proline, EDCI, HOBt, DIPEA, CH2Cl2, rt, 88% e. TFA, CH2Cl2, rt, 99%
Scheme 2. Synthesis of cyclization precursor 6
3
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With pyrrolidine 6 in hand we explored the cyclization process as outlined in Table 1. Various conditions based around
metal-promoted transformations were screened in the reaction employing benzyl protected amide 6b.
Table 1. Optimization of metal-catalysed cyclisation of allene-amine
MX
(mol %)
NMR-yield
(%)
Entry
MX/additives
solvent
time
Ratio (7a/7b)
a
b
c
d
e
f
AuCl3
AuCl3/CaCO3/MS4Å
Ph3PAuCl
Cu(OTf)2
5
5
DCM
DCM + 5% ACN
DCM
5d
5d
48
39:61
55
21:79
5
5d
/
Trace
57
/
5
DCM
5d
/
Cu(OTf)2
5
Acetone
Acetone
DCM
5d
21:79
Cu(OTf)2/CaCO3/MS4Å
TiCl4
5
5d
Trace
/
/
g
h
i
5
5d
/
K2PtCl4
20
20
20
20
20
20
20
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
DCM
5d
/
/
Ag2O
18h
18h
18h
18h
3d
28
29:71
/
j
Ag2CO3
Trace
19
k
l
AgNO3
31:69
30:70
/
CH3COOAg
AgOTf
21
m
n
/
AgOTf
18h
38
26:74
o
p
q
r
AgNO3/K2CO3
AgNO3/CaCO3
AgNO3/CaCO3
AgNO3/CaCO3
AgOTf/CaCO3
AgOTf/CaCO3
20
20
40
80
20
40
Acetone + H2O
Acetone + H2O
Acetone + H2O
Acetone + H2O
Acetone + H2O
Acetone + H2O
18h
18h
18h
18h
18h
18h
25
21
55
83a
50
74
33:67
31:69
14:86
17:83
19:81
23:77
s
t
a
Isolated yield
With catalytic amount of metal salts all reactions were very slow and needed up to five days for good conversion. Metals
such as Au3+ and Cu2+ afforded products 7a/7b in moderate yields (entries b and e Table 1) and with moderate
diastereoselectivity. The Ag+ salts performed generally better (entries i-t Table 1), but, unfortunately, at the expense of
quantities used to promote the reaction efficiently. Even so, the availability of Ag-salts prompted their detailed study.51 After
experimentation with additives and various quantities of metal salts the cyclization protocol was established. The reaction
time was decreased to 18h and yield was increased to 83% with 80 mol% of the metal salt (entry r, Table 1). Under these
conditions the product was obtained as a separable mixture of 7a and 7b in 17:83 ratio respectively. The stereochemistry of
the major component, examined by NOESY experiments, was established as trans. Comparison of AgNO3 and AgOTf
under the same conditions (entries p/s and entries q/t, Table 1) suggested that the efficiency of the cyclization process was
reliant on Lewis acidity of the metal salt as better yields were generally afforded with AgOTf.
Having optimized the annulation step to access bicyclic compound 7, longamide B was then synthesized through several
additional steps (Scheme 3). Oxidation of pyrrolidine 7c, employing MnO2, proceeded in moderate yield to afford pyrrole 8.
Hydroboration of 8 followed by oxidation with peroxide gave the primary alcohol which was thereupon used in deprotection
step. Our initial approach involved utilization of benzyl protection (benzyl in place of PMB in 8), however, the cleavage of this
group proved to be challenging with all attempts giving back starting materials or complex mixtures. Interestingly, cerium
ammonium nitrate (CAN) attempted deprotection of N-benzyl derivative gave 5-nitropyrrole product with intact protecting
4
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European Journal of Organic Chemistry
group. To circumvent this problem we utilized p-methoxybenzyl (PMB) protection of the amide and that group was readily
cleaved with warm trifluoroacetic acid (TFA) in the presence of 2 equivalents of anisole to afford compound 9. The
deprotection step was followed by the esterification of primary alcohol functionality. This did not hinder the subsequent
bromination step (Scheme 3, reaction d.), on the contrary, the ester functionality increased the overall lipophilicity of the
compound allowing for an easier purification process. Thus, the bromination of 9 mediated by N-bromosuccinimide (NBS)
followed by hydrolysis of trifluoroacetic ester afforded dibromopyrrole 11. The final oxidation of the primary alcohol
functionality proceeded in 83% yield to give the targeted longamide B with spectra and optical rotation matching the ones
reported in the literature ([α]D = -5.5 (c 0.20, CH3OH) in comparison to Fukase et al. ([α]D = -5.6 (c 0.40, CH3OH)).37. Another
bromopyrrole, recently isolated from marine sponge Stylissa massa, stylisine D, was easily synthesised by transforming the
carboxylic group of longamide B into the amide.52
a. AgNO3, CaCO3, Acetone/H2O, rt, 69% b. MnO2, THF, 85oC, 57% c. (i) 9-BBN, THF, then NaOH, H2O2, (ii) anisole, TFA, 60oC, 55% d. NBS, THF, rt,
85% e. NaOH, THF/H2O, rt, 99% f. TEMPO, PhI(OAc)2, NaHCO3, MeCN/H2O, rt, 83% g. NH4OH, EDCI, HOBt, DIPEA, THF, rt, 81%
Scheme 3. Synthesis of Longamide B and Stylisine D
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European Journal of Organic Chemistry
Having completed the synthetic route for the preparation of bromopyrrole natural products we next explored the possibility of
applying the related Pd-promoted transformations to access longamide B derivatives. Hypothetically, carbopalladation of 6,
followed by an intramolecular nucleophilic substitution would produce analogues of this natural product with functionalization
of α-carbon next to carboxylic acid. Compounds possessing substituents in this position with antifungal potential have
recently been isolated from natural sources.53
Scheme 4. Access to α-substituted longamide derivatives
The optimization of cyclization process of 6a under Pd-catalysis is outlined in Table 2.54 The reaction was performed with 1.2
equivalents of arylhalide and Pd(OAc)2/PPh3 catalytic system in DMF and in the presence of K2CO3 as a base. Primarily
formed π-allylpalladium intermediate, obtained upon addition of arylpalladium species onto the allenic functionality, reacted
intramolecularly with the secondary amine to produce bicyclic product. Unfortunately, the expected product was isolated in
only 20% yield as 1:1 mixture of diastereomers 12aa and 12ba (Table 2, entry a).
Table 2. Pd-catalysed cyclisation of proline derivative 6a
entrya
a
b
c
ligand
PPh3
XantPhos
XantPhos
solvent
DMF
DMF
yield (%)b
20
38
58
MeCN
a Conditions: allene 6a (0.1 mmol); ArI, (0.1 mmol); Pd(OAc)2, (0.01 mmol); PPh3 (0.02 mmol) or XantPhos, (0.01 mmol); K2CO3, (0.23 mmol); MeCN,
(3 mL); reflux, 18h. b Isolated combined yield.
When PPh3 ligand was replaced with XantPhos the yield improved to 38% (Table 2, entry b), while performing the reaction
with XantPhos and in MeCN (Table 2, entry c) advanced the reaction yield further to 58%. These optimized conditions were
used for brief exploration of the reaction scope (Table 3). All products (Table 3, 12aa – 12be) were isolated in moderate to
good yields but, disappointingly, with almost no diastereoselectivity.
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European Journal of Organic Chemistry
Table 3. Variation of the iodide in the Pd-catalysed cyclisation reaction
entry
ArI
Product
yield% (12a/12b ratio)
a
58 (55:45)
b
59 (56:44)
c
53 (56:44)
d
68 (57:43)
e
75 (57:43)
aConditions: allene 6a or 6b, (0.1 mmol); ArI, (0.1 mmol); Pd(OAc)2, (0.01 mmol); XantPhos, (0.01 mmol); K2CO3, (0.23 mmol); MeCN, (3 mL); reflux,
18h. bIsolated yields; the ratio established by 1H NMR.
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After a brief exploration of the Pd-promoted cyclisations, we continued with transformation of the cyclic product 12ba as
already described for the preparation of parent molecule longamide B in order to demonstrate appropriateness of the
developed synthetic route for the preparation of longamide derivatives. All previously utilized synthetic steps, as outlined in
Scheme 5, proceeded satisfyingly. The hydroboration of 13 gave a mixture of diastereisomers with major component 14
isolated in an overall 32% yield after the subsequent removal of PMB protecting group. The stereochemistry of newly
created stereogenic center was proposed based on the previously developed models for the hydroboration processes.55 The
final oxidation of primary alcohol, however, gave a mixture of diastereoisomers due to sensitivity of a new chiral center now
being next to a carboxylic group. At this point, we did not explore other oxidative procedures in order to reduce the extent of
the isomerization process.
a. ArI, Pd(OAc)2, XantPhos, K2CO3, MeCN, 90 oC, 26% b. MnO2, THF, 85oC, 56% c. (i) 9-BBN, THF, then NaOH, H2O2, (ii) anisole, TFA, 60oC, 32% d.
NBS, THF, rt, 75% e. NaOH, THF/H2O, rt, 99% f. TEMPO, PhI(OAc)2, NaHCO3, MeCN/H2O, rt, 83%
Scheme 5. Synthesis of longamide derivative 17.
The above results demonstrated application of metal promoted annulation of pyrrolidine ring in the synthesis of bromopyrrole
alkaloids but the method might have wider potential as it can be adjusted to meet structural requirements of large classes of
pyrrolizidine and indolizidine alkaloids.
Although both metal catalysed processes are relatively efficient, the significant difference in diastereoselectivity of the
cyclisation steps was quite intriguing. Introduction of an additional substituent by Pd-catalysed processes did not create
opportunity to improve the stereoselectivity due to additional steric requirements, but it rather had the opposite effect.
Further to this, it seemed that variation of the aryl substituent did not influence selectivity at all. Inspection of the molecular
models suggested likely transition states for the cyclisation step and they are delineated in Figure 1 and Figure 2 The
stereoselectivity of Ag-catalysed process (Table 1) was significantly better than that of the corresponding Pd-catalysed
transformation (Table 3). Mechanistically these two processes differ and therefore involve unlike intermediates. While Pd-
catalysis created π-allylpalladium functionality which then underwent the cyclisation, Ag-promoted transformation resided on
coordination of the allene by Ag-salt prior to the cyclisation. As expected and as experimental results demonstrated, the
product of the favored 6-exo cyclisation was the only one obtained. In the case of Pd-catalysed cyclisation (Figure 1) two
most likely modes of cyclisation involve either Re face (Figure 1a) or Si face (Figure 1b) of the prochiral, bond forming C-
atom of the π-allylpalladium moiety. Although transition state resulting from the nucleophilic attack from the Si face (Figure
8
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European Journal of Organic Chemistry
1b) would be expected to be less favored due to 1,3-diaxial interactions of the π-allylpalladium group and the pseudoaxial
pyrrolidine C(2)H/C(5)H bonds, what would consequently result in some degree of selectivity, that was not the observed
outcome. The stereoselectivity of the cyclisation step is insignificant and two stereoisomers, in all cases, were isolated in
almost equal amounts. This may be attributed to the stereochemical properties of the allyl moiety which is planar with the
aromatic ring positioned in the same plane to minimize the steric interactions with the pseudoaxial C-H bonds. On the other
hand, the diaxial interactions in transition state b (Figure 1) may be paralleled by steric interactions between the
pseudoequatorial allyl group and the C(5)H2 substituent of the proline ring in transition state a (Figure 1). This model might
also account for insignificant effect of the aryl group on the diastereoselectivity.

-allylpalladium moiety in grey colour, Pd omitted for clarity
Figure 1. Transition state for the Pd-catalysed cyclisation reaction
Inspection of molecular models of the transition state for the Ag-catalysed transformation revealed possible origin of the
observed results (Figure 2). It is likely that detrimental steric interactions are created when the allenyl moiety is orientated
pseudoequatorially (Figure 2a). In that position allenic fragment locates the terminal methylene group in close proximity to
the proline C(5)H2. These repulsions may outweigh potential 1,3-diaxial interactions of the pseudoaxial allene (Figure 2b)
favoring more stable transition state b (Figure 2) and formation of trans product 7b as a major component.
co-ordinated Ag omitted for clarity
Figure 2. Transition state for the Ag-catalysed cyclization reaction
9
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European Journal of Organic Chemistry
Conclusions
In conclusion, our study demonstrated that intramolecular amination of the proline derived allene is a viable route for
preparation of the bicyclic derivatives possessing bridgehead nitrogen. Two processes, Pd- or Ag-catalysed cyclisations
afforded the expected products in comparable yields although Ag-catalysis showed higher degree of diastereoselectivity.
Bicyclic product accessible by the reported methodology can be further transformed and this route was utilized in the
synthesis of longamide B, stylisine D and their derivatives.
Experimental Section
General information
The NMR spectra were recorded on a Bruker Ascend 400 (400 MHz) spectrometer. Chemical shifts are given in parts per
million (δ) downfield from tetramethylsilane as the internal standard. Deuterochloroform was used as a solvent, unless
otherwise stated. Mass spectral data were recorded using an Agilent Technologies 6520 Q-TOF spectrometer coupled with
an Agilent 1200 HPLC system or an Agilent Technologies 5975C MS system coupled with an Agilent Technologies 6890N
GC system. IR spectra were recorded on an IR Thermo Scientific NICOLET iS10 (4950) spectrometer. Optical rotations
were measured on an AUTOPOL IV Automatic Polarimeter Rudolph Research Analytical. [α]D values are given in deg mL g–
1dm–1. Flash chromatography employed silica gel 60 (230–400 mesh) while thin layer chromatography was carried out using
alumina plates with a 0.25 mm silica layer (Kieselgel 60 F254, Merck). Compounds were visualized by staining with
potassium permanganate solution. The solvents were purified by distillation before use.
Tert-butyl 4-methoxybenzyl(prop-2-yn-1-yl)carbamate (2a) - The title compound was prepared following the procedures
described in the literature starting from p-methoxybenzylamine (4.20 g, 30.66 mmol) to afford 2a in a 79 % yield (6.67 g,
24.25 mmol) as a clear oil.48,56 Spectral data were in accordance with the reported ones.55
Tert-butyl benzyl(prop-2-yn-1-yl)carbamate (2b) - The title compound was prepared following the procedure for 2a
starting from benzylamine (3,00 g, 28.04 mmol) to afford 2b in a 72 % yield (4.95g, 20.19 mmol) as a clear oil. Spectral data
were in accordance with the reported ones.48
Tert-butyl buta-2,3-dien-1-yl(4-methoxybenzyl)carbamate (3a) - The title compound was prepared following the
procedures described in the literature starting from 2a (5.00 g, 18.18 mmol) to afford 3a in a 72 % yield (3.79 g, 13.11 mmol)
as a pale yellow oil. Spectral data were in accordance with the reported ones.57
Tert-butyl benzyl(buta-2,3-dien-1-yl)carbamate (3b) - The title compound was prepared following the procedure for 3a
starting from 2b (4.95 g, 20.19 mmol) in a 69 % yield (3.61 g, 13.93 mmol) as a pale yellow oil. Spectral data were in
accordance with the reported ones.57
N-(4-methoxybenzyl)buta-2,3-dien-1-amine (4a) - To a stirred solution of 3a (3.41 g, 11.80 mmol) in dichloromethane (25
mL), TFA (9.0 mL, 118 mmol) was added and left stirring for 12 h at room temperature. The reaction mixture was
evaporated, redissolved in ethyl acetate (30 mL) and washed with saturated NaHCO3 (3 x 30 mL) and with brine (30 mL).
Organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure to afford 4a in a 96 %
yield (2.14 g, 11.32 mmol) as light brown oil. 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H),
5.23 (p, J = 6.5 Hz, 1H), 4.83 – 4.73 (m, 2H), 3.80 (s, 3H), 3.76 (s, 2H), 3.26 (dt, J = 6.0, 2.9 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 208.46, 158.69, 132.22, 129.45, 113.80, 89.23, 76.02, 67.10, 55.27, 52.44, 47.04. IR (ATR): ν 2997, 2908, 2834,
1955, 1511, 831 cm−1. HRMS (ESI/Q-TOF) m/z calcd for [C12H15NO + H+]: 190.1226, found 190.1230.
N-benzylbuta-2,3-dien-1-amine (4b) - The title compound was prepared following the procedure for 4a starting from 3b
1
(923 mg, 3.56 mmol) and TFA (2.73 mL, 35.6 mmol) in a 99 % yield (561 mg, 3.53 mmol) as brown oil. H NMR (400 MHz,
CDCl3) δ 7.42 - 7.30(m, 5H), 5.22 (p, J = 6.5 Hz, 1H), 4.87 – 4.74 (m, 2H), 3.82 (s, 2H), 3.27 (dt, J = 6.2, 3.0 Hz, 2H), 2.65
(s, 1H). 13C NMR (101 MHz, CDCl3) δ 208.61, 139.34, 128.45, 128.38, 127.16, 88.66, 76.15, 52.78, 46.97. IR (ATR): ν
3026, 2835, 1954, 1674, 1453, 1120 cm−1. HRMS (ESI/Q-TOF) m/z calcd for [C11H13N + H+]: 160.1121, found 160.1125.
(S)-tert-butyl 2-(buta-2,3-dien-1-yl(4-methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate (5a) - To a stirred solution of
boc-L-proline (2.13 g, 9.89 mmol) in anhydrous dichloromethane (30 mL), under nitrogen atmosphere, EDCI (2.16 g, 1.35
mmol), and HOBt (1.80 g, 1.35 mmol) and DIPEA (3.12 mL, 19.78 mmol) were added. The mixture was cooled to 0oC and
4a (1.70 g, 9.00 mmol) was added. Solution was stirred for 12h at room temperature. The reaction mixture was concentrated
under reduced pressure and purified by chromatography on silica gel to afford 5a in an 88 % yield (3.36 g, 8.70 mmol) as a
1
yellow oil. TLC: Rf 0.50 (PE : EtOAc = 1 : 1). H NMR (400 MHz, CDCl3) mixture of rotamers δ 7.33 – 7.15 (m, 2H), 6.93 -
10
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European Journal of Organic Chemistry
6.80 (m, 2H), 5.23 – 5.04 (m, 1H), 4.91 – 4.82 (m, 1H), 4.79 - 4.73 (m, 1H), 4.73 – 4.62 (m, 1H), 4.60 - 4.53 (m, 1H), 4.52 –
4.42 (m, 0.5H), 4.30 (d, J = 14.4 Hz, 0.5H), 4.03 – 3.91 (m, 1H), 3.86 - 3.74 (m, 3H), 3.72 - 3.57 (m, 1H), 3.55 – 3.37 (m,
1H), 2.25 – 2.06 (m, 2H), 2.01 – 1.76 (m, 3H), 1.51 - 1.45 (m, 6H), 1.33 (s, 3H). 13C NMR (101 MHz, CDCl3) mixture of
rotamers δ 209.60, 209.29, 208.87, 208.65, 173.45, 173.13, 173.04, 172.78, 159.25, 159.09, 158.82, 154.52, 153.93,
153.78, 130.18, 129.60, 129.53, 129.36, 128.81, 128.58, 128.33, 114.20, 113.93, 113.90, 87.46, 86.92, 86.43, 86.13, 79.81,
79.68, 79.41, 56.28, 56.02, 55.29, 55.25, 48.40, 47.00, 46.96, 46.88, 45.30, 45.24, 31.44, 31.38, 30.30, 28.56, 28.51, 28.34,
24.47, 23.54. IR (ATR): ν 2974, 1954, 1693, 1394, 1162, 847 cm−1. HRMS (ESI/Q-TOF) m/z calcd for [C22H30N2O4 + H+]:
387.2278, found 387.2285.
(S)-tert-butyl 2-(benzyl(buta-2,3-dien-1-yl)carbamoyl)pyrrolidine-1-carboxylate (5b) - The title compound was prepared
following the procedure for 5a starting from 4b (470 mg, 2.96 mmol), Boc-L-Proline (700 mg, 3.25 mmol), EDCI (682 mg,
3.55 mmol), HOBt (480 mg, 3.55 mmol) and DIPEA (1.03 mL, 5.92 mmol) in a 76% yield (800 mg, 2.25 mmol) as a pale
1
yellow oil. TLC: Rf 0.30 (PE : EtOAc = 7 : 3). H NMR/13C NMR - attempts were not made to assign the signals as both
spectra (enclosed in SI) suggested formation of complex mixture of rotamers; full characterization was carried out for the
product (6b) obtained in the following step. IR (ATR): ν 2975, 2876, 1954, 1694, 1396, 1163 cm−1. [α]D = +29.0 (c 0.10,
CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C21H28N2O3 + Na+]: 379.1992, found 379.2001.
(S)-N-(buta-2,3-dien-1-yl)-N-(4-methoxybenzyl)pyrrolidine-2-carboxamide (6a) - To a stirred solution of 5a (3.00 g, 7.77
mmol) in dichloromethane (20 mL), TFA (5.90 mL 77.7 mmol) was added and left stirring for 12 h at room temperature. The
reaction mixture was evaporated, redissolved in ethyl acetate (30 mL) and washed with saturated NaHCO3 (3 x 30 mL) and
with brine (1 x 30 mL). Organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under reduced
1
pressure to afford 6a in a 99 % yield (2.20 g, 7.69 mmol) as a brown oil. H NMR (400 MHz, CDCl3) mixture of rotamers δ
7.19 - 7.08 (m, 2H), 6.92 - 6.82 (m, 2H), 5.41 (bs, 1.5H), 5.15 – 5.02 (m, 1H), 4.90 (s, 1H), 4.81 – 4.77 (m, 0.5H), 4.68 (d, J =
14.5 Hz, 0.5H), 4.58 (d, J = 16.2 Hz, 0.5H), 4.49 – 4.38 (m, 1H), 4.27 - 4.20 (m, 1H), 3.93 – 3.70 (m, 5H), 3.33 - 3.23 (m,
1H), 3.13 – 2.96 (m, 1H), 2.31 – 2.08 (m, 1H), 1.97 – 1.73 (m, 3H). 13C NMR (101 MHz, CDCl3) mixture of rotamers δ
209.05, 208.79, 172.76, 172.56, 159.33, 159.13, 129.65, 128.72, 128.25, 127.49, 114.36, 114.08, 86.30, 77.99, 58.28,
58.12, 55.32, 55.27, 49.25, 47.98, 47.34, 47.29, 44.37, 43.63, 31.16, 31.01, 26.16, 26.11. IR (ATR): ν 2956, 1955, 1645,
1512, 1247, 848 cm−1.[α]D = -57.0 (c 0.10, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C17H22N2O2 + H+]: 287.1754, found
287.1762.
(S)-N-benzyl-N-(buta-2,3-dien-1-yl)pyrrolidine-2-carboxamide (6b) - The title compound was prepared following the
procedure for 6a starting from 5b (400 mg, 1.12 mmol) and TFA (0.86 mL, 11.2 mmol) in 92 % yield (264 mg, 1.03 mmol) as
1
a dark orange oil. H NMR (400 MHz, CDCl3) mixture of rotamers δ 7.40 – 7.27 (m, 3H), 7.25 – 7.18 (m, 2H), 5.17 – 5.04
(m, 1H), 4.93 – 4.85 (m, 1H), 4.81 – 4.73 (m, 1.5H), 4.65 (d, J = 16.7 Hz, 0.5H), 4.50 (d, J = 15.4 Hz, 1H), 4.23 – 4.14 (m,
0.5H), 4.13 – 4.07 (m, 0.5H), 4.06 – 3.99 (m, 0.5H), 3.94 - 3.72 (m, 1.5H), 3.35 - 3.19 (m, 2H), 3.01 – 2.85 (m, 1H), 2.24 -
2.14 (m, 0.5H), 2.11 – 2.01 (m, 0.5H), 1.94 – 1.69 (m, 3H). 13C NMR (101 MHz, CDCl3) mixture of rotamers δ 209.09,
208.80, 173.97, 173.74, 136.95, 136.01, 128.97, 128.68, 128.21, 127.83, 127.55, 126.77, 86.40, 77.91, 58.44, 58.28, 49.70,
48.50, 47.72, 47.67, 44.58, 43.94, 31.38, 31.28, 26.53, 26.48. IR (ATR): ν 3300, 2964, 2871, 1964, 1640, 1219 cm−1. [α]D = -
237.0 (c 0.10, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C16H20N2O + H+]: 257.1648, found 257.1658.
(4R,8aS)-2-benzyl-4-vinylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one
(7a)
and
(4S,8aS)-2-benzyl-4-
vinylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (7b) - 6b (50 mg, 0.195 mmol), was dissolved in a mixture of acetone and
water (5 mL, 1:1) in a foil-wrapped round-bottom flask. Calcium-carbonate (15.6 mg, 0.156 mmol) and silver-nitrate (26.6
mg, 0.156 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was thereupon
filtered and acetone was removed under reduced pressure. The reaction mixture should not at any point be heated over 30
°C due to the formation of a purple colored side product. The remaining water solution was extracted with diethyl ether (3 x 5
mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by chromatography on silica gel to
afford 7a in a 14 % yield (7 mg, 0.027 mmol) as a pale yellow oil and 7b in a 69% yield (34.4 mg, 0.134 mmol) as a pale
yellow oil which quickly turns purple upon heat and air exposure. TLC: Rf7a 0.55 (EtOAc : MeOH = 4 : 1) and Rf7b 0.40
(EtOAc : MeOH = 4 : 1).
7a: 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.26 (m, 4H), 7.25 - 7.23 (m, 1H), 5.72 (ddd, J = 17.4, 10.2, 7.4 Hz, 1H), 5.28 – 5.12
(m, 2H), 4.74 (d, J = 14.6 Hz, 1H), 4.41 (d, J = 14.6 Hz, 1H), 3.26 – 3.15 (m, 2H), 3.12 - 3.07 (m, 1H), 3.03 - 2.96 (m, 2H),
2.28 – 2.17 (m, 2H), 2.05 – 1.93 (m, 1H), 1.88 – 1.73 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 169.86, 136.91, 136.33, 128.62,
128.18, 127.42, 118.62, 65.18, 62.05, 50.89, 50.23, 49.31, 26.46, 21.42. IR (ATR): ν 3465, 2919, 1639, 1494, 926, 700
cm−1. [α]D = -138.0 (c 0.05, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C16H20N2O + H+]: 257.1648, found 257.1660.
7b: 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.26 (m, 4H), 7.25 - 7.23 (m, 1H), 5.72 – 5.57 (m, 1H), 5.23 - 5.14 (m, 2H), 4.61 (q,
J = 14.6 Hz, 2H), 3.78 (t, J = 8.5 Hz, 1H), 3.25 - 3.12 (m, 3H), 2.96 - 2.89 (m, 1H), 2.85 - 2.78 (m, 1H), 2.34 - 2.24 (m, 1H),
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10.1002/ejoc.201901554
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2.08 – 1.99 (m, 1H), 1.89 – 1.69 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.88, 136.83, 136.77, 128.67, 128.17, 127.56,
118.37, 61.50, 59.21, 52.52, 49.90, 49.68, 28.70, 22.86. IR (ATR): ν 3466, 2917, 1640, 1494, 927, 700 cm−1. [α]D = -29.0 (c
0.10, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C16H20N2O + H+]: 257.1648, found 257.1658.
(4R,8aS)-2-(4-methoxybenzyl)-4-vinylhexahydropyrrolo
[1,2-a]
pyrazin-1(2H)-one
(7d)
and (4S,8aS)-2-(4-
methoxybenzyl)-4-vinylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (7c) – The title compounds were prepared following
the procedure for 7a/7b starting from 6a (1.3 g, 4.54 mmol), CaCO3 (363 mg, 3.63 mmol) and AgNO3 (618 mg, 3.63 mmol) to
afford 7d in a 14 % yield (184 mg, 0.64 mmol) as a pale yellow oil and 7c in a 69 % yield (896 mg, 3.13 mmol) as a pale
yellow oil which quickly turns purple upon heat and air exposure. TLC: Rf7d 0.35 (EtOAc :MeOH = 9 : 1), Rf7c 0.20 (EtOAc :
MeOH = 9 : 1).
7d:*1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.71 (ddd, J = 10.2, 8.8, 5.4 Hz, 1H),
5.25 (d, J = 17.2 Hz, 1H), 5.17 (d, J = 10.3 Hz, 1H), 4.67 (d, J = 14.4 Hz, 1H), 4.34 (d, J = 14.4 Hz, 1H), 3.79 (s, 3H), 3.25 –
3.12 (m, 2H), 3.11 - 3.05 (m, 1H), 3.02 - 2.93 (m, 2H), 2.22 (dt, J = 16.8, 8.2 Hz, 2H), 1.98 (ddd, J = 21.7, 11.4, 8.4 Hz, 1H),
1.88 – 1.73 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 169.75, 159.07, 136.30, 129.63, 128.99, 118.80, 114.05, 65.19, 62.12,
55.28, 50.66, 50.30, 48.68, 26.43, 21.40.
1
7c: H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.64 (ddd, J = 17.0, 10.2, 6.6 Hz, 1H),
5.23 - 5.14 (m, 2H), 4.54 (q, J = 14.4 Hz, 2H), 3.80 (s, 3H), 3.76 (t, J = 8.6 Hz, 1H), 3.25 – 3.10 (m, 3H), 2.97 – 2.87 (m, 1H),
2.85 - 2.77 (m, 1H), 2.33 - 2.22 (m, 1H), 2.07 - 1.96 (m, 1H), 1.87 – 1.68 (m, 2H).13C NMR (101 MHz, CDCl3) δ 170.71,
159.13, 136.79, 129.55, 128.84, 118.43, 114.06, 61.50, 59.20, 55.28, 52.49, 49.61, 49.04, 28.68, 22.82. IR (ATR): ν 2956,
2835, 1644, 1512, 1246, 1033 cm−1. [α]D = -25.0 (c 0.10, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C17H22N2O2 + H+]:
287.1754, found 287.1764.
*Due to its low stability the compound was oxidized as described below (compound 8) and stored and further characterized
as other enantiomer of 8 named 8a.
(S)-2-(4-methoxybenzyl)-4-vinyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (8)- To a flame-dried round-bottom flask
was added 7c (800 mg, 2.80 mmol), freshly distilled THF (20 mL) and MnO2 (6.16 g, 70.80 mmol) were added. The reaction
was heated to 85 °C and stirred overnight. The reaction mixture was filtered through a pad of Celite. The Celite was washed
with hot THF and then placed again into a round-bottom flask and refluxed in THF for 30 minutes. The mixture was then
filtered through a new pad of Celite and the combined filtrate concentrated under reduced pressure and purified by
chromatography on silica gel to afford 8 in a 57 % yield (450 mg, 1.60 mmol) as a clear pale yellow oil. TLC: Rf 0.28 (Et2O :
1
PE = 3 : 1). H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.5 Hz, 2H), 7.01 (dd, J = 3.7, 1.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H),
6.71 (s, 1H), 6.32 – 6.21 (m, 1H), 5.77 (ddd, J = 17.1, 10.2, 7.0 Hz, 1H), 5.33 (d, J = 10.2 Hz, 1H), 5.12 (d, J = 17.0 Hz, 1H),
4.77 – 4.58 (m, 3H), 3.79 (s, 3H), 3.53 (dd, J = 12.7, 4.5 Hz, 1H), 3.40 (dd, J = 12.7, 7.6 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 159.33, 159.12, 133.70, 129.72, 129.04, 124.41, 121.95, 120.71, 114.02, 109.98, 56.76, 55.28, 49.88, 48.55. IR
(ATR): ν 2911, 2836, 1634, 1511, 1242, 733 cm−1. [α]D = -1.3 (c 0.30, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for
[C17H18N2O2+ H+]: 283.1441, found 283.1449.
8a - IR (ATR): ν 2911, 2836, 1634, 1512, 1243, 732 cm−1. [α]D = +1.0 (c 0.20, CH2Cl2).HRMS (ESI/Q-TOF) m/z calcd for
[C17H18N2O2 + H+]: 283.1441, found 283.1455.
(S)-4-(2-hydroxyethyl)-2-(4-methoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (9a) and (S)-2-(1-oxo-1,2,3,4-
tetrahydropyrrolo [1,2-a]pyrazin-4-yl)ethyl 2,2,2-trifluoroacetate (9) - To a solution of 8 (400 mg, 1.42 mmol) in THF
(15 mL), a solution of 9-BBN in THF (0.5 M, 4.26 mmol, 8.51 mL) was added. The reaction was monitored by TLC for the
consumption of starting alkene and was completed after 3 hours. Thereafter the reaction mixture was cooled to 0 °C, and
NaOH (1.0 M, 12.76 mL) and H2O2 (35 wt %/vol, 1.54 mL) were added. The reaction was thereafter stirred overnight at room
temperature. The reaction was then transferred into a separatory funnel with saturated NaHCO3 (10 mL) and extracted with
ethyl acetate (3 x 10 mL). The combined organic fractions were dried, filtered, concentrated under reduced pressure and
purified by chromatography on silica gel to afford 352 mg of clear colorless oil, slightly contaminated with 9-BBN residues
(9a). TLC: Rf 0.30 (EtOAc : Benzene = 1 : 1). The oil was used without further purification in the following step. Under
nitrogen atmosphere the crude oil was dissolved in TFA (5 mL) and anisole (0.26 mL, 2.37 mmol) was added. The reaction
was stirred at 60 °C overnight. The reaction mixture was evaporated and the remaining residue diluted with ethyl acetate (15
mL) and transferred into a separatory funnel and washed with NaHCO3 (3 x 15 mL). The combined organic layer was dried,
filtered, concentrated under reduced pressure and purified by chromatography on silica gel to afford 9 in a 55% yield over 2
steps (216 mg, 0.78 mmol) as a pale yellow oil. TLC: Rf 0.35 (EtOAc = 100%).
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10.1002/ejoc.201901554
European Journal of Organic Chemistry
1
9a: H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 3.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H),
6.23 – 6.14 (m, 1H), 4.90 (d, J = 14.4 Hz, 1H), 4.42 – 4.29 (m, 2H), 3.83 – 3.74 (m, 4H), 3.54 - 3.46 (m, 1H), 3.45 - 3.38 (m,
1H), 3.30 (dd, J = 12.8, 2.6 Hz, 1H), 1.88 - 1.83 (m, 1H), 1.74 – 1.65 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 159.39, 159.20,
129.97, 129.12, 128.34, 123.69, 122.59, 114.07, 113.87, 109.66, 58.61, 55.31, 50.85, 49.00, 48.56, 35.58. HRMS (ESI/Q-
TOF) m/z calcd for [C17H20N2O3 + H+]: 301.1547, found 301.1555.
9: 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 3.0 Hz, 1H), 6.85 - 6.72 (m, 2H), 6.31 – 6.24 (m, 1H), 4.55 – 4.45 (m, 1H), 4.40 -
4.32 (m, 1H), 4.17 – 4.09 (m, 1H), 3.98 (dd, J = 12.8, 3.9 Hz, 1H), 3.50 - 3.42 (m, 1H), 2.42 – 2.30 (m, 1H), 2.22 (ddd, J =
14.9, 9.9, 5.2 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 161.15, 157.16, 134.77, 123.26, 114.67, 110.25, 64.44, 50.82, 44.76,
31.63. IR (ATR): ν 2884, 1784, 1634, 1552, 1334, 741 cm−1. [α]D = -57.6 (c 0.34, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for
[C11H11F3N2O3 + H+]: 277.0795, found 277.0792.
(S)-2-(6,7-dibromo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl) ethyl 2,2,2-trifluoroacetate (10) - To a solution
of 9 (120 mg, 0.44 mmol) in THF (5 mL), was added a solution of NBS (162 mg, 0.913 mmol) in THF (1 mL) at room
temperature. The reaction was stirred overnight at room temperature. The reaction mixture was evaporated under reduced
pressure and the residue purified by chromatography on silica gel to afford 10 in an 85% yield (160 mg, 0.37 mmol) as a
pale yellow oil. TLC: Rf 0.40 (EtOAc = 100%). 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 4.52 - 4.46 (m, 1H), 4.45 - 4.40 (m,
2H), 3.96 (dd, J = 13.2, 3.9 Hz, 1H), 3.56 (dd, J = 12.9, 4.7 Hz, 1H), 2.40 – 2.26 (m, 1H), 2.26 – 2.13 (m, 1H). 13C NMR (101
MHz, CDCl3) δ 159.41, 157.21, 124.74, 116.56, 106.94, 101.42, 64.16, 51.05, 43.32, 31.04. IR (ATR): ν 2927, 1651, 1428,
1337, 943, 750 cm−1. [α]D = -18.6 (c 0.50, CH3OH). HRMS (ESI/Q-TOF) m/z calcd for [C11H9Br2F3N2O3 + H+]: 432.9005,
found 432.9001.
(S)-6,7-dibromo-4-(2-hydroxyethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)- one (11) - To a stirred solution of 10 (50
mg, 0.115 mmol) in a mixture of methanol, THF and water (5 mL, 1 : 2 : 1), NaOH (0.46 mL of 1M solution) was added
dropwise. After 3h methanol and THF were evaporated under reduced pressure and the remaining water solution was
extracted with ethyl acetate (3 x 5 mL). The combined organic layer was dried, filtered, concentrated under reduced
1
pressure to afford 11 in a 99% yield (38.5 mg, 0.114 mmol) as a pale yellow oil. TLC: Rf 0.40 (EtOAc :MeOH = 9 : 1). H
NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 5.91 (s, 1H), 4.61 – 4.47 (m, 1H), 3.90 (dd, J = 12.9, 3.9 Hz, 1H), 3.78 (s, 2H), 3.69
(dd, J = 12.6, 5.0 Hz, 1H), 2.16 - 2.05 (m, 1H), 1.97 – 1.87 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 159.03, 121.81, 116.13,
106.66, 100.84, 59.26, 52.16, 43.31, 34.47. IR (ATR): ν 3306, 2360, 1645, 1549, 1338, 1063 cm−1. [α]D = -27.0 (c 0.10,
CH3OH). HRMS (ESI/Q-TOF) m/z calcd for [C9H10Br2N2O2 + H+]: 336.9182, found 336.9188.
Longamide B - To a stirred solution of 11 (15 mg, 0.045 mmol) in a mixture of acetonitrile and water (3 mL, 1 : 1),
iodobenzene diacetate (BAIB) (36 mg, 0.112 mmol), NaHCO3 (15 mg, 0.176 mmol) and 2,2,6,6-tetramethyl-piperidine-1-oxyl
(TEMPO) (1.6 mg, 0.011 mmol) were added. The mixture was stirred for 18h at room temperature. Upon completion
saturated solution of NaHCO3 (5 mL) was added to the reaction mixture and the aqueous phase was washed with ethyl
acetate (3 x 5 mL). The remaining water solution was acidified with 2M HCl to pH 2 and extracted with ethyl acetate (3 x 5
mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude white solid was washed with the mixture of dichloro methane and petroleum ether (2 : 8), and recrystalysed from the
mixture of dichlormethane and methanol (98 : 2) to afford Longamide B in an 83 % yield (12.5 mg, 0.037 mmol) as a white
crystalline solid. 1H NMR (400 MHz, 98% CDCl3 + 2% MeOD) δ 7.00 (s, 1H), 4.75 (d, J = 11.6 Hz, 1H), 3.89 (d, J = 13.5 Hz,
1H), 3.70 (d, J = 13.5 Hz, 1H), 2.97 – 2.89 (m, 1H), 2.56 (d, J = 16.6 Hz, 1H). 13C NMR (101 MHz, 98% CDCl3 + 2% MeOD)
δ 171.90, 159.57, 124.68, 116.39, 106.88, 101.29, 50.53, 42.86, 35.38. IR (ATR): ν 3305, 2359, 1634, 1338, 1059, 749
cm−1. [α]D = -5.5 (c 0.20, CH3OH). HRMS (ESI/Q-TOF) m/z calcd for [C9H8Br2N2O3 + H+]: 350.8974, found 350.8971.
Stylisine D - To a stirred solution of longamide B (10 mg, 0.028 mmol) in THF (5 mL), EDCI (8.2 mg, 0.043 mmol), HOBt
(5.8 mg, 0.043 mmol) and DIPEA (8.4 μL, 0.048 mmol) were added at 0°C. After stirring for 5 minutes, the solution of 25%
ammonium hydroxide (6.8 mg, 0.048 mmol) was added and the solution was stirred for 18h at room temperature. Upon
completion the solvents were evaporated under reduced pressure, residues redissolved in ethyl acetate (5 mL) and washed
with HCl 0.5 M (3 x 5 mL), then with NaHCO3 (3 x 5 mL) and finally with brine (2 x 5 mL). The organic layer was dried over
anhydrous Na2SO4 concentrated under reduced pressure and the residue purified by chromatography on silica gel to afford
stylisine D in an 81 % yield (8.1 mg, 0.023 mmol) as a pale yellow amorphous solid. TLC: Rf 0.15 (EtOAc :MeOH = 9 : 1).
1H NMR (400 MHz, 98% CDCl3 + 2% MeOD) δ 6.99 (s, 1H), 4.82 (d, J = 10.6 Hz, 1H), 3.87 (d, J = 12.7 Hz, 1H), 3.63 (d, J =
13.2 Hz, 1H), 2.84 – 2.73 (m, 1H), 2.49 (d, J = 14.9 Hz, 1H). 13C NMR (101 MHz, 98% CDCl3 + 2% MeOD) δ 171.69,
124.72, 116.43, 107.10, 101.23, 50.96, 42.94, 36.41. IR (ATR): ν 3381, 1635, 1349, 1331, 999, cm−1. [α]D = -7.0 (c 0.10,
CH3OH). HRMS (ESI/Q-TOF) m/z calcd for [C9H9Br2N3O2 + H+]: 349.9134, found 349.9139.
(4R,8aS)-4-(1-(3-chloro-4-methylphenyl)vinyl)-2-(4-methoxybenzyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (12aa)
and
(4S,8aS)-4-(1-(3-chloro-4-methylphenyl)vinyl)-2-(4-methoxybenzyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one
(12ba) - To a solution of 6a (1114 mg, 3.90 mmol) in acetonitrile (10 mL), under the atmosphere of nitrogen, K2CO3 (1075
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European Journal of Organic Chemistry
mg, 7.79 mmol), Pd(OAc)2 (87.3 mg, 0.39 mmol), XantPhos (225.5 mg, 0.39 mmol) and 2-chloro-4-iodo-1-methylbenzene
(982.8 mg, 3.90 mmol) were added. The solution was refluxed for 18h. Upon completion the reaction mixture was
concentrated under reduced pressure and the residue purified by chromatography on silica gel to afford 12aa in a 32 % yield
(512.9 mg, 1.25 mmol) as a pale yellow oil and 12ba in a 26% yield (416.8 mg, 1.01 mmol) as a pale yellow oil. TLC: Rf12aa
0.50 (Et2O = 100%) and Rf12ba 0.40 (Et2O = 100%).
1
12aa: H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 1.4 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.18 - 7.12 (m, 3H), 6.84 (d, J = 8.6 Hz,
2H), 5.42 (s, 1H), 5.26 (s, 1H), 4.75 (d, J = 14.5 Hz, 1H), 4.21 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H), 3.64 (dd, J = 10.6, 4.6 Hz,
1H), 3.37 (t, J = 11.3 Hz, 1H), 3.19 – 3.08 (m, 2H), 2.98 (td, J = 8.6, 3.9 Hz, 1H), 2.36 (s, 3H), 2.29 - 2.18 (m, 2H), 2.03 (dt, J
= 12.7, 9.6 Hz, 1H), 1.87 – 1.71 (m, 2H), 1.64 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 158.99, 145.09, 138.83, 135.62,
134.32, 130.79, 129.44, 128.97, 127.35, 125.03, 117.20, 114.01, 65.26, 62.86, 55.26, 49.84, 49.77, 48.70, 26.86, 21.64,
19.74. IR (ATR): ν 2923, 1645, 1512, 1246, 821, 734 cm−1. [α]D = -55.0 (c 0.10, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for
[C20H29NO4 + H+]: 411.1834, found 411.1837.
12ba:1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 1.5 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 7.9 Hz, 1H), 7.00 (dd, J =
7.9, 1.6 Hz, 1H), 6.86 – 6.79 (m, 2H), 5.38 (d, J = 15.7 Hz, 2H), 4.65 (d, J = 14.4 Hz, 1H), 4.31 (d, J = 14.3 Hz, 1H), 3.87 (t, J
= 8.1 Hz, 1H), 3.79 (s, 3H), 3.50 (dd, J = 8.1, 4.4 Hz, 1H), 3.22 – 3.11 (m, 2H), 3.11 – 3.04 (m, 1H), 2.67 - 2.57 (m, 1H), 2.34
(s, 3H), 2.28 - 2.14 (m, 2H), 1.90 – 1.75 (m, 2H).13C NMR (101 MHz, CDCl3) δ 171.62, 159.09, 145.47, 139.30, 135.32,
134.27, 130.74, 129.62, 129.55, 128.90, 128.31, 127.13, 126.51, 124.77, 116.26, 114.04, 62.32, 60.98, 55.23, 53.47, 49.32,
49.03, 28.45, 24.00, 19.72. IR (ATR): ν 2915, 1646, 1511, 1245, 818, 734 cm−1. [α]D = -7.0 (c 0.20, CH2Cl2). HRMS (ESI/Q-
TOF) m/z calcd for [C24H27ClN2O2 + H+]: 411.1834, found 411.1836.
(4R,8aS)-4-(1-(3,4-dichlorophenyl)vinyl)-2-(4-methoxybenzyl) hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (12ab) and
(4S,8aS)-4-(1-(3,4-dichlorophenyl)vinyl)-2-(4-methoxybenzyl) hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (12bb) - The
title compounds were prepared following the procedure for 12aa/12ba starting from 6a (30.0 mg, 0.105 mmol), K2CO3 (29.0,
0.210 mmol), Pd(OAc)2 (2.4 mg. 0.0105 mmol), XantPhos (6.1 mg, 0.0105 mmol) and 1,2-dichloro-4-iodobenzene (28.7 mg,
0.105 mmol) to afford 12ab in a 33 % yield (15.1 mg, 0.035 mmol) as a yellow oil and 12bb in a 26 % yield (11.8 mg, 0.028
mmol) as a yellow oil. TLC: Rf12ab 0.40 (Et2O = 100%), Rf12bb0.30 (Et2O = 100%).
12ab: 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.36 (s, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.44 (s, 1H),
5.30 (s, 1H), 4.72 (d, J = 14.5 Hz, 1H), 4.25 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H), 3.65 (dd, J = 10.6, 4.7 Hz, 1H), 3.35 (t, J =
11.3 Hz, 1H), 3.21 – 3.07 (m, 2H), 2.92 (td, J = 8.4, 4.1 Hz, 1H), 2.30 - 2.18 (m, 2H), 2.04 (dt, J = 12.9, 9.4 Hz, 1H), 1.87 –
1.71 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.23, 159.09, 144.41, 139.46, 132.46, 131.96, 130.26, 129.45, 128.90,
128.84, 126.25, 118.23, 114.07, 65.07, 62.65, 55.28, 49.60, 49.18, 48.76, 26.96, 21.75. IR (ATR): ν 2920, 2645, 1511, 1244,
1029, 817 cm−1. [α]D = -65.7 (c 0.30, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C23H24Cl2N2O2 + H+]: 431.1288, found
431.1303.
12bb: 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.03 (dd, J =
8.3, 2.0 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 5.39 (d, J = 24.0 Hz, 2H), 4.67 (d, J = 14.4 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H), 3.86
(t, J = 7.9 Hz, 1H), 3.80 (s, 3H), 3.46 (dd, J = 8.2, 4.2 Hz, 1H), 3.21 – 3.11 (m, 2H), 3.11 – 3.03 (m, 1H), 2.59 (dd, J = 15.9,
9.1 Hz, 1H), 2.30 - 2.16 (m, 2H), 1.90 - 1.75 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 171.58, 159.22, 144.85, 140.08, 132.41,
131.65, 130.20, 129.65, 128.86, 128.67, 126.01, 117.36, 114.11, 62.59, 60.79, 55.27, 53.48, 49.04, 48.86, 28.39, 24.10.IR
(ATR): ν 2932, 1645, 1511, 1245, 1029, 818 cm−1. [α]D = -7.6 (c 0.50, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for
[C23H24Cl2N2O2 + H+]: 431.1288, found 431.1302.
(4R,8aS)-4-(1-(3,5-dimethoxyphenyl)vinyl)-2-(4-methoxybenzyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (12ac) and
(4S,8aS)-4-(1-(3,5 dimethoxyphenyl)vinyl)-2-(4-methoxybenzyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (12bc): The
title compounds were prepared following the procedure for 12aa/12ba starting from 6a (30.0 mg, 0.105 mmol), K2CO3 (29.0,
0.210 mmol), Pd(OAc)2 (2.4 mg. 0.0105 mmol), XantPhos (6.1 mg, 0.0105 mmol) and 1-iodo-3,5-dimethoxybenzene (27.7
mg, 0.105 mmol) to afford 12ac in a 29 % yield (12.8 mg, 0.030 mmol) as a yellow oil and 12bc in a 24 % yield (10.6 mg,
0.025 mmol) as a yellow oil. TLC: Rf12ac 0.35 (Et2O = 100%), Rf12bc 0.25 (Et2O = 100%).
1
12ac: H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 2.1 Hz, 2H), 6.41 (d, J =
2.1 Hz, 1H), 5.45 (s, 1H), 5.29 (s, 1H), 4.75 (d, J = 14.5 Hz, 1H), 4.20 (d, J = 14.5 Hz, 1H), 3.82 - 3.75 (m, 9H), 3.62 (dd, J =
10.3, 4.3 Hz, 1H), 3.38 (t, J = 11.3 Hz, 1H), 3.16 (dd, J = 11.9, 4.6 Hz, 1H), 3.12 – 3.01 (m, 2H), 2.30 - 2.18 (m, 2H), 2.02
(dt, J = 12.3, 10.0 Hz, 1H), 1.87 – 1.72 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.14, 160.63, 158.97, 146.23, 141.85,
129.45, 129.04, 117.32, 113.98, 105.23, 99.55, 65.42, 63.29, 55.31, 55.25, 50.31, 50.02, 48.65, 26.76, 21.57. IR (ATR): ν
2954, 2835, 1651, 1589, 1155, 846 cm−1. [α]D = -66.7 (c 0.34, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C25H30N2O4 + H+]:
423.2278, found 423.2296.
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European Journal of Organic Chemistry
1
12bc: H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.44 (d, J = 2.1 Hz, 2H), 6.38 (t, J =
2.1 Hz, 1H), 5.39 (d, J = 8.5 Hz, 2H), 4.59 (d, J = 14.4 Hz, 1H), 4.35 (d, J = 14.5 Hz, 1H), 3.89 (t, J = 8.1 Hz, 1H), 3.79 (s,
3H), 3.76 (s, 6H), 3.53 (dd, J = 8.3, 4.2 Hz, 1H), 3.24 – 3.13 (m, 2H), 3.13 – 3.06 (m, 1H), 2.66 (dd, J = 16.3, 8.7 Hz, 1H),
2.31 - 2.23 (m, 1H), 2.24 – 2.14 (m, 1H), 1.85 (ddd, J = 27.5, 14.5, 8.3 Hz, 2H).13C NMR (101 MHz, CDCl3) δ 171.60,
160.62, 160.38, 159.04, 146.91, 142.49, 129.46, 128.96, 125.53, 116.17, 113.99, 105.09, 99.34, 62.30, 61.10, 55.29, 55.21,
53.50, 49.60, 49.13, 30.33, 28.59, 23.95. IR (ATR): ν 2935, 2837, 1645, 1589, 1154, 734 cm−1.[α]D = -9.3 (c 0.30, CH2Cl2).
HRMS (ESI/Q-TOF) m/z calcd for [C25H30N2O4 + H+]: 423.2278, found 423.2298.
(4R,8aS)-4-(1-(4-fluorophenyl)vinyl)-2-(4-methoxybenzyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one
(12ad)
and
(4S,8aS)-4-(1-(4-fluorophenyl)vinyl)-2-(4-methoxybenzyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (12bd) - The title
compounds were prepared following the procedure for 12aa/12ba starting from 6a (30.0 mg, 0.105 mmol), K2CO3 (29.0,
0.210 mmol), Pd(OAc)2 (2.4 mg. 0.0105 mmol), XantPhos (6.1 mg, 0.0105 mmol) and 1-fluoro-4-iodobenzene (23.3mg,
0.105 mmol) to afford 12ad in a 39 % yield (15.4 mg, 0.041 mmol) as an orange oil and 12bd in a 29 % yield (11.7mg, 0.031
mmol) as an orange oil. TLC: Rf12ad 0.40 (Et2O = 100%), Rf12bd0.35 (Et2O = 100%).
12ad: 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.42 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.98 (t, J = 8.6 Hz, 2H), 6.83 (d, J = 8.4 Hz,
2H), 5.39 (s, 1H), 5.25 (s, 1H), 4.74 (d, J = 14.4 Hz, 1H), 4.20 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H), 3.64 (dd, J = 10.9, 4.6 Hz,
1H), 3.36 (t, J = 11.2 Hz, 1H), 3.20 – 3.08 (m, 2H), 2.98 (td, J = 8.6, 3.9 Hz, 1H), 2.28 - 2.16 (m, 2H), 2.10 - 1.97 (m, 1H),
1.86 – 1.69 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.26, 159.05, 145.39, 129.47, 129.04, 128.62, 128.54, 128.36, 126.83,
116.90, 115.30, 115.09, 114.03, 65.29, 63.21, 55.27, 49.78, 49.74, 48.75, 26.89, 21.68. IR (ATR): ν 2958, 2835, 1651,
1509, 1245, 842 cm−1. [α]D = -72.1 (c 0.38, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C23H25FN2O2 + H+]: 381.1973, found
381.1992.
12bd: 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.10 (m, 4H), 6.92 (t, J = 8.6 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.35 (d, J = 24.5
Hz, 2H), 4.69 (d, J = 14.4 Hz, 1H), 4.26 (d, J = 14.4 Hz, 1H), 3.88 (t, J = 7.9 Hz, 1H), 3.80 (s, 3H), 3.47 (dd, J = 8.3, 4.2 Hz,
1H), 3.21 – 3.12 (m, 2H), 3.12 – 3.04 (m, 1H), 2.66 - 2.56 (m, 1H), 2.28 - 2.20 (m, 2H), 1.91 – 1.75 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 171.67, 159.18, 145.76, 129.69, 129.65, 129.03, 128.30, 128.22, 126.55, 115.83, 115.24, 115.03, 114.07,
62.84, 60.99, 55.28, 53.52, 49.18, 49.00, 28.38, 24.08. IR (ATR): ν 2903, 1634, 1508, 1245, 840, 816 cm−1. [α]D = -2.1 (c
0.47, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C23H25FN2O2 + H+]: 381.1973, found 381.1992.
(4R,8aS)-2-benzyl-4-(1-(naphthalen-2-yl)vinyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one(12ae)
and
(4S,8aS)-2-
benzyl-4-(1-(naphthalen-2-yl)vinyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (12be) - The title compounds were
prepared following the procedure for 12aa/12ba starting from 6b (26.9 mg, 0.105 mmol), K2CO3 (29.0, 0.210 mmol),
Pd(OAc)2 (2.4 mg. 0.0105 mmol), XantPhos (6.1 mg, 0.0105 mmol) and 2-iodonaphthalene (26.7 mg, 0.105 mmol) to afford
12ae in a 43 % yield (17.3 mg, 0.045 mmol) as an orange oil and 12be in a 32 % yield (12.7 mg, 0.033 mmol) as an orange
oil. TLC: Rf12ae 0.60 (Et2O = 100%), Rf12be 0.40 (Et2O = 100%).
1
12ae: H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.83 - 7.75 (m, 3H), 7.60 (d, J = 7.2 Hz, 1H), 7.51 – 7.41 (m, 2H), 7.32 –
7.27 (m, 2H), 7.24 - 7.20 (m, 2H), 5.58 (s, 1H), 5.38 (s, 1H), 4.83 (d, J = 14.7 Hz, 1H), 4.27 (d, J = 14.7 Hz, 1H), 3.82 (dd, J
= 10.7, 4.6 Hz, 1H), 3.48 (t, J = 11.3 Hz, 1H), 3.23 (dd, J = 12.0, 4.7 Hz, 1H), 3.18 (t, J = 8.3 Hz, 1H), 3.10 (td, J = 8.5, 3.6
Hz, 1H), 2.34 – 2.20 (m, 2H), 2.16 – 2.02 (m, 1H), 1.89 – 1.72 (m, 2H), 1.61 – 1.49 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
170.46, 146.33, 137.03, 136.95, 133.27, 132.96, 128.62, 128.29, 128.06, 127.92, 127.54, 127.41, 126.24, 126.13, 125.68,
125.07, 117.41, 65.47, 63.18, 50.58, 49.98, 49.34, 26.86, 21.67. IR (ATR): ν 3058, 2961, 1645, 1453, 752, 700 cm−1. [α]D = -
48.0 (c 0.05, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C26H26N2O + H+]: 383.2118, found 383.2123.
1
12be: H NMR (400 MHz, CDCl3) δ 7.83 – 7.77 (m, 1H), 7.75 - 7.70 (m, 2H), 7.66 (s, 1H), 7.50 – 7.44 (m, 2H), 7.41 (d, J =
8.6 Hz, 1H), 7.30 - 7.26 (m, 2H), 7.22 – 7.16 (m, 2H), 5.53 (d, J = 4.4 Hz, 2H), 4.72 (d, J = 14.6 Hz, 1H), 4.37 (d, J = 14.6
Hz, 1H), 3.95 (t, J = 7.9 Hz, 1H), 3.73 (dd, J = 8.7, 4.0 Hz, 1H), 3.31 - 3.19 (m, 2H), 3.18 – 3.12 (m, 1H), 2.75 – 2.67 (m, 1H),
2.32 – 2.21 (m, 2H), 1.94 – 1.80 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 171.85, 146.71, 137.53, 136.98, 133.23, 132.84,
128.67, 128.19, 127.94, 127.56, 127.53, 126.20, 126.04, 125.16, 125.02, 116.42, 62.42, 61.18, 53.65, 50.01, 49.74, 28.55,
24.06. IR (ATR): ν 3058, 2922, 1652, 1454, 753, 701 cm−1. [α]D = 0.0 (c 0.10, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for
[C26H26N2O + H+]: 383.2118, found 383.2124.
(S)-4-(1-(3-chloro-4-methylphenyl)vinyl)-2-(4-methoxybenzyl)-3,4-dihydropyrrolo [1,2-a]pyrazin-1(2H)-one(13) - The
title compound was prepared following the procedure for 8 starting from 12ba (320 mg, 0.78 mmol) and MnO2 (1716 mg,
1
19.5 mmol) to afford 13 in a 56% yield (178 mg, 0.44 mmol) as a pale yellow oil. TLC: Rf 0.20 (PE : Et2O = 1 : 1). H NMR
(400 MHz, CDCl3) δ 7.13- 7.08 (m, 3H), 7.06 - 7.02 (m, 2H), 6.83 - 6.75 (m, 4H), 6.39 – 6.24 (m, 1H), 5.24 (s, 1H), 5.12 -
5.06 (s, 1H), 4.76 (d, J = 14.5 Hz, 1H), 4.34 – 4.22 (m, 2H), 3.80 (s, 3H), 3.75 (dd, J = 12.9, 4.7 Hz, 1H), 3.25 (dd, J = 12.8,
2.8 Hz, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.13, 144.51, 137.49, 136.08, 134.64, 131.06, 129.87, 128.92,
15
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European Journal of Organic Chemistry
128.66, 126.98, 126.50, 125.00, 124.61, 122.88, 116.50, 113.92, 113.72, 110.49, 57.15, 55.24, 48.45, 48.17, 19.76. IR
(ATR): ν 2912, 2835, 1634, 1243, 1072, 733 cm−1. [α]D = -72.5 (c 0.20, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for
[C24H23ClN2O2 + H+]: 407.1521, found 407.1526.
(S)-4-((S)-1-(3-chloro-4-methylphenyl)-2-hydroxyethyl)-2-(4-methoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-
one(14a) and (S)-2-(3-chloro-4-methylphenyl)-2-((S)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)ethyl 2,2,2-
trifluoroacetate (14) - The title compound was prepared following the procedure for 9 starting from 13 (170 mg, 0.42 mmol),
9-BBN (0.5 M solution in THF) (2.52 mL, 1.26 mmol), followed by NaOH (1M, 3.77 mL) and H2O2 (35 wt %/vol, 0.46 mL) to
afford crude 14a which was then treated with anisole (90.1 mg, 0.84 mmol) in TFA (5 mL) to afford 14 in an overall 32 %
yield (53.9 mg, 0.134 mmol) as a pale yellow oil. TLC: Rf14a 0.5 (Et2O = 100 %), Rf14 0.3 (Et2O = 100 %).
14a: 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 7.7 Hz, 1H), 7.01 (s, 2H), 6.97 (d, J = 2.8 Hz, 1H),
6.82 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 7.6 Hz, 1H), 6.28 – 6.19 (m, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.53 (dd, J = 10.9, 3.5 Hz,
1H), 4.28 (d, J = 14.4 Hz, 1H), 3.80 (s, 3H), 3.69 (dd, J = 12.9, 4.1 Hz, 1H), 3.50 - 3.38 (m, 2H), 3.01 (d, J = 12.9 Hz, 1H),
2.95 – 2.85 (m, 1H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.43, 159.17, 138.47, 135.21, 134.70, 131.26, 130.05,
129.07, 128.58, 126.87, 124.37, 123.50, 114.05, 109.56, 63.04, 55.25, 54.51, 48.72, 48.39, 47.73, 19.71. IR (ATR): ν 3376,
2919, 2870, 2161, 1616, 751 cm−1. [α]D = -91.0 (c 0.10, CH2Cl2). HRMS (ESI/Q-TOF) m/z calcd for [C24H25ClN2O3 + H+]:
425.1626, found 425.1637.
1
14: H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.00 (d, J = 3.5 Hz, 1H),
6.91 (d, J = 4.3 Hz, 1H), 6.85 (s, 1H), 6.38 – 6.24 (m, 1H), 4.58 (dd, J = 10.9, 2.7 Hz, 1H), 4.40 (dd, J = 11.2, 2.4 Hz, 1H),
4.04 (dd, J = 11.3, 4.8 Hz, 1H), 3.79 (dd, J = 13.0, 3.7 Hz, 1H), 3.57 (dd, J = 7.2, 3.6 Hz, 1H), 3.20 (dd, J = 12.9, 4.8 Hz,
1H), 2.38 (s, 3H).13C NMR (101 MHz, CDCl3) δ 161.31, 157.19, 156.84, 156.41, 136.55, 136.22, 135.38, 131.94, 128.55,
126.44, 124.00, 123.31, 114.87, 110.31, 68.15, 54.80, 45.24, 42.93, 19.75.IR (ATR): ν 3298, 2923, 1545, 1330, 1061, 742
cm−1. [α]D = -44.5 (c 0.20, CH3OH). HRMS (ESI/Q-TOF) m/z calcd for [C18H16ClF3N2O3 + H+]: 401.0874, found 401.0885.
(S)-2-(3-chloro-4-methylphenyl)-2-((S)-6,7-dibromo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)ethyl
2,2,2-
trifluoroacetate(15) - The title compound was prepared following the procedure for 10 starting from 14 (25 mg, 0.062 mmol)
and NBS (23 mg, 0.124 mmol) to afford 15 in a 75% yield (26 mg, 0.046 mmol) as a yellow oil. TLC: Rf 0.35 (Et2O = 100 %).
1H NMR (400 MHz, CDCl3) δ 7.30 - 7.24 (m, 2H), 7.11 – 7.05 (m, 2H), 6.19 (d, J = 4.9 Hz, 1H), 4.63 (dd, J = 10.5, 2.7 Hz,
1H), 4.53 (dd, J = 11.3, 7.0 Hz, 1H), 4.26 (dd, J = 11.3, 5.4 Hz, 1H), 3.72 (dd, J = 13.2, 3.6 Hz, 1H), 3.67 – 3.58 (m, 1H),
3.23 (dd, J = 13.2, 4.5 Hz, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.76, 156.95, 156.52, 136.92, 135.51, 135.41,
132.03, 128.42, 126.36, 125.53, 125.12, 117.19, 107.74, 101.69, 67.53, 55.19, 46.09, 43.02, 19.80. IR (ATR): ν 3234, 1775,
1705, 1335, 1181, 749 cm−1.[α]D = -6.0 (c 0.10, CH3OH). HRMS (ESI/Q-TOF) m/z calcd for [C18H14Br2ClF3N2O3 + H+]:
556.9085, found 556.9075.
(S)-6,7-dibromo-4-((S)-1-(3-chloro-4-methylphenyl)-2-hydroxyethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (16) -
The title compound was prepared following the procedure for 11 starting from 15 (15 mg, 0.029 mmol) and NaOH (0.1 mL,
1
1M) to afford 16 in a 99% yield (13.2 mg, 0.029 mmol) as a yellow oil. TLC: Rf 0.40 (EtOAc = 100 %). H NMR (400 MHz,
CDCl3) δ 7.29 (d, J = 1.3 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.12 – 7.05 (m, 1H), 7.03 (s, 1H), 6.29 (d, J = 5.0 Hz, 1H), 4.52 (dd, J
= 10.2, 3.0 Hz, 1H), 3.88 (dd, J = 10.6, 8.9 Hz, 1H), 3.67 (dd, J = 13.2, 3.7 Hz, 1H), 3.50 (dd, J = 10.8, 4.6 Hz, 1H), 3.42 –
3.32 (m, 1H), 3.23 (dd, J = 13.1, 5.3 Hz, 1H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.90, 137.55, 136.12, 135.29,
131.83, 128.65, 126.80, 125.20, 116.60, 108.05, 101.10, 63.35, 55.59, 49.73, 42.94, 19.77. IR (ATR): ν 3310, 2879, 1660,
1335, 1053, 749 cm−1. [α]D = +12.5 (c 0.20, CH3OH). HRMS (ESI/Q-TOF) m/z calcd for [C16H15Br2ClN2O2 + H+]: 460.9262,
found 460.9276.
2-(3-chloro-4-methylphenyl)-2-((S)-6,7-dibromo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetic acid (17) -
The title compound was prepared following the procedure for Longamide B starting from 16 (4.00 mg, 0.009 mmol), BAIB
(7.24 mg, 0.022 mmol), NaHCO3 (3.00 mg 0.036 mmol) and TEMPO (0.15 mg, 0.001 mmol) to afford a crude product that
was purified by column chromatography to afford 17 as an unseparable mixture of diastereoisomers (44 % : 56 %) in a 83%
yield (3.56 mg, 0.007 mmol) as a pale yellow amorphous solid. Rf 0.50 (EtOAc = 100 %). 1H NMR (400 MHz, CDCl3) mixture
of diastereomers (44 % : 56 %), δ 7.42 (bs, 1H), 7.19 (s, 0.5H), 7.16 – 7.09 (m, 1.5H), 7.01 - 6.85 (m, 2H), 4.86 - 4.78 (m,
1H), 4.03 (d, J = 6.1 Hz, 1H), 3.93 – 3.77 (m, 1.5H), 3.76 - 3.72 (m, 0.5H), 2.34 - 2.27 (m, 3H). 13C NMR (101 MHz, CDCl3)
mixture of diastereomers (44 % : 56 %) δ 159.96, 159.18, 136.73, 134.86, 132.07, 131.43, 131.31, 129.42, 127.35, 125.03,
116.51, 108.65, 101.68, 55.79, 55.00, 53.19, 42.39, 29.70, 19.76. IR (ATR): ν 3255, 2923, 2498, 2161, 1201, 751 cm−1.
HRMS (ESI/Q-TOF) m/z calcd for [C16H13Br2ClN2O3 + H+]: 474.9054, found 474.9068.
16
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10.1002/ejoc.201901554
European Journal of Organic Chemistry
Acknowledgments
Financial support from the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant
no. 172009) is greatly appreciated.
Keywords: annulation • Ag-catalysis • Pd-catalysis • longamide B • stylisine D
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