Biomimetic Approach toward the Total Synthesis of rac-2-(Acylmethylene)pyrrolidine Alkaloids

Article abstract of DOI:10.1021/acs.joc.5b00836

2-(Acylmethylene)pyrrolidine derivatives were synthesized via intermolecular decarbonylative Mannich reaction from various methyl ketones and 1-alkyl-1-pyrroliniums, generated in situ from 1-alkylprolines. This approach mimics the biosynthetic pathway and provides a direct access to a series of 2-(acylmethylene)pyrrolidine alkaloids, including hygrine, N-methylruspolinone, dehydrodarlinine, and ruspolinone.

Full text of DOI:10.1021/acs.joc.5b00836

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Article
Biomimetic Approach toward the Total Synthesis
of rac-2-(Acylmethylene)pyrrolidine Alkaloids
Yu-Chiao Shih, Pei-Hua Tsai, Chia-Chun Hsu, Chih-Wei Chang,
Yuandong Jhong, Yun-Chung Chen, and Tun-Cheng Chien
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00836 • Publication Date (Web): 01 Jun 2015
Downloaded from http://pubs.acs.org on June 12, 2015
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Biomimetic Approach toward the Total Synthesis of
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rac-2-(Acylmethylene)pyrrolidine Alkaloids
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YuꢀChiao Shih, PeiꢀHua Tsai, ChiaꢀChun Hsu, ChihꢀWei Chang, Yuandong Jhong,
YunꢀChung Chen, and TunꢀCheng Chien*
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
tcchien@ntnu.edu.tw
GRAPHIC ABSTRACT
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ABSTRACT
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2ꢀ(Acylmethylene)pyrrolidine derivatives were synthesized via intermolecular
decarbonylative Mannich reaction from various methyl ketones and
1ꢀalkylꢀ1ꢀpyrroliniums, generated in situ from 1ꢀalkylprolines. This approach mimics the
biosynthetic pathway and provides a direct access to a series of
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2ꢀ(acylmethylene)pyrrolidine alkaloids, including hygrine, Nꢀmethylruspolinone,
dehydrodarlinine and ruspolinone.
INTRODUCTION
Pyrrolidine represents a heterocyclic C4N skeleton existing in a wide variety of
natural products. These pyrrolidineꢀcontaining alkaloids exhibit immense structural
diversities and a broad range of biological activities, which makes these alkaloids
attractive targets for total synthesis.1 2ꢀ(Acylmethylene)pyrrolidines belong to the
simplest family of pyrrolidine alkaloids (Figure 1),2ꢀ4 of which the pyrrolidine nucleus is
biogenetically derived from ornithine. The biosynthesis involves decarboxylation of
ornithine followed by oxidative cyclization to form 1ꢀpyrrolinium as a reactive
intermediate. Subsequently, the Mannichꢀtype reactions with carbon nucleophiles take
place to provide the 2ꢀsubstituted pyrrolidine skeletons.5 (Scheme 1) These 2ꢀsubstituted
pyrrolidines can be further derived into various pyrrolidine, indolizidine and tropane
alkaloids.5ꢀ8
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Figure 1. Naturally occurring 2ꢀ(acylmethylene)pyrrolidine alkaloids
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Scheme 1. Proposed biosynthesis of hygrine
Proline is the most abundant naturally occurring pyrrolidineꢀcontaining compound
and frequently used as the C4N+C pyrrolidine precursor for the synthesis of 2ꢀsubstituted
pyrrolidine derivatives. Proline supplies its pyrrolidine unit and the carboxylic carbon
that is incorporated into the substituent at the 2ꢀposition of the pyrrolidine. Alternatively,
proline can also be utilized as C4N pyrrolidine synthon for 2ꢀsubstituted pyrrolidines, of
which the pyrrolidine ring was abstracted from proline via decarbonylation or
decarboxylation and the 2ꢀsubstituents were introduced by CꢀC bond formation reaction.
This strategy was first demonstrated by Rapoport et al. in their syntheses of several
pyrrolidine alkaloids and only applicable to intramolecular reactions. The Nꢀalkylprolines
equipped with suitable side chains at N1 or C5 were converted to the acid chloride
followed by thermal decarbonylation to afford the pyrrolinium intermediates.
Subsequently, intramolecular Mannich or FriedelꢀCrafts reaction with unactivated CꢀH
nucleophiles took place to furnish the pyrrolidineꢀcontaining skeletons (Scheme 2(A)).9,10
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Based on the same approach, an intermolecular vinylogous Mannich reaction with
triisopropylsilyloxyfuran was applied to the total synthesis of croomine by Martin and
Barr (Scheme 2(B)).11
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Hernández et al. reported that Nꢀacylprolines underwent the oxidative radical
decarboxylation in the presence of hypervalent iodobenzene oxidants followed by the
reaction with vinylogous nucleophiles to furnish the 2ꢀsubstituted pyrrolidines (Scheme
2(C)).12 It is noteworthy that the intermolecular reactions required the use of vinylogous
nucleophiles, including 2ꢀsilyloxyfuran, silyl enol ethers and allylsilanes, as activated
carbon nucleophiles. MacMillan et al. further demonstrated that the carbon radical
generated by the photonꢀinduced radical decarboxylation of Nꢀacylprolines could be
directly trapped by radical conjugated addition reaction with electronꢀdeficient olefins
(Scheme 2(D)).13
C.ꢀJ. Li et al. reported an intermolecular decarboxylative coupling reaction of
Nꢀalkylprolines with terminal alkynes or πꢀelectronꢀexcess (hetero)arenes in the presence
of Cu or Fe catalysts with tertꢀbutyl peroxide as the oxidant. The proposed mechanism
involves oxidative decarboxylation of Nꢀalkylprolines followed by metal ionꢀmediated
crossꢀcoupling reaction with unactivated CꢀH nucleophiles (Scheme 2(E)).14 Zhang and
Seidel reported a threeꢀcomponent decarboxylative coupling reaction of proline,
arylaldehydes and unactivated CꢀH nucleophiles, which involved the formation of the
azomethine ylide intermediate in the reaction. Subsequently, protonation of the
azomethine ylide afforded the iminium intermediate to undergo the CꢀC bond formation
with terminal alkynes or πꢀelectronꢀexcess (hetero)arenes to afford the 2ꢀsubstituted
Nꢀalkylpyrrolidines (Scheme 2(F)).15
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Scheme 2. Decarboxylative and decarbonylative CꢀC bond formation of proline
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derivatives
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In our attempt to carry out the FriedelꢀCrafts acylation of 2ꢀacetylpyrrole (4k),
1ꢀbenzylproline (1a) was treated with thionyl chloride, which was intended to convert 1a
to the corresponding acid chloride. The presumable acid chloride immediately reacted
with 2ꢀacetylpyrrole (4k) but neither the FriedelꢀCrafts nor the Nꢀacylated adduct (2 and
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3, respectively) was obtained. Instead, the only product isolated from the reaction in a
minuscule yield was 2ꢀ(2ꢀ(1ꢀbenzylpyrrolidinꢀ2ꢀyl)acetyl)pyrrole (5ka) (Scheme 3). We
postulated that 1ꢀbenzylꢀ1ꢀpyrrolinium as the reactive intermediate was formed from the
decarbonylation of 1ꢀbenzylproline acid chloride and reacted with the enolꢀform of
2ꢀacetylpyrrole (4k) via a Mannichꢀtype reaction to afford 5ka. The CꢀC bond formation
step closely resembles the hypothetical biosynthetic pathway of pyrrolidineꢀcontaining
alkaloids from ornithine (Scheme 1),8,16 which suggested the potential application of this
reaction to the synthesis of 2ꢀ(acylmethylene)pyrrolidine alkaloids.
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Scheme 3. Reaction of 1ꢀbenzylproline (1a) with 2ꢀacetylpyrrole (4k)
reagents and condition
(a) SOCl2, 0 oC~rt, 8 h; (b) 2ꢀacetylpyrrole (4k), DIPEA, DMF, rt, 1 h
RESULTS AND DISCUSSIONS
Our study focused on the conversion of 1ꢀalkylprolines to the acid chlorides
followed by the decarbonylative CꢀC bond formation with methyl ketones. The reaction
of 1ꢀbenzylproline (1a) and acetophenone (4a) was chosen for our initial evaluation.
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1ꢀBenzylproline (1a) was first dissolved and reacted in SOCl2 at room temperature. After
removal of SOCl2, the reaction mixture was dissolved in dichloromethane then
acetophenone (4a) was added. The reaction proceeded to give 41% yield of desired
2ꢀ(benzoylmethylene)pyrrolidine (5aa, entry 1 in Table 1). The preliminary success
confirmed that the reaction is amenable for the CꢀC bond formation between the proline
C4 and the acetyl αꢀcarbon of acetophenone (4a).
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Table 1. Examination of various chlorinating reagents
solvent resulta
entry
reagent (3 equiv)
(0.5 M) (%)
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ꢀꢀꢀꢀꢀ
SOCl2
CH2Cl2
CH2Cl2
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0
SOCl2
POCl3
(COCl)2 with one drop of DMF CH2Cl2
ClCOOEt CH2Cl2
a The yields were determined by 1H NMR analysis of the crude products after workꢀup
using 1,3,5ꢀtrimethoxybenzene as an internal standard
Several chlorinating reagents for converting 1ꢀbenzylproline (1a) to its acid chloride,
as shown in Table 1, were first tested. Oxalyl chloride with a catalytic amount of DMF
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was found to be the most effective chlorinating condition and was adopted for the
following investigation (entry 4 in Table 1). Subsequently, different solvents for the
reaction with acetophenone (4a) were tested in order to optimize the CꢀC bond formation
step (entries 1ꢀ9 in Table 2). It was beyond our expectation that alcoholic solvents were
superior while most of polar aprotic solvents gave only poor to moderate yields. In
particular, tꢀbutyl alcohol gave the best yield and was used for further investigation (entry
9 in Table 2). In addition, during our investigation with alcoholic solvents, 1ꢀalkylproline
esters were not observed in the reaction mixture.
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The effects of basic and acidic additives were also examined. The addition of base
was intended to neutralize HCl generated from the reaction. Nevertheless, when a series
of bases were applied to the CꢀC bond formation step, except the less soluble Na2CO3
gave 41% yield, the rest of the reactions did not result in any desired product. Meanwhile,
protic or Lewis acids were anticipated to facilitate the ketoꢀenol tautomerization of
acetophenone (4a) and, therefore, were also screened. Our investigations revealed that
these acidic additives inhibited the CꢀC bond formation and the reactions did not afford
the desired product (entries 10ꢀ19 in Table 2).
Table 2. Optimization for the CꢀC bond formation
entry additive (1 equiv) solvent (0.5 M) resulta (%)
1
ꢀꢀꢀꢀꢀ
CH2Cl2
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ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
MeCN
DMF
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34b (32)b,c
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THF
0
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5
ꢀꢀꢀꢀꢀ
toluene
MeOH
EtOH
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6
ꢀꢀꢀꢀꢀ
39
7
ꢀꢀꢀꢀꢀ
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8
ꢀꢀꢀꢀꢀ
iꢀPrOH
tꢀBuOH
TFEd
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ꢀꢀꢀꢀꢀ
78b (69)b,c
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20
ꢀꢀꢀꢀꢀ
48b
0
Et3Ne
NMMe
DIPEAe
DBUe
tꢀBuOLie
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
0
0
0
0
e
Na2CO3
41
0
TMSClf,g
.
f,g
BF3 OEt2
0
AcClf,g
0
TsOH . H2Of
0
a unless specified otherwise, the yields were determined by 1H NMR analysis of the crude
products after workꢀup using 1,3,5ꢀtrimethoxybenzene as an internal standard; b isolated
yield; c the reaction time in step (iii) was changed to 1 h; d TFE = 2,2,2ꢀtrifluoroethanol; e
the base was added in prior to acetophenone; f the acid was added after acetophenone was
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added; g both 0.1 and 1 equiv were tested
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Under the established reaction sequence and the optimized condition, the reaction of
1ꢀalkylprolines (1aꢀb) with a series of methyl ketones (4aꢀn) were surveyed to establish
the scope and generality of the reaction. Our investigation showed that 1ꢀalkylprolines
(1aꢀb) could react with (hetero)aryl methyl ketones (4aꢀi, 4kꢀm) to give moderate to
good yields of the targeted 2ꢀ(acylmethylene)pyrrolidines (5). The reaction condition was
also applicable to methyl 2ꢀphenylethylene ketone (4j) to afford the corresponding
products (5ja and 5jb) in good yields. We demonstrated that this methodology provided a
facile and concise synthesis of (±)ꢀNꢀmethylruspolinone3,17,18 (5hb) and
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(±)ꢀdehydrodarlinine2,17,19 (5jb). A series of alkyl methyl ketones (4nꢀo) and other acetyl
derivatives (4pꢀr) were also tested. However, none of these nucleophilic counterparts
could proceed to the desired products under the optimized condition. Notably, the desired
2ꢀ(acetylmethylene)pyrrolidines (5na and 5nb) could be obtained in moderate yields
from the reaction of 1ꢀalkylprolines 1aꢀb with acetone (4n) only when large excess of
acetone (4n) was used as the coꢀsolvent and reactant, which allowed the completion of
synthesis of (±)ꢀhygrine4,20 (5nb) (Scheme 4).
Scheme 4. The reaction of 1ꢀalkylprolines (1aꢀb) with methyl ketones (4aꢀn) or acetyl
derivatives (4oꢀr)a
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a isolated yields; b unless specified otherwise, tꢀBuOH was used as the solvent; c solvent =
DMF; d solvent = CH2Cl2; e solvent = acetone / tꢀBuOH (v/v = 1 : 1); f the yield was based
on the 1ꢀalkylproline; g solvent = acetone / DMF (v/v = 1 : 1)
Moreover, a series of αꢀmonoꢀ or α,αꢀdiꢀsubstituted methyl ketones (6aꢀc) as well as
1,3ꢀdicarbonyl compounds (6dꢀg) were also subjected to the reaction with
1ꢀbenzylproline (1a) under the optimized condition. The reaction of the αꢀbranched
methyl ketones (6aꢀc) and the acyclic 1,3ꢀdicarbonyl compounds (6dꢀe) gave no desired
products. But, surprisingly, the reaction of cyclic 1,3ꢀdicarbonyl compounds, such as
5,5ꢀdimethylꢀ1,3ꢀcyclohexanedione (6f) and 1,3ꢀdimethylbarbituric acid (6g), afforded
the desired CꢀC bond formation products (7fa and 7ga, respectively) in moderate yields
(Scheme 5).
Scheme 5. The reaction of 1ꢀbenzylproline (1a) with αꢀsubstituted methyl ketones (6aꢀc)
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or 1,3ꢀdicarbonyl compounds (6dꢀg)a
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a isolated yields; b both tꢀBuOH and DMF as solvents were tested; c solvent = tꢀBuOH
Survey of the substrate scope reflected that the differences in reactivities among
these ketones were mainly attributed to the ketoꢀenol tautomerism. (Hetero)aryl methyl
ketones (4aꢀi and 4kꢀm) as well as α,βꢀunsaturated methyl ketone (4j) are more
enolizable than alkyl methyl ketones (4nꢀo) and acetyl derivatives (4pꢀr) and, therefore,
allowed to undergo the Mannichꢀtype reaction. Besides, both steric and electronic effects
of the nucleophilic ketone counterparts played important roles. The acyclic
1,3ꢀdicarbonyl compounds (6dꢀe), although readily enolizable, along with the αꢀbranched
methyl ketones (6aꢀc) were too hindered for the Mannich reaction with 1ꢀpyrrolinium.
Remarkably, cyclic 1,3ꢀdicarbonyl compounds (6fꢀg) are conformationally restricted and
their enolꢀforms are sufficiently nucleophilic and less hindered to undergo the Mannich
reaction.
In an endeavor to pursue the synthesis of the Nꢀunsubstituted pyrrolidine alkaloids,
the removal of the Nꢀbenzyl group from 1ꢀbenzylꢀ2ꢀ(acylmethylene)pyrrolidines was also
attempted. Our initial trials by catalytic hydrogenolysis of 5ha not only removed the
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benzyl group, but also accompanied with the reduction of the carbonyl functionality to
methylene (9 in Scheme 6). While introducing the protecting group for the ketone
functionality encountered unforeseen difficulty, the carbonyl group was temporarily
protected by reduction, which resulted in a mixture of two diastereomeric alcohols 10.
Subsequently, catalytic hydrogenolysis to remove the Nꢀbenzyl group followed by
oxidation of the secondary alcohols afforded the targeted ruspolinone3,16,21ꢀ23 (8) (Scheme
6). Direct removal of the benzyl group from 5ha or the choice of other suitable alkyl
protecting groups to facilitate the synthesis of ruspolinone (8) still remains to be further
investigated.
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Scheme 6. Concise total synthesis of (±)ꢀruspolinone (8) (unoptimized)
reagents and condition
.
(a) H2, 10% Pd/C, MeOH, rt, 12 h; (b) NaBH4, CeCl3 7H2O, MeOH, rt, 6 h, 61%; (c)
PCC, CH2Cl2, rt, 12 h, 33% from 10
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The success in the decarbonylative CꢀC bond formation of 1ꢀalkylprolines (2) with
methyl ketones (4) prompted us to further expand the scope of nucleophilic counterparts
to πꢀelectronꢀexcess aromatic nucleophiles. A series of pyrrole (12) and indole (13)
derivatives were subjected to the reactions with 1ꢀalkylprolines (1aꢀb) under the
optimized condition and the reactions gave the corresponding
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1ꢀalkylꢀ2ꢀheteroarylpyrrolidines (14 and 15, respectively) in very good yields. The
reactions took place exclusively at the C2ꢀposition of pyrroles and C3ꢀposition of indoles.
The regiostructure of pyrrole adducts (14) was deduced based on the Xꢀray crystal
structure of 14aa as a representative compound, while the regiostructure of indole
adducts (15) was established by comparing the NMR spectra with several known
compounds previously reported in the literature.14,15 Furthermore, both
2,5ꢀdimethylpyrrole (12e) and 3ꢀmethylindole (13g) showed no reaction under the same
reaction condition, which confirmed the regioselectivities unambiguously (Scheme 7).
Scheme 7. The reaction of 1ꢀalkylprolines (1aꢀb) with pyrrole and indole derivatives
(12aꢀe and 13aꢀg, respectively)
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R
N
Bn
N
Me
R
N
Bn
N
Et
N
N
H
N
Me
N
H
Me
H
14aa R = Bn 95% 14ba R = Bn 95%
14ca 61%
14da 67%
14ab
Me 90% 14bb
Me 85%
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N
N
N
N
Bn
Bn
R
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Me
Ph
N
H
N
N
H
N
H
Me
15aa 94%
15ba 90%
15ca R = Bn 74% 15da R = Bn 96%
15cb
Me 83% 15db
Me 67%
no reaction:
N
N
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R
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MeO
Br
Me
Me
N
H
N
N
N
H
13g
H
H
12e
15ea R = Bn 95%
15eb
Me 94%
15fa 70%
CONCLUSION
In summary, we have developed a facile and practical synthesis for
2ꢀ(acylmethylene)pyrrolidine derivatives. This methodology, although sensitive to steric
effects, features the advantages that direct formation of pyrrolinium intermediates from
1ꢀalkylprolines and subsequent intermolecular Mannich reactions with aromatic methyl
ketones, pyrroles or indoles could both be carried out under simple and mild conditions
without the use of metal catalysts and other additives. We have demonstrated that the
synthesis of several Nꢀmethyl 2ꢀ(acylmethylene)pyrrolidine alkaloids, including
(±)ꢀhygrine (5nb), (±)ꢀNꢀmethylruspolinone (5hb) and (±)ꢀdehydrodarlinine (5jb), could
be accomplished in only three steps from proline and corresponding methyl ketones,
albeit few in lower yields. The investigation could illuminate understanding of the
biological formation of these pyrrolidine alkaloids.7,8 Further application of this
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methodology may be amenable to the synthesis of versatile pyrrolidine, indolizidine and
phenanthroindolizidine alkaloids.21,23,24
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EXPERIMENTAL SECTION
General chemical procedures
The chemical shift values are reported in δ values (parts per million, ppm) relative to the
standard chemical shift for the hydrogen residue peak and carbonꢀ13 peak in the
deuterated solvent, CDCl3, or DMSOꢀd6.25 The coupling constant (J) values are expressed
in hertz (Hz). The numbers of protons directly attached to the individual carbons were
determined by 13C NMR DEPT experiments. Thinꢀlayer chromatography (TLC) was
performed on silica gel plates. Compounds on TLC were visualized by illumination under
UV light (254 nm), or dipped into 10% phosphomolybdic acid in ethanol followed by
charring on a hot plate. Solvent systems are expressed as a percentage of the more polar
component with respect to total volume (v/v%). Silica gel (230ꢀ400 mesh) was used for
flash column chromatography and this technique has been described by W. C. Still et al.26
Evaporations were carried out under reduced pressure (water aspirator or vacuum pump)
with the bath temperature below 50 oC unless specified otherwise. Materials obtained
from commercial suppliers were used without further purification.
[General procedure A] Chlorination of 1-benzylproline (1a)
To a mixture of 1ꢀbenzylproline (0.2053 g, 1.00 mmol) in CH2Cl2 (2.0 mL, 0.5 M) was
added one drop of DMF and oxalyl chloride (0.1904 g, 0.130 mL, 1.50 mmol). The
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mixture was stirred at room temperature for 3 h. The solution was concentrated to dryness
under reduced pressure. The resulting residue (containing 1ꢀbenzylpyrrolinium) was used
for the subsequent reaction without further purification.
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[General procedure B] Chlorination of 1-methylproline (1b)
To a mixture of 1ꢀmethylproline (0.2583 g, 2.00 mmol) in CH2Cl2 (10.0 mL, 0.2 M) was
added one drop of DMF and oxalyl chloride (0.5077 g, 0.344 mL, 4.00 mmol). The
mixture was stirred at room temperature for 3 h. The solution was concentrated to dryness
under reduced pressure. The resulting residue (containing 1ꢀmethylpyrrolinium) was used
for the subsequent reaction without further purification.
[General procedure C] Preparation of N-substituted 2-(acylmethylene)pyrrolidines (5)
To a mixture of the crude product from General procesure A or B (prepared from 2.0
mmol of 1ꢀalkylproline 1a or 1b) in tꢀBuOH (2.0 mL, alternatively, DMF or CH2Cl2) was
added the methyl ketone (4, 1.0 mmol). The solution was stirred at room temperature for
15 h. The solvent was removed under reduced pressure. The residue was partitioned
between CH2Cl2 and saturated aqueous Na2CO3 solution. The organic layer was washed
with brine, dried over anhydrous MgSO4, and concentrated to dryness under reduced
pressure. The resulting residue was purified by flash column chromatography to give the
product 5.
2-(1-Benzylpyrrolidin-2-yl)-1-phenylethanone27 (5aa)
Compound 5aa was prepared from 1ꢀbenzylproline (2a) and acetophenone (4a) by
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General procedures A and C. The product was purified by flash column chromatography
(Hex / EtOAc = 8.5 : 1.5) to give 5aa (brown oil, 0.1084 g, 0.78 mmol, 78%, Rf = 0.13,
Hex / EtOAc = 8 : 2). 1H NMR (CDCl3, 400 MHz) δ 7.93 (d, 2 H, J = 7.5 Hz), 7.55 (t, 1
H, J = 7.3 Hz), 7.45 (t, 2 H, J = 7.6 Hz), 7.35ꢀ7.23 (m, 5 H), 3.99 (d, 1 H, J = 13.0 Hz),
3.37 (d, 1 H, J = 12.8 Hz), 3.31 (d, 1 H, J = 3.3 Hz), 3.15ꢀ3.09 (m, 1 H), 3.06ꢀ2.93 (m, 2
H), 2.24 (q, 1 H, J = 7.8 Hz), 2.20ꢀ2.11 (m, 1 H), 1.80ꢀ1.70 (m, 2 H), 1.59ꢀ1.51 (m, 1 H);
13C NMR (CDCl3, 100 MHz) δ 199.8, 137.4, 133.2 (CH), 129.1 (CH), 128.8 (CH), 128.5
(CH), 128.3 (CH), 127.2 (CH), 60.9 (CH), 59.2 (CH2), 54.2 (CH2), 44.3 (CH2), 31.5
(CH2), 22.6 (CH2); MS (ESI) m/z 280 (100) (M + 1); HRMS (ESI, TOF) calcd for
C19H22NO (M + H): 280.1701. Found: 280.1700.
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2-(1-Methylpyrrolidin-2-yl)-1-phenylethanone17,23 (5ab)
Compound 5ab was prepared from 1ꢀmethylproline (2b) and acetophenone (4a) by
General procedures B and C. The product was purified by flash column chromatography
(CH2Cl2 / MeOH = 9 : 1, Rf = 0.18) to give 5ab (yellow oil, 0.0375 g, 0.19 mmol, 37%).
1H NMR (CDCl3, 400 MHz) δ 7.95 (t, 2 H, J = 4.2 Hz), 7.55 (t, 1 H, J = 7.3 Hz), 7.45 (t,
2 H, J = 7.6 Hz), 3.38 (dd, 1 H, J = 4.0 & 16.7 Hz), 3.17ꢀ3.12 (m, 1 H), 3.07ꢀ3.00 (m, 1
H), 2.88ꢀ2.81 (m, 1 H), 2.40 (s, 3 H), 2.29 (q, 1 H, J = 9.3 Hz), 2.22ꢀ2.13 (m, 1 H),
1.89ꢀ1.70 (m, 2 H), 1.56ꢀ1.46 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 199.1, 137.0,
133.2 (CH), 128.7 (CH), 128.1 (CH), 62.4 (CH), 56.7 (CH2), 43.0 (CH2), 40.4 (CH3),
31.5 (CH2), 22.1 (CH2); MS (ESI) m/z 204 (100) (M + 1); HRMS (ESI, TOF) calcd for
C13H18NO (M + H): 204.1388. Found: 204.1383.
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2-(1-Benzylpyrrolidin-2-yl)-1-(4-methoxyphenyl)ethanone (5ba)
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Compound 5ba was prepared from 1ꢀbenzylproline (2a) and 4’ꢀmethoxyacetophenone
(4b) by General procedures A and C. The product was purified by flash column
chromatography (Hex / EtOAc = 6 : 4, Rf = 0.16) to give 5ba (brown oil, 0.1017 g,
0.3287 mmol, 66%). 1H NMR (CDCl3, 500 MHz) δ 7.91 (d, 2 H, J = 8.8 Hz), 7.35ꢀ7.29
(m, 4 H), 7.25ꢀ7.22 (m, 1 H), 6.92 (d, 2 H, J = 8.9 Hz), 3.99 (d, 1 H, J = 13.0 Hz), 3.85 (s,
3 H), 3.34 (d, 1 H, J = 13.0 Hz), 3.28 (dd, 1 H, J = 3.9 & 15.8 Hz), 3.12ꢀ3.07 (m, 1 H),
2.99ꢀ2.92 (m, 2 H), 2.22 (dd, 1 H, J = 9.2 & 17.3 Hz), 2.16ꢀ2.09 (m, 1 H), 1.80ꢀ1.67 (m, 2
H), 1.57ꢀ1.50 (m, 1 H); 13C NMR (CDCl3, 125 MHz) δ 198.1, 163.3, 139.4, 130.32,
130.28 (CH), 128.8 (CH), 128.1 (CH), 126.8 (CH), 113.6 (CH), 60.7 (CH), 58.9 (CH2),
55.3 (CH3), 53.9 (CH2), 43.7 (CH2), 31.2 (CH2), 22.3 (CH2); MS (ESI) m/z 310 (100) (M
+ 1); HRMS (ESI, TOF) Calcd for C20H24NO2 (M + H): 310.1807. Found 310.1804.
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2-(1-Benzylpyrrolidin-2-yl)-1-(4-nitrophenyl)ethanone (5ca)
Compound 5ca was prepared from 1ꢀbenzylproline (2a) and 4’ꢀnitroacetophenone (4c) by
General procedures A and C. The product was purified by flash column chromatography
(Hex / EtOAc = 7.5 : 2.5 to 6 : 4) to give 5ca (yellow oil, 0.0303 g, 0.09 mmol, 19%, Rf
= 0.15, Hex / EtOAc = 8 : 2). 1H NMR (CDCl3, 400 MHz) δ 8.28 (d, 2 H, J = 8.8 Hz),
8.01 (d, 2 H, J = 8.8 Hz), 7.32ꢀ7.25 (m, 5 H), 3.93 (d, 1 H, J = 13.0 Hz), 3.46 (d, 1 H, J =
13.3 Hz), 3.35ꢀ3.29 (m, 1 H), 3.15 (m, 1 H), 3.06ꢀ3.00 (m, 1 H), 2.31 (q, 1 H, J = 8.8 Hz),
2.21ꢀ2.11 (m, 1 H), 1.80ꢀ1.74 (m, 2 H), 1.62 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ
198.2, 150.5, 141.7, 129.3 (CH), 129.1 (CH), 128.6 (CH), 127.4 (CH), 124.0 (CH), 60.7
(CH), 59.3 (CH2), 54.4 (CH2), 45.0 (CH2), 31.6 (CH2), 22.7 (CH2); MS (ESI) m/z 191
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(38), 325 (100) (M + 1); HRMS (ESI, TOF) Calcd for C19H21N2O3 (M + H): 325.1552.
Found: 325.1562.
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2-(1-Benzylpyrrolidin-2-yl)-1-(p-tolyl)ethanone (5da)
Compound 5da was prepared from 1ꢀbenzylproline (2a) and 4’ꢀmethylacetophenone (4d)
by General procedures A and C. The product was purified by flash column
chromatography (CHCl3 / MeOH = 10 : 0 to 99: 1) to give 5da (brown oil, 0.0623 g, 0.21
mmol, 43%, Rf = 0.20 (Hex / EtOAc = 7 : 3)). 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, 2
H, J = 8.2 Hz), 7.35ꢀ7.29 (m, 5 H ), 7.25 (d, 2 H, J = 8.2 Hz), 3.99 (d, 1 H, J = 12.9 Hz),
3.36 (d, 1 H, J = 13.0 Hz), 3.31 (dd, 1 H, J = 15.8 & 3.7 Hz), 3.14ꢀ3.07 (m, 1 H),
3.02ꢀ2.93 (m, 2 H), 2.41 (s, 3 H), 2.24 (q, 1 H, J = 9.0 Hz), 2.18ꢀ2.09 (m, 1 H), 1.82ꢀ1.66
(m, 2 H), 1.58ꢀ1.50 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 199.3, 143.8, 139.4, 134.8,
129.3 (CH), 128.9 (CH), 128.30 (CH), 127.0 (CH), 60.8 (CH), 59.0 (CH2), 54.0 (CH2),
44.0 (CH2), 31.3 (CH2), 22.4 (CH2), 21.7 (CH3); MS (ESI) m/z 294 (100) (M + 1); HRMS
(ESI, TOF) Calcd for C20H24NO (M + H): 294.1858. Found: 294.1850.
2-(1-Benzylpyrrolidin-2-yl)-1-(4-hydroxyphenyl)ethanone (5ea)
Compound 5ea was prepared from 1ꢀbenzylproline (2a) and 4’ꢀhydroxyacetophenone (4e)
by General procedures A and C. The product was purified by flash column
chromatography (CHCl3 / MeOH = 10 : 0 to 95: 5) to give 5ea (brown oil, 0.0449 g, 0.15
mmol, 30%, Rf = 0.23 (Hex / EtOAc = 0 : 10)). 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, 2
H, J = 8.6 Hz), 7.36ꢀ7.24 (m, 5 H), 6.78 (d, 2 H, J = 8.6 Hz), 6.22 (br, 1 H), 4.07 (d, 1 H,
J = 12.8 Hz), 3.46 (d, 1 H, J = 12.8 Hz), 3.33 (dd, 1 H, J = 3.9 & 16.0 Hz), 3.27ꢀ3.20 (m,
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1 H), 3.10ꢀ3.00 (m, 2 H), 2.36 (q, 1 H, J = 8.9 Hz), 2.21ꢀ2.12 (m, 1 H), 1.80ꢀ1.17 (m, 2
H), 1.61ꢀ1.52 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 198.0, 163.0, 137.3, 131.1 (CH),
129.7 (CH), 128.7 (CH), 127.8 (CH), 116.3 (CH), 61.5 (CH), 58.8 (CH2), 53.8 (CH2),
42.5 (CH2), 31.2 (CH2), 22.1 (CH2); MS (ESI) m/z 296 (100) (M + 1); HRMS (ESI, TOF)
Calcd for C19H22NO2 (M + H): 296.1651. Found: 296.1642; HRMS (ESI, TOF) Calcd for
C19H20NO2 (M – 1): 294.1494. Found: 294.1510.
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2-(1-Benzylpyrrolidin-2-yl)-1-(o-tolyl)ethanone (5fa)
Compound 5fa was prepared from 1ꢀbenzylproline (2a) and 2’ꢀmethylacetophenone (4f)
by General procedures A and C. The product was purified by flash column
chromatography (CHCl3 / MeOH = 10 : 0 to 99: 1) to give 5fa (oil, 0.0278 g, 0.10 mmol,
19%, Rf = 0.25 (Hex / EtOAc = 7 : 3)). 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, 1 H, J =
7.3 Hz), 7.38ꢀ7.23 (m, 8 H), 3.97 (d, 1 H, J = 12.9 Hz), 3.35 (d, 1 H, J = 12.9 Hz), 3.27
(dd, 1 H, J = 3.6 & 15.8 Hz), 3.05 (m, 1 H), 2.96 (d, 1 H, J = 9.0 Hz), 2.92 (d, 1 H, J =
8.8 Hz), 2.22 (q, 1 H, J = 8.9 Hz), 2.17ꢀ2.08 (m, 1 H), 1.77ꢀ1.67 (m, 2 H), 1.59ꢀ1.50 (m, 1
H); 13C NMR (CDCl3, 100 MHz) δ 204.0, 139.4.5, 138.5, 138.1, 132.1 (CH), 131.4 (CH),
129.1 (CH),128.8 (CH), 128.5 (CH), 127.2 (CH), 125.9 (CH), 61.1 (CH), 59.1 (CH2),
54.1 (CH2), 47.2 (CH2), 31.4 (CH2), 22.5 (CH2), 21.4 (CH3); MS (ESI) m/z 294 (M + 1);
HRMS (ESI, TOF) Calcd for C20H24NO (M + H): 294.1858. Found: 294.1838.
2-(1-Benzylpyrrolidin-2-yl)-1-(2-methoxyphenyl)ethanone (5ga)
Compound 5ga was prepared from 1ꢀbenzylproline (2a) and 2’ꢀmethoxyacetophenone
(4g) by General procedures A and C. The product was purified by flash column
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chromatography (Hex / Ether = 5 : 5 to 4 : 6) to give 5ga (oil, 0.0566 g, 0.1829 mmol,
37%, Rf = 0.15 (Hex / Ether = 5 : 5)). 1H NMR (CDCl3, 500 MHz) δ 7.68 (dd, 1 H, J =
1.7 & 7.7 Hz), 7.50ꢀ7.46 (m, 1 H), 7.36ꢀ7.31 (m, 4 H), 7.28ꢀ7.25 (m, 1 H), 7.02 (t, 1 H, J
= 7.5 Hz), 6.98 (d, 1 H, J = 8.4 Hz), 4.05 (d, 1 H, J = 12.9 Hz), 3.90 (s, 3 H), 3.45 (dd, 1
H, J = 2.8 & 15.8 Hz), 3.31 (d, 1 H, J = 13.0 Hz), 3.11ꢀ3.01 (m, 2 H), 2.96ꢀ2.92 (m, 1 H),
2.22ꢀ2.10 (m, 2 H), 1.78ꢀ1.68 (m, 2 H), 1.60ꢀ1.53 (m, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 201.9, 158.3, 139.5, 133.3 (CH), 130.1 (CH), 128.9 (CH), 128.8, 128.1 (CH), 126.8
(CH), 120.6 (CH), 111.4 (CH), 60.7 (CH), 58.8 (CH2), 55.4 (CH3), 53.8 (CH2), 49.2
(CH2), 31.1 (CH2), 22.2 (CH2); MS (ESI) m/z 160 (16), 310 (100) (M + 1); HRMS (ESI,
TOF) Calcd for C20H24NO2 (M + H): 310.1807. Found 310.1803.
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2-(1-Benzylpyrrolidin-2-yl)-1-(3,4-dimethoxyphenyl)ethanone (5ha)
Compound 5ha was prepared from 1ꢀbenzylproline (2a) and
3’,4’ꢀdimethoxyacetophenone (4h) by General procedures A and C. The product was
purified by flash column chromatography (Hex / EtOAc = 7.5 : 2.5) to give 5ha (oil,
0.1236 g, 0.4472 mmol, 89%, Rf = 0.16 (Hex / EtOAc = 7 : 3)). 1H NMR (CDCl3, 500
MHz) δ 7.57 (dd, 1 H, J = 2.1 & 8.4 Hz), 7.53 (d, 1 H, J = 2.0 Hz), 7.37ꢀ7.31 (m, 4 H),
7.28ꢀ7.24 (m, 1 H), 6.90 (d, 1 H, J = 8.4 Hz), 4.01 (d, 1 H, J = 12.9 Hz), 3.97 (s, 3 H),
3.95 (s, 3 H), 3.38 (d, 1 H, J = 13.0 Hz), 3.30 (dd, 1 H, J = 3.8 & 15.8 Hz), 3.15ꢀ3.09 (m,
1 H), 3.03ꢀ2.95 (m, 2 H), 2.25 (dd, 1 H, J = 9.2 & 17.4 Hz), 2.19ꢀ2.12 (m, 1 H), 1.81ꢀ1.70
(m, 2 H), 1.59ꢀ1.52 (m, 1 H); 13C NMR (CDCl3, 125 MHz) δ 198.2, 153.2, 149.0, 139.4,
130.5, 128.9 (CH), 128.2 (CH), 126.9 (CH), 122.8 (CH), 110.1 (CH), 110.0 (CH), 60.9
(CH), 59.0 (CH2), 56.0 (CH3), 55.9 (CH3), 54.0 (CH2), 43.6 (CH2), 31.2 (CH2), 22.3
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(CH2); MS (ESI) m/z 160 (21), 340 (100) (M + 1); HRMS (ESI, TOF) Calcd for
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C21H26NO3 (M + H): 340.1913. Found: 340.1914.
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2-(1-Methylpyrrolidin-2-yl)-1-(3,4-dimethoxyphenyl)ethanone3,17,18 (5hb,
N-methylruspolinone)
Compound 5hb was prepared from 1ꢀmethylproline (2b) and
3’,4’ꢀdimethoxyacetophenone (4h) by General procedures B and C. The product was
purified by flash column chromatography (Hex / EtOAc = 7.5 : 2.5) to give 5hb (oil,
0.1236 g, 0.4472 mmol, 89%, Rf = 0.16 (Hex / EtOAc = 7 : 3)). 1H NMR (CDCl3, 500
MHz) δ 7.63 (dd, 1 H, J = 2.0 & 8.4 Hz), 7.51 (d, 1 H, J = 1.9 Hz), 6.89 (d, 1 H, J = 8.4
Hz), 3.93 (s, 3 H), 3.92 (s, 3 H), 3.49 (dd, 1 H, J = 4.1 & 16.6 Hz), 3.38ꢀ3.34 (m, 1 H),
3.20 (dd, 1 H, J = 8.6 & 16.6 Hz), 3.15ꢀ3.09 (m, 1 H), 2.52 (s, 3 H), 2.47 (dd, 1 H, J = 9.0
& 18.6 Hz), 2.29ꢀ2.21 (m, 1 H), 2.00ꢀ1.81 (m, 2 H), 1.70ꢀ1.63 (m, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 196.8, 153.6, 149.1, 129.9, 123.1 (CH), 110.13 (CH), 110.07 (CH),
63.3 (CH), 56.5 (CH2), 56.1 (CH3), 56.0 (CH3), 41.3 (CH2), 40.1 (CH3), 31.2 (CH2), 22.0
(CH2); MS (ESI) m/z 264 (100) (M + 1); HRMS (ESI, TOF) Calcd for C15H22NO3 (M +
H): 264.1600. Found: 264.1590.
2-(1-Benzylpyrrolidin-2-yl)-1-(naphthalen-2-yl)ethanone (5ia)
Compound 5ia was prepared from 1ꢀbenzylproline (2a) and 2ꢀacetonaphthone (4i) by
General procedures A and C. The product was purified by flash column chromatography
(CHCl3 / MeOH = 10 : 0 to 99: 1) to give 5ia (yellow oil, 0.0558 g, 0.17 mmol, 34%, Rf
= 0.25 (Hex / EtOAc = 7 : 3)). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1 H), 8.02 (d, 1 H,
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J = 1.6 Hz), 8.00 (d, 1 H, J = 1.6 Hz), 7.97 (s, 1 H), 7.95 (s, 1 H), 7.62ꢀ7.54 (m, 2 H),
7.38ꢀ7.30 (m, 4 H), 7.27ꢀ7.23 (m, 1 H), 4.04 (d, 1 H, J = 13.0 Hz), 3.45 (d, 1 H, J = 12.2
Hz), 3.41 (d, 1 H, J = 13.0 Hz), 3.22ꢀ3.12 (m, 2 H), 3.01ꢀ2.96 (m, 1 H), 2.27 (q, 1 H, J =
9.1 Hz), 2.22ꢀ2.13 (m, 1 H), 1.85ꢀ1.69 (m, 2 H), 1.64ꢀ1.55 (m, 1 H); 13C NMR (CDCl3,
100 MHz) δ 199.8, 139.6, 135.7, 134.8, 132.7, 130.0 (CH), 129.8 (CH), 129.1 (CH),
128.6 (CH), 128.4 (CH), 127.9 (CH), 127.1 (CH), 126.9 (CH), 124.0 (CH), 61.0 (CH),
59.2 (CH2), 54.2 (CH2), 44.4 (CH2), 31.5 (CH2), 22.6 (CH2); MS (ESI) m/z 330 (100) (M
+ 1); HRMS (ESI, TOF) Calcd for C23H24NO (M + H): 330.1858. Found 330.1839.
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(E)-1-(1-Benzylpyrrolidin-2-yl)-4-phenylbut-3-en-2-one (5ja)
Compound 5ja was prepared from 1ꢀbenzylproline (2a) and
transꢀ4ꢀphenylꢀ3ꢀbutenꢀ2ꢀone (4j) by General procedures A and C. The product was
purified by flash column chromatography (Hex / EtOAc = 8 : 2 to 7: 3) to give 5ja
(yellow oil, 0.1293 g, 0.42 mmol, 85%, Rf = 0.28 (Hex / EtOAc = 0 : 10)). 1H NMR
(CDCl3, 400 MHz) δ 7.54ꢀ7.24 (m, 11 H), 6.75 (d, 1 H, J = 16.2 Hz), 4.00 (d, 1 H, J =
13.0 Hz), 3.35 (d, 1 H, J = 13.0 Hz), 3.07ꢀ2.99 (m, 2 H), 2.97ꢀ2.92 (m, 1 H), 2.78ꢀ2.71 (m,
1 H), 2.22 (q, 1 H, J = 9.1 Hz), 2.16ꢀ2.07 (m, 1 H), 1.81ꢀ1.66 (m, 2 H), 1.61ꢀ1.52 (m, 1
H); 13C NMR (CDCl3, 100 MHz) δ 199.6, 142.7 (CH), 139.5, 134.5, 130.5 (CH), 129.0
(CH), 128.9 (CH), 128.3 (CH), 127.0 (CH), 126.8 (CH), 60.7 (CH), 58.9 (CH2), 54.0
(CH2), 46.1 (CH2), 31.2 (CH2), 22.3 (CH2); MS (ESI) m/z 306 (100) (M + 1); HRMS
(ESI, TOF) Calcd for C21H24NO (M + H): 306.1858. Found 306.1857.
(E)-1-(1-Methylpyrrolidin-2-yl)-4-phenylbut-3-en-2-one2,17,19 (5jb, dehydrodarlinine)
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Compound 5jb was prepared from 1ꢀmethylproline (2b) and
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transꢀ4ꢀphenylꢀ3ꢀbutenꢀ2ꢀone (4j) by General procedures B and C. The product was
purified by flash column chromatography (CHCl3 / MeOH = 9 : 1) to give 5jb (brown oil,
0.2002 g, 0.87 mmol, 87%, Rf = 0.22 (CHCl3 / MeOH = 95 : 5)). 1H NMR (CDCl3, 600
MHz) δ 7.56 (d, 1 H, J = 16.3 Hz), 7.53ꢀ7.55 (m, 2 H), 7.39ꢀ7.40 (m, 3 H), 6.74 (d, 1 H, J
= 16.2 Hz), 3.09 (ddd, 1 H, J = 2.1, 7.8, 8.7 Hz), 3.03 (dt, 1 H, J = 6.8, 12.8 Hz), 2.69
(ddd, 2 H, J = 6.0, 7.8, 10.4 Hz), 2.36 (s, 3 H), 2.24 (dd, 1 H, J = 9.5, 17.7 Hz), 2.08ꢀ2.14
(m, 1 H), 1.77ꢀ1.83 (m, 1 H), 1.70ꢀ1.76 (m, 1 H), 1.46ꢀ1.52 (m, 1 H); 13C NMR (CDCl3,
150 MHz) δ 199.3, 142.9 (CH), 134.4, 130.5 (CH), 128.9 (CH), 128.3 (CH), 126.7 (CH),
62.3 (CH), 56.8 (CH2), 45.3 (CH2), 40.5 (CH3), 31.4 (CH2), 22.1 (CH2); MS (EI, 20 eV)
m/z 84 (100), 229 (20) (M+); HRMS (EI, magnetic sector) Calcd for C15H19NO (M+):
229.1467. Found 229.1466.
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2-(1-Benzylpyrrolidin-2-yl)-1-(pyrrol-2-yl)ethanone (5ka)
Compound 5ka was prepared from 1ꢀbenzylproline (2a) and 2ꢀacetylpyrrole (4k) by
General procedures A and C. The product was purified by flash column chromatography
(Hex / EtOAc = 8.5 : 1.5 to 7.5 : 2.5) to give 5ka (brown oil, 0.0868 g, 0.65 mmol, 65%,
Rf = 0.10, Hex / EtOAc = 7 : 3). 1H NMR (CDCl3, 400 MHz) δ 9.87 (br, 1 H), 7.34ꢀ7.23
(m, 5 H), 7.02 (s, 1 H), 6.91 (s, 1 H), 6.28ꢀ6.26 (m, 1 H), 4.03 (d, 1 H, J = 12.8 Hz), 3.33
(d, 1 H, J = 12.8 Hz), 3.13ꢀ3.02 (m, 2 H), 2.96ꢀ2.91 (m, 1 H), 2.88ꢀ2.83 (m, 1 H), 2.22 (q,
1 H, J = 8.8 Hz), 2.08ꢀ1.99 (m, 1 H), 1.78ꢀ1.66 (m, 2 H), 1.65ꢀ1.57 (m, 1 H); 13C NMR
(CDCl3, 100 MHz) δ 189.7, 139.3, 132.6 129.0 (CH), 128.3 (CH), 127.0 (CH), 124.8
(CH), 116.7 (CH), 110.7 (CH), 61.3 (CH), 58.9 (CH2), 53.9 (CH2), 43.5 (CH2), 30.9
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(CH2), 22.3 (CH2). MS (ESI) m/z 160 (33), 269 (100) (M + 1); HRMS (ESI, TOF) Calcd
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for C17H21N2O (M + H): 269.1654. Found: 269.1658.
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2-(1-Benzylpyrrolidin-2-yl)-1-(furan-2-yl)ethanone (5la)
Compound 5la was prepared from 1ꢀbenzylproline (2a) and 2ꢀacetylfuran (4l) by General
procedures A and C. The product was purified by flash column chromatography (CHCl3 /
MeOH = 10 : 0 to 99: 1) to give 5la (brown oil, 0.0584 g, 0.22 mmol, 43%, Rf = 0.13
(Hex / EtOAc = 7 : 3)). 1H NMR (CDCl3, 400 MHz) δ 7.57 (s, 1 H), 7.32ꢀ7.22 (m, 5 H),
7.14 (d, 1 H, J = 3.5 Hz), 6.51 (dd, 1 H, J = 2.1 & 3.1 Hz), 4.00 (d, 1 H, J = 13.0 Hz),
3.33 (d, 1 H, J = 13.0 Hz), 3.15 (dd, 1 H, J = 4.1 & 15.0 Hz), 3.10ꢀ3.03 (m, 1 H),
2.95ꢀ2.85 (m, 2 H), 2.21 (q, 1 H, J = 8.8 Hz), 2.12ꢀ2.03 (m, 1 H), 1.78ꢀ1.68 (m, 2 H),
1.63ꢀ1.55 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 188.6, 153.1, 146.6 (CH), 139.4,
129.0 (CH), 128.3 (CH), 127.0 (CH), 117.4 (CH), 112.3 (CH), 60.8 (CH), 58.9 (CH2),
54.0 (CH2), 43.9 (CH2), 31.1 (CH2), 22.4 (CH2); MS (EI, 20 eV) m/z 91 (19), 160 (100),
178 (40), 269 (17) (M+); HRMS (EI, magnetic sector) Calcd for C17H19NO2 (M+):
269.1416. Found: 269.1418.
2-(1-Benzylpyrrolidin-2-yl)-1-(thiophen-2-yl)ethanone (5ma)
Compound 5ma was prepared from 1ꢀbenzylproline (2a) and 2ꢀacetylthiophene (4m) by
General procedures A and C. The product was purified by flash column chromatography
(CHCl3 / MeOH = 10 : 0 to 99: 1) to give 5ma (brown oil, 0.0595 g, 0.21 mmol, 42%, Rf
= 0.13 (Hex / EtOAc = 7 : 3)). 1H NMR (CDCl3, 400 MHz) δ 7.65 (dd, 1 H, J = 0.9 & 3.9
Hz), 7.62 (dd, 1 H, J = 0.7 & 4.9 Hz), 7.34ꢀ7.24 (m, 5 H), 7.11 (dd, 1 H, J = 4.0 & 4.7
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Hz), 3.99 (d, 1 H, J = 13.0 Hz), 3.37 (d, 1 H, J = 13.0 Hz), 3.24 (dd, 1 H, J = 4.1 & 15.2
Hz), 3.15ꢀ3.08 (m, 1 H, J = 4.9 Hz), 2.98ꢀ2.92 (m, 2 H), 2.24 (q, 1 H, J = 9.1 Hz),
2.16ꢀ2.06 (m, 1 H), 1.83ꢀ1.66 (m, 2 H), 1.64ꢀ1.55 (m, 1 H); 13C NMR (CDCl3, 100 MHz)
δ 192.5, 145.0, 139.4, 133.8(CH), 132.2(CH), 129.0 (CH), 128.4 (CH), 128.2 (CH), 127.1
(CH), 61.0 (CH), 59.1 (CH2), 54.1 (CH2), 44.9 (CH2), 31.3 (CH2), 22.5 (CH2); MS (EI,
20 eV) m/z 91 (26), 160 (100), 194 (58), 285 (10) (M+); HRMS (EI, magnetic sector)
Calcd for C17H19NOS (M+): 285.1187. Found: 285.1185.
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1-(1-Benzylpyrrolidin-2-yl)propan-2-one28 (5na)
To a mixture of 1ꢀbenzylproline (2a, 0.2053 g, 1.00 mmol) in CH2Cl2 (2.0 mL, 0.5 M)
was added one drop of DMF and oxalyl chloride (0.1904 g, 0.130 mL, 1.50 mmol). The
mixture was stirred at room temperature for 3 h. The solution was concentrated to dryness
under reduced pressure. The resulting residue (containing 1ꢀbenzylpyrrolinium) was
dissolved in a mixture of tꢀBuOH (1.0 mL) and acetone (1.0 mL). The mixture was stirred
at room temperature for 1 h. The solvent was removed under reduced pressure. The
residue was partitioned between CHCl3 and H2O. The organic layer was washed with
saturated aqueous Na2CO3 solution and brine, dried over anhydrous MgSO4, and then
concentrated to dryness under reduced pressure. The product was purified by flash
column chromatography (Hex / EtOAc = 8 : 2 to 6 : 4) to give 5na (yellow oil, 65.2 mg,
0.30 mmol, 30%, Rf = 0.13 (Hex / EtOAc = 0: 10)). 1H NMR (CDCl3, 400 MHz) δ
7.27ꢀ7.18 (m, 5 H), 3.88 (d, 1 H, J = 13.0 Hz), 3.24 (d, 1 H, J = 13.0 Hz), 2.88ꢀ2.81 (m, 1
H), 2.73 (dd, 1 H, J = 3.9 & 16.2 Hz), 2.47ꢀ2.41 (m, 1 H), 2.16ꢀ2.00 (m, 2 H), 2.10 (s, 3
H), 1.70ꢀ1.62 (m, 2 H), 1.47ꢀ1.38 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 208.1, 139.3,
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128.8 (CH), 128.2 (CH), 126.9 (CH), 60.1 (CH), 58.8 (CH2), 53.8 (CH2), 48.9 (CH2),
31.0 (CH2), 30.8 (CH3), 22.2 (CH2); MS (ESI) m/z 218 (100) (M + 1); HRMS (ESI, TOF)
Calcd for C14H20NO (M + H): 218.1545. Found: 218.1543.
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1-(1-Methylpyrrolidin-2-yl)propan-2-one20 (5nb, hygrine)
To a mixture of 1ꢀmethylproline (2b, 0.2583 g, 2.00 mmol) in CH2Cl2 (10.0 mL, 0.2 M)
was added one drop of DMF and oxalyl chloride (0.34 mL, 0.5077 g, 4.00 mmol). The
mixture was stirred at room temperature for 3 h. The solution was concentrated to dryness
under reduced pressure. The resulting residue (containing 1ꢀmethylpyrrolinium) was
dissolved in a mixture of DMF (10 mL) and acetone (10 mL). The mixture was stirred at
room temperature for 15 h. The solvent was removed under reduced pressure. The
resulting residue was purified by flash column chromatography (CH2Cl2 / MeOH = 9 : 1,
Rf = 0.15) to give 5nb (oil, 0.0504 g, 0.3569 mmol, 18%). 1H NMR (CDCl3, 400 MHz) δ
3.39ꢀ3.34 (m, 1 H), 3.07 (dd, 1 H, J = 4.7 & 17.0 Hz), 3.04ꢀ2.96 (m, 1 H), 2.72 (dd, 1 H,
J = 7.6 & 17.1 Hz), 2.51ꢀ2.44 (m, 1 H), 2.50 (s, 3 H), 2.23ꢀ2.15 (m, 1 H), 2.17 (s, 3 H),
1.99ꢀ1.78 (m, 2 H), 1.64ꢀ1.54 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 206.5, 62.7 (CH),
56.3 (CH2), 46.2 (CH2), 40.1 (CH3), 30.8 (CH2), 30.5 (CH3), 21.9 (CH2); MS (ESI) m/z
130 (6), 142 (100) (M + 1); HRMS (ESI, TOF) Calcd for C8H16NO (M + H): 142.1232.
Found: 142.1229.
2-(1-Benzylpyrrolidin-2-yl)-5,5-dimethylcyclohexane-1,3-dione (7fa)
Compound 7fa was prepared from 1ꢀbenzylproline (2a) and
5,5ꢀdimethylcyclohexaneꢀ1,3ꢀdione (6f) by General procedures A and C. The product
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was purified by flash column chromatography (CH2Cl2 / MeOH = 95: 5, Rf = 0.38) to
give 7fa (oil, 0.1048 g, 0.35 mmol, 35%). 1H NMR (DMSOꢀd6, 500 MHz) δ 7.41ꢀ7.36 (m,
3 H), 7.35ꢀ7.32 (m, 2 H), 4.35 (t, 1 H, J = 8.6 Hz), 4.16 (d, 1 H, J = 12.8 Hz), 3.49 (d, 1 H,
J = 13.2 Hz), 3.16 (dd, 1 H, J = 6.2 & 11.4 Hz), 2.67 (dd, 1 H, J = 5.0 & 13.8 Hz),
2.36ꢀ2.28 (m, 1 H), 2.25ꢀ2.22 (m, 4 H), 1.95ꢀ1.88 (m, 2 H), 1.86ꢀ1.76 (m, 1 H), 0.96 (s, 6
H); 13C NMR (DMSOꢀd6, 125 MHz) δ 188.8, 133.4, 129.7 (CH), 128.7 (CH), 129.3 (CH),
129.2 (CH), 129.0 (CH), 128.3, 104.6, 65.7 (CH), 57.2 (CH2), 51.1 (CH2), 49.0 (CH2),
32.3, 3.08 (CH2), 28.7 (2 x CH3), 22.5 (CH2); MS (ESI) m/z 300 (100) (M + 1); HRMS
(ESI, TOF) Calcd for C19H26NO2 (M + H): 300.1964. Found: 300.1951.
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5-(1-Benzylpyrrolidin-2-yl)-1,3-dimethylpyrimidine-2,4,6-trione (7ga)
Compound 7ga was prepared from 1ꢀbenzylproline (2a) and 1,3ꢀdimethylbarbituric acid
(6g) by General procedures A and C. The product was purified by flash column
chromatography (CHCl3 / MeOH = 99: 1 to 98 : 2) to give 7ga (yellow oil, 0.0472 g, 0.15
mmol, 30%, Rf = 0.47 (CH2Cl2 / MeOH = 9: 1)). 1H NMR (CDCl3, 500 MHz) δ 11.93 (br,
1 H), 7.42ꢀ7.39 (m, 3 H), 7.32ꢀ7.30 (m, 2 H), 4.6 (t, 1 H, J = 6.6 Hz), 4.37 (d, 1 H, J =
10.4 Hz), 3.70 (d, 1 H, J = 10.4 Hz), 3.32ꢀ3.28 (m, 1 H), 3.31 (s, 6 H), 2.98ꢀ2.92 (m, 1 H),
2.42ꢀ2.37 (m, 1 H), 2.10ꢀ2.02 (m, 3 H); 13C NMR (CDCl3, 125 MHz) δ 163.6, 153.0,
130.7, 129.7 (CH), 129.53 (CH), 129.45 (CH), 78.4, 67.5 (CH), 56.3 (CH2), 50.8 (CH2),
29.6 (CH2), 27.2 (CH3), 21.8 (CH2); MS (ESI) m/z 314 (100) (M ꢀ 1); HRMS (ESI, TOF)
Calcd for C17H20N3O3 (M ꢀ 1): 314.1505. Found: 314.1520; HRMS (ESI, TOF) Calcd for
C17H22N3O3 (M + H): 316.1661. Found: 316.1659.
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