N -Acyliminium Ion Chemistry: Improving the Access to Unsaturated γ-Lactams and Their N -α-Methoxylated Derivatives: Application to an Expeditive Synthesis of (±)-Crispine A

Article abstract of DOI:10.1055/s-0040-1707886

An improved synthesis of unsaturated γ-lactams by condensation of various primary amines with 2,5-dimethoxy-2,5-dihydrofuran is described. A modified mechanism for this reaction is suggested. Synthesis of their N -α-methoxylated derivatives, as N -acyliminium ion precursors, is also reported. Finally, a short synthesis of (±)-crispine A is presented as an illustrative application.

Full text of DOI:10.1055/s-0040-1707886

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
psp
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F. Souquet et al.
PSP
Synthesis
N-Acyliminium Ion Chemistry: Improving the Access to Unsaturated
-Lactams and Their N--Methoxylated Derivatives: Application to
an Expeditive Synthesis of (±)-Crispine A
Florence Souqueta
Wassila Dricib
Sandra Abi Fayssala,1
Imane Lazounib
MeOH
HCl (12 M; 2 equiv)
r.t., 4 h
1) R-NH2, HCl (1 M),
40 °C
2) Na2HPO4
R
N
R
N
R
N
O
MeO
O
OMe
O
MeO
O
69–91%
7 examples
39–78%
8 examples
Sébastien Thueillona
Joëlle Pérard-Viret*a
allylamine, aniline, benzylamine, (S)-1-phenylethan-1-amine,
2-(3,4-dimethoxyphenyl)ethanamine, L-Lys(Z)-OMe,
L-Phe-OMe, L-Val-OMe
R-NH2
=
0
0
0
0-0
0
0
2-
4
4
1
9-8
4
9
9
a Université de Paris, CiTCoM, CNRS, 4 avenue de l’observatoire,
75006 Paris, France
Joelle.perard@parisdescartes.fr
b Université de Tlemcen, Laboratoire de chimie organique,
substances naturelles et analyses (COSNA), département de
chimie, faculté des sciences, 22 Rue Abi Ayed Abdelkrim Fg
Pasteur B.P 119 13000, Tlemcen, Algérie
Dedicated to Dr. Jacques Royer
Received: 01.04.2020
Accepted after revision: 20.05.2020
Published online: 23.06.2020
O
O
N
O
H
DOI: 10.1055/s-0040-1707886; Art ID: ss-2020-t0173-psp
H
O
H
H
N
O
HO
O
Abstract An improved synthesis of unsaturated -lactams by conden-
sation of various primary amines with 2,5-dimethoxy-2,5-dihydrofuran
is described. A modified mechanism for this reaction is suggested. Syn-
thesis of their N--methoxylated derivatives, as N-acyliminium ion pre-
cursors, is also reported. Finally, a short synthesis of (±)-crispine A is
presented as an illustrative application.
(–)-stemoamide
(–)-cephalotaxine
H
H
H
R
N
R = n-Pr
R = n-Pent
N
H
N
H
Key words unsaturated -lactams, aza-heterocycles, N-acyliminium,
5-methoxypyrrolidin-2-one, crispine A
(–)-monomorine
tetraponerine
Figure 1 Aza-heterocycle-containing natural products synthesized by
silyloxy pyrrole (3)- or N-acyliminium (4)-based methods
Isomeric unsaturated -lactams 1 or 2 are useful build-
ing blocks that can be converted easily into silyloxy pyrroles
3 or N-acyliminium derivatives 4 (Scheme 1).2
In 2015, Pelkey and co-workers6 compiled the known
syntheses of 3-pyrrolin-2-ones 1. Indeed, compounds 1 or 2
can be synthesized by different methods: oxidation of pyr-
role (R = H, Me),7 cyclization (especially for the synthesis of
substituted unsaturated -lactams),8 elimination,9 via diazo
compounds,10 condensation with 2,5-dimethoxy-2,5-dihy-
drofuran (5),11 and metathesis.12 The latter two methods
are the most popular for the synthesis of unsubstituted
compound 1.
R
N
R
N
R
N
R
N+
E
H+
Et3N
O
OTBS
O
O
or
Nu
TBSCl
E
Nu
1
2
4
3
Scheme 1 Reactivity of unsaturated -lactams 1 or 2
Compound 3 is reactive towards electrophiles (ketone,
aldehyde, imine, etc.);3 on the other hand, N-acyliminium
ion 4 is prone to nucleophilic (allylTMS, silyl enol ether,
diketone, MeOH, etc.) additions.4 Both reactivities are com-
plementary, giving access to advanced intermediates for the
preparation of biologically relevant aza-heterocycles, found
in many alkaloid natural products (Figure 1).5
As discovered twenty years ago in our laboratory,11a un-
saturated -lactams are easily synthesized by condensation
between 5 and a primary amine 6 in acidic medium
(Scheme 2).
We searched to improve this reaction and to understand
its mechanism. In fact, we wanted to minimize the forma-
tion of red polymeric pyrrole side products. For that pur-
pose, the reaction between 5 and L-phenylalanine methyl
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. Souquet et al.
PSP
Synthesis
O
R
MeO
OMe
H
O
R
N
R
N
H2N+
conjugation speed
depends
on the amine
H
O
MeO
MeO
OMe
5
O
O
OMe
1) HCl (1 M; 1 equiv)
+
MeO
+
R–NH2
+
– MeOH
2) Na2HPO4 (sat.),
CH2Cl2
6
5
R-NH2
1
2
R
R
N
R
6
H2O
N–
N+
HO
OH
OH
OH
Scheme 2 Synthesis of unsaturated -lactams by condensation with 5
– MeOH
H
2–
7
HPO4
R
N
R
R
N
ester hydrochloride (6g) was monitored by NMR spectros-
copy in D2O (Table 1, entry 7). By varying the temperature,
reaction time, and the nature of the base used at the end of
the reaction, a set of optimized conditions was established
to perform the reaction: 40 °C in acid medium (pH 1) for 7
to 20 minutes (Table 1), followed by neutralization to pH 7
with saturated aqueous Na2HPO4 and addition of dichloro-
methane. Na2HPO4 was chosen instead of NaHCO3 to de-
crease the pH from 8 to 7 and to shift the equilibrium from
hydroxypyrrole 8 to 2 (Scheme 3). Isolated yields were
moderate to good (61% to 78%) except for aniline (entry 2);
this finding can be explained by the different pKa value of
aniline (4.6) and other amines (9–10). Thus all amines with
pKa of 9–10 should be able to efficiently form unsaturated
lactams.
–
H2PO4
N
O
O
HO
+
2
1
8
Scheme 3 Mechanism of the condensation between amine 6 and 5
this isomerization depended on the nature of the amine R
residue.
Pelkey and co-workers reviewed the reactivity of com-
pounds 2 in 2019.14 Herein, we focused on the possibility to
Table 1 Synthesis of Unsaturated -Lactams
O
O
Entry Amine 6
Time
Yield
(min) (%)a
N
HO
OH
1
2
3
4
5
6
7
8
allylamine (6a)
15
7
1a 92 (61)
7g
aniline·HCl (6b)
1b 99 (39)
1c 95 (67)
1d 98 (77)
1e 99 (75)
1f 99 (78)
1g 95 (67)
1h 90 (76)
benzylamine (6c)
10
15
20
15
10
10
(S)-1-phenylethan-1-amine (6d)
2-(3,4-dimethoxyphenyl)ethanamine (6e)
L-Lys(Z)-OMe·HCl (6f)
Figure 2 1H NMR spectrum of intermediate 7g in D2O
L-Phe-OMe·HCl (6g)
L-Val-OMe·HCl (6h)
a Yield of the crude product. Isolated yield of the pure product (either ,- or
,- plus the ,-isomer) is given in the parentheses.
O
O
In 1998, Poli et al.11b hypothesized a mechanism in ace-
tic acid. We suggested some modifications (Scheme 3). In
the course of our NMR studies of the reaction, we observed
the rapid formation (within a few minutes) of 7 in acidic
medium (Figures 2 and 3).13 The second step consisted of a
hydroxyl elimination promoted by hydrogen phosphate
dianion acting as a mild base. At first ,-unsaturated -lac-
tam 2 is the only visible product in the spectra. Afterwards,
build-up of compound 1 occurred by thermodynamically
driven conjugation with the carbonyl group. The kinetics of
N
HO
OH
7g
Figure 3 13C NMR spectrum of intermediate 7g in D2O
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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F. Souquet et al.
PSP
Synthesis
transform them into N-acyliminium ions 4 by treatment
with Brønsted acids (Scheme 1). Iminium ion intermediates
could be trapped with methanol leading to stable N--methoxy-
lated derivatives 9 (Table 2).
N-Acyliminium ions precursors 9 or 10 were mostly
synthesized via reduction of succinimides.15 Typical reduc-
ing reagents such as NaBH4,16 DIBAL-H,17 LiBH4,18 LiEt3BH19
required careful control of temperature and pH to avoid un-
desired side products. Hydrogenation with Co or Ru cataly-
sis20 and Zn catalysis with hydroxysilane21 were used more
recently. We describe here an alternate practical synthetic
route to -lactams 9 (Table 2).
Treatment of unsaturated -lactams 1 or 2 with concen-
trated (12 M) HCl (2 equiv) in MeOH for 4 hours at room
temperature furnished the N--methoxylated compounds 9
in good yields (Table 2). The amount of hydrochloric acid
has to be kept as small as possible to avoid the formation of
N--hydroxy--lactam 10. This reaction could be per-
formed from crude product 1 or 2, global yields are almost
the same (entry 3 and 7).22
The procedure is simple, efficient, green, and cheap –
the starting materials are inexpensive and neither boron
nor any metal catalysis was necessary. Ester and carbamate
functions were unaffected unlike in the reduction with hy-
drides.
N--Methoxylated derivatives 9 could be engaged in nu-
cleophilic addition via N-acyliminium ions 4 generated by
Brønsted or Lewis acid. To illustrate this application we se-
lected two representative compounds 9d and 9h and al-
lowed them to react with allyltrimethylsilane in the pres-
ence of boron trifluoride diethyl etherate as Lewis acid in
acetonitrile (Scheme 4) to give 5-allylpyrrolidin-2-ones 11d
and 11h in good yields (79% and 85%, respectively) and
moderate diastereoselectivities (dr 77:23 and 70:30).
These building blocks could be converted into natural
Table 2 Synthesis of N--Methoxylated Compounds 9
R
N
R
N
R
N
R
N
O
O HCl (12 M; 2 equiv)
MeOH
+
MeO
O
HO
O
2
1
9
10
Entry
Lactam 1
Product 9
Yielda (%)
Entry
Lactam 1
Product 9
Yielda (%)
O
O
O
O
NH
O
NH
O
O
O
O
N
O
N
N
N
O
O
O
O
1
67
5
82
1a
9a
9f
1f
O
O
O
2
75
6
7
81
O
O
O
N
N
O
O
O
N
N
N
O
O
9b
1b
1g
9g
O
O
O
O
O
3
4
91 (65)b
70 (58)b
N
N
N
O
O
O
O
1h
9h
9c
1c
74
N
N
O
O
O
1d
9d
a Purified product.
b From crude 1 or 2.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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F. Souquet et al.
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Synthesis
alkaloids5c,23 or to peptidomimetics24 by functionalization
of the double bond. It should be noted that direct treatment
of unsaturated -lactams 1 with Lewis acid and allyl-
trimethylsilane did not provide compounds 11 and only
starting material was recovered. Migration of the double
bond of unsaturated -lactams 1 or 2 requires proton catal-
ysis, therefore addition of Brønsted acid.5a
In conclusion, we have developed a practical, scalable
(up to 100 mmol for 1f), low cost, green synthesis of pyro-
lidinone ,-unsaturated -lactams 1 and their N--me-
thoxylated derivatives 9. These compounds are useful syn-
thetic scaffolds, as exemplified by a three-step preparation
of racemic crispine A from 2,5-dimethoxy-2,5-dihydro-
furan in 34% overall yield.
R
N
R
N
AllylTMS
BF3·OEt2
MeO
O
O
All reagents were purchased from commercial suppliers and used
without further purification. MeCN was dried on 3Å molecular sieves
and kept under inert atmosphere prior to its use. The reactions were
monitored by TLC. TLC analyses were performed using aluminum
plates coated with silica gel 60F 254 from Macherey-Nagel and re-
vealed under ultraviolet light (254 nm) and with a 5% ethanolic phos-
phomolybdic acid bath. Common silica gel (40–70 mesh) was used for
column chromatography purifications. IR spectra were recorded on a
PerkinElmer Spectrum 65 FT-IR spectrophotometer. NMR spectra
were recorded on a Bruker Avance 400 spectrometer operating at 400
MHz for 1H and at 100 MHz for 13C and on a Bruker Avance 300 spec-
trometer operating at 300 MHz for 1H and at 75 MHz for 13C. For 1H
and 13C NMR spectra analyses, CHCl3 (7.26 ppm) and 13CDCl3 (77.0
ppm) were used as the internal references, respectively. The NMR
spectra were processed with TopSpin 3.61 software. High-resolution
mass spectra (HRMS) were performed on a Bruker maXi spectrome-
ter by the ‘Fédération de Recherche’ ICOA/CBM (FR2708) platform.
Melting points were measured on a Kofler apparatus. Optical rotation
data were obtained on a PerkinElmer 541 polarimeter at ambient
temperature using a 100 mm cell with a 1 mL capacity.
MeCN
–78 °C to rt
11d R = (S)-1-phenylethyl dr 77:23 (79%)
11h R = i-PrCHCO2Me dr 70:30 (85%)
9d,h
Scheme 4 Addition of allylTMS via N-acyliminium ion
Compound 11d was also obtained from N--hydroxy--
lactam 10d instead of the methoxy derivative 9d. The reac-
tivities of both these precursors for N-acyliminium are very
close (90% vs 79% yield, dr 82:18 vs 77:23).18,23a However,
the synthetic route involving the methoxy derivative 9d is
more convenient, since compound 9d is easier to handle
and to purify, due to its high level of chemical stability com-
pared to the hemiaminal 10d.
Twenty years ago, Katritzky et al.25 synthesized com-
pound 12 by reaction of 6e, 5, and benzotriazole followed
by cyclization using TiCl4 as Lewis acid. Royer et al.26 were
able to obtain 12 by refluxing amine 6e and 5 in acetic acid.
In 2016, compound 1e was obtained by Le Breton et al. by
metathesis8b followed by cyclization using trifluoroacetic
acid to give 12. We took up this synthesis starting from un-
saturated -lactams 1e prepared in good yield (75%) as de-
scribed in Table 1 (entry 5). Treatment of 1e with two
equivalents of concentrated HCl in methanol led directly to
isoquinolinone 12 in 60% yield. The benefits of our synthe-
sis of 12 include shorter reaction time, no heating, and no
use of metal, compared with those described previously.
Reduction with LiAlH4 gave (±)-crispine A (13) in 75% yield
(Scheme 5).27
Unsaturated -Lactams 1 or 2; General Procedure
In a round-bottomed flask, amine or amino hydrochloride salt (5
mmol) were dissolved in aq 1 M HCl (5 mL, 5 mmol) or in H2O (5 mL)
(for hydrochloride salts). A few drops of aq 1 M HCl could be added to
adjust the pH to 1. The solution was kept at 40 °C and 2,5-dimethoxy-
2,5-dihydrofuran (5; 5 mmol, 610 L) was added. The reaction was al-
lowed to progress until it became lightly yellow (7 to 20 min). The
solution was then refrigerated with a cool bath (0 °C) and the reaction
quenched by CH2Cl2 (5 mL) and sat. aq Na2HPO4 (12 mL); the pH
should increase to 7. The cooling bath was removed and the mixture
stirred vigorously for 2 h at rt and extracted with CH2Cl2 (3 × 30 mL).
The combined organic phases were dried (MgSO4) and the solvent
was evaporated under vacuum. The crude product could be used
without further purification in the next step or purified by flash chro-
matography on silica gel.
HCl (12 M; 2 equiv)
O
O
O
O
MeOH
N
N
O
60%
O
-Methoxy--lactams 9; General Procedure
Unsaturated -lactam 1 or 2 (6.3 mmol) was dissolved in MeOH
(25 mL). After cooling with an ice bath, concd HCl (12 M, 1 mL,
12 mmol) was added. The mixture was kept at rt under stirring for 4
h. The reaction was quenched with sat. aq NaHCO3 (17 mL, impera-
tively until pH ≈ 8). Most of the MeOH was evaporated and the mix-
ture extracted with EtOAc (2 × 150 mL). The combined extracts were
washed with brine. After drying the combined organic phases
(MgSO4), the solvent was evaporated under vacuum. The crude prod-
uct could be used in the next step or purified by flash chromatogra-
phy on silica gel.
1e
12
LiAlH4
75%
O
N
O
(
)-crispine A (13)
Scheme 5 synthesis of (±)-crispine A
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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F. Souquet et al.
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Synthesis
Allylation of 9d,h; General Procedure
(S)-1-(1-Phenylethyl)-1,5-dihydro-2H-pyrrol-2-one (1d)11b
-Methoxy--lactam (0.5 mmol) was dissolved in anhyd MeCN (2.5
mL) and cooled to –78 °C with a dry ice bath under argon. AllylTMS
(158 L, 1 mmol, 2 equiv) was added, followed by BF3·OEt2 (125 L,
1 mmol, 2 equiv). The mixture was allowed to warm slowly to rt un-
der stirring for 3 h. The reaction was quenched with sat. aq NaHCO3
(3 mL) and extracted with EtOAc (2 × 25 mL). After drying the com-
bined organic phases (MgSO4), the solvent was removed under vacu-
um. Compounds were purified by flash chromatography on silica gel.
Following the general procedure on 6d (303 mg, 2.5 mmol) and after
purification by column chromatography on silica gel, compound 1d
was obtained as a yellow oil in 48% yield (225 mg) and compound 2d
in 29% yield (135 mg).
1d
Rf = 0.22 (EtOAc/cyclohexane 50:50); []D20 –154.7 (c 1.2, CHCl3).
IR (neat): 2978, 1685, 1658, 1446, 1239, 1220, 801, 748, 698 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.35–7.19 (m, 5 H), 7.01 (dt, J = 5.9, 1.8
Hz, 1 H), 6.39 (dt, J = 5.9, 1.8 Hz, 1 H), 5.54 (q, J = 7.0 Hz, 1 H), 3.91 (dt,
J = 20.5, 1.8 Hz, 1 H), 3.59 (dt, J = 20.5, 1.8 Hz, 1 H), 1.58 (d, J = 7.2 Hz,
3 H).
The known compounds 1a, 1b, 1c, 1d, 1e, 9a, 9b, 9c, 9d, 11d, 12, 13
showed characterization data in full agreement with those previously
reported.
1-Allyl-1,5-dihydro-2H-pyrrol-2-one (1a)9b
13C NMR (CDCl3, 75 MHz):  = 171.1, 143.1, 140.9, 128.6, 127.7, 127.5,
126.9, 48.9, 48.7, 17.8.
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO: 188.1070; found:
188.1073.
Following the general procedure on 6a (228 mg, 4 mmol) and after
purification by column chromatography on silica gel, a mixture of
compounds 1a and 2a was obtained as a brown oil; yield: 300 mg
(61%); Rf = 0.52 (2a), 0.25 (1a) (EtOAc).
IR (neat): 2928, 1663, 1415, 1331, 1176, 1060, 989, 928 cm–1
.
(S)-1-(1-Phenylethyl)-1,3-dihydro-2H-pyrrol-2-one (2d)
Rf = 0.62 (EtOAc/cyclohexane 50:50).
1H NMR (CDCl3, 300 MHz):  = 7.39–7.25 (m, 5 H), 6.39 (dt, J = 5.0, 2.0
Hz, 1 H), 5.47 (q, J = 7.1 Hz, 1 H), 5.28 (dt, J = 5.0, 2.4 Hz, 1 H), 3.12 (t,
J = 2.2 Hz, 2 H), 1.61 (d, J = 7.1 Hz, 3 H).
1H NMR (CDCl3, 300 MHz):  = 7.11 (td, J = 5.9, 1.8 Hz, 1 H, 1a), 6.40
(td, J = 4.9, 2.1 Hz, 1 H, 2a), 5.32 (td, J = 4.9, 2.5 Hz, 1 H, 2a), 5.8 (m, 1
H), 5.13–5.26 (m, 2 H, 1a), 4.08 (m, 2 H), 3.99 (t, J = 1.9 Hz, 2 H), 3.10
(t, J = 2.3 Hz, 2 H, 2a).
13C NMR (CDCl3, 75 MHz):  = 171.3, 133.2 (1a), 132.8 (2a), 132.7 (2a),
128.0 (1a), 117.7 (2a), 117.6 (1a), 143.0 (1a), 104.5 (2a), 52.5 (1a),
44.6 (1a), 44.2 (2a), 37.5 (2a).
13C NMR (CDCl3, 75 MHz):  = 176.5, 140.9, 130.2, 128.7, 127.6, 126.7,
104.6, 49.2, 37.8, 18.8.
HRMS (ESI): m/z [M + H]+ calcd for C7H10NO: 124.0757; found:
124.0762.
1-[3-(3,4-Dimethoxyphenyl)propyl]-1,5-dihydro-2H-pyrrol-2-one
(1e)8b
Following the general procedure on 6e (4.35 g, 24 mmol) and after
purification by column chromatography on silica gel, compound 1e
was obtained as a yellow oil; yield: 4.44 g (75%); Rf = 0.21 (EtOAc).
1-Phenyl-1,5-dihydro-2H-pyrrol-2-one (1b)10
Following the general procedure on 6b (648 mg, 5 mmol) and after
purification by column chromatography on silica gel, compound 1b
was obtained as a beige solid; yield: 310 mg (39%); mp 90 °C; Rf = 0.46
(CH2Cl2/EtOAc 10:1).
IR (neat): 2934, 1659, 1514, 1451, 1260, 1233, 1139, 1024, 800 cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.02 (td, J = 6.0, 1.8 Hz, 1 H), 6.85–6.72
(m, 3 H), 6.18 (td, J = 6.0, 1.8 Hz, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.80
(t, J = 1.8 Hz, 2 H), 3.71 (t, J = 7.2 Hz, 2 H), 2.88 (t, J = 7.2 Hz, 2 H).
13C NMR (CDCl3, 75 MHz):  = 171.5 148.9, 147.6, 142.8, 131.3, 128.1,
120.6, 111.8, 111.3, 55.9, 53.7, 43.9, 34.5.
IR (neat): 3080, 2906, 1683, 1500, 1429, 1371, 1210, 1143, 796, 754,
660 cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.71 (m, 2 H), 7.37 (m, 2 H), 7.15 (m, 2
H), 6.24 (td, J = 6.0, 1.9 Hz, 1 H), 4.40 (t, J = 1.9 Hz, 2 H).
13C NMR (CDCl3, 75 MHz):  = 170.2, 142.6, 139.1, 129.1, 129.0, 124.2,
HRMS (ESI): m/z [M + H]+ calcd for C14H18NO3: 248.1287; found:
248.1278.
118.8, 53.2.
HRMS (ESI): m/z [M + H]+ calcd for C10H10NO: 160.0757; found:
160.0759.
Methyl (S)-6-{[(Benzyloxy)carbonyl]amino}-2-(2-oxo-2,5-dihy-
dro-1H-pyrrol-1-yl)hexanoate (1f)
Following the general procedure on 6f (32.1 g, 97 mmol) and after pu-
rification by column chromatography on silica gel, compound 1f was
obtained as a yellow oil; yield: 27.3 g (78%); Rf = 0.31 (EtOAc/cyclo-
hexane 70:30); []D20 +3.8 (c 1, CH2Cl2).
1-Benzyl-1,5-dihydro-2H-pyrrol-2-one (1c)9b
Following the general procedure on 6c (2.14 g, 20 mmol) and after
purification by column chromatography on silica gel, compound 1c
was obtained as a pale yellow solid; yield: 2.32 g (67%); mp 60 °C; Rf =
0.24 (EtOAc/cyclohexane 60:40).
IR (neat): 3322, 2930, 2864, 1673, 1529, 1444, 1239, 1203, 802, 739,
697 cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.36 (m, 5 H), 7.15 (dt, J = 6.1 1.7 Hz, 1
H), 6.19 (dt, J = 6.1, 1.7 Hz, 1 H), 5.10 (s, 2 H), 4.99 (br t, 1 H, NH), 4.90
(dd, J = 10.8, 4.9 Hz, 1 H), 4.27 (d, J = 20.1 Hz, 1 H), 3.94 (d, J = 20.1 Hz,
1 H), 3.73 (s, 3 H), 3.19 (dd, J = 13.1, 6.7 Hz, 2 H), 1.96–2.13 (m, 1 H),
1.89–1.74 (m, 1 H), 1.58 (m, 2 H), 1.30 (m, 2 H).
IR (neat): 3089, 2923, 1699, 1668, 1450, 1404, 1341, 1242, 799, 698
cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.42–7.23 (m, 5 H), 7.09 (dt, J = 6.0, 1.8
Hz, 1 H), 6.25 (dt, J = 6.0, 1.8 Hz, 1 H), 4.67 (s, 2 H), 3.92 (t, J = 1.7 Hz, 2
H).
13C NMR (CDCl3, 75 MHz):  = 172.0, 171.9, 156.5, 144.1, 136.7, 128.5,
13C NMR (CDCl3, 75 MHz):  = 171.4, 142.9, 137.3, 128.8, 127.9, 127.6,
128.1, 127.2, 66.6, 53.0, 52.3, 49.7, 40.6, 29.7, 29.2, 23.1.
52.3, 45.9.
HRMS (ESI): m/z [M + H]+ calcd for C19H25N2O5: 361.1758; found:
HRMS (ESI): m/z [M + H]+ calcd for C11H12NO: 174.0913; found:
361.1756.
174.0919.
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Methyl (S)-2-(2-Oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-phenylpropa-
Methyl (2S)-2-(2,5-Dihydroxy-2,5-dihydro-1H-pyrrol-1-yl)-3-
noate (1g)
phenylpropanoate (7g)
Following the general procedure on 6g (2.16 g, 10 mmol) and after
purification by column chromatography on silica gel, compound 1g
was obtained as a yellow oil in 65% yield (1.6 g) and compound 2g in
2% (50 mg) yield.
In an NMR tube, L-phenylalanine methyl ester hydrochloride (6g;
43 mg, 0.2 mmol) was dissolved in D2O (0.6 mL). A few drops of aq 1
M HCl were added to adjust the pH to 1, followed by 2,5-dimethoxy-
2,5-dihydrofuran (5; 25 L, 0.2 mmol). After 10 min at 25 °C, the reac-
tion was complete (see NMR spectra in Figures 2 and 3).
1H NMR (D2O, 300 MHz):  = 7.28–7.23 (m, 3 H), 7.15–7.12 (m, 2 H),
6.00 (m, 3 H), 5.70 (m, 1 H), 4.70 (s, 2 H), 4.28 (dd, J = 7.5, 6.0 Hz, 1 H),
3.68 (s, 3 H), 3.22 (m, 1 H), 3.19 (s, 6 H, CH3OH), 3.11 (m, 1 H).
1g
Rf = 0.27 (EtOAc/cyclohexane 50:50); []D20 –36.1 (c 0.2, CH2Cl2).
IR (neat): 3029, 2952, 1739, 1682, 1662, 1436, 1241, 1207, 1168, 802,
13C NMR (D2O, 75 MHz):  = 169.9, 133.6, 131.9, 131.5, 129.3, 129.2,
748, 699 cm–1
.
128.0, 101.6, 100.4, 54.0, 53.5, 48.8 (CH3OH), 35.5.
1H NMR (CDCl3, 300 MHz):  = 7.36–7.19 (m, 5 H), 7.10 (dt, J = 6.1, 1.9
Hz, 1 H), 6.15 (dt, J = 6.1, 1.9 Hz, 1 H), 5.24 (dd, J = 10.5, 5.8 Hz, 1 H),
4.20 (dt, J = 19.8, 1.7 Hz, 1 H), 3.95 (dt, J = 19.8, 1.7 Hz, 1 H), 3.76 (s, 3
H), 3.45 (dd, J = 14.3, 5.8 Hz, 1 H), 3.13 (dd, J = 14.3 10.3 Hz, 1 H).
13C NMR (CDCl3, 75 MHz):  = 171.7, 171.5, 143.9, 136.3, 128.7, 128.6,
127.1, 127.2, 54.4, 52.4, 50.5, 36.1.
1-Allyl-5-methoxypyrrolidin-2-one (9a)16b
Following the general procedure on purified 1a (190 mg, 1.54 mmol)
after evaporation, compound 9a was obtained as a pale yellow oil;
yield: 160 mg (67%).
IR (neat): 2935, 1685, 1444, 1414, 1245, 1188, 1075, 884, 656 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C14H16NO3: 246.1125; found:
240.1124.
1H NMR (CDCl3, 300 MHz):  = 5.87–5.72 (m, 1 H), 5.30–5.19 (m, 2 H),
4.93 (dd, J = 6.2, 1.4 Hz, 1 H), 4.30 (dddd, J = 15.3, 4.6, 3.3, 1.7 Hz, 1 H),
3.63 (dddd, J = 15.3, 7.5, 2.0, 1.0 Hz, 1 H), 3.30 (s, 3 H), 2.56 (ddd, J =
17.2, 9.0, 9.0 Hz, 1 H), 2.38 (ddd, J = 17.2, 9.7, 3.1 Hz, 1 H), 2.26–2.11
(m, 1 H), 2.10–1.98 (m, 1 H).
13C NMR (CDCl3, 75 MHz):  = 174.8, 132.4, 117.9, 89.4, 53.0, 42.8,
29.0, 23.9.
Methyl (S)-2-(2-Oxo-2,3-dihydro-1H-pyrrol-1-yl)-3-phenylpropa-
noate (2g)
Rf = 0.50 (EtOAc/cyclohexane 50:50).
1H NMR (CDCl3, 300 MHz):  = 7.36–7.15 (m, 5 H), 6.57 (dt, J = 5.1, 2.1
Hz, 1 H), 5.29 (dq, J = 2.5, 0.5 Hz, 1 H), 5.12 (dd, J = 9.8, 5.8 Hz, 1 H),
3.75 (s, 3 H), 3.35 (dd, J = 14.2, 5.8 Hz, 1 H), 3.07 (dd, J = 14.2, 5.8 Hz, 1
H), 3.00 (t, J = 2.3 Hz, 1 H), 2.96 (t, J = 2.3 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C8H14NO2: 156.1025; found:
156.1018.
13C NMR (CDCl3, 75 MHz):  = 176.7, 170.8, 135.9, 130.8, 129.0, 128.6,
127.1, 104.2, 54.5, 52.5, 37.1, 36.9.
5-Methoxy-1-phenylpyrrolidin-2-one (9b)20b
Following the general procedure (except stirring for 22 h) on purified
1b (111 mg, 0.7 mmol) and after purification by column chromatog-
raphy on silica gel, compound 9c was obtained as a pale yellow oil;
yield: 102 mg (75%); Rf = 0.4 (CH2Cl2/MeOH 10:1).
Methyl (S)-3-Methyl-2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)buta-
noate (1h)
Following the general procedure on 6h (335 mg, 2 mmol) and after
purification by column chromatography on silica gel, compound 2h
was obtained as a yellow oil in 51% yield (200 mg) and compound 1h
in 25% (98 mg).
IR (neat): 2935, 2828, 1698, 1497, 1394, 1293, 1193, 1067, 756, 692
cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.54 (m, 2 H), 7.40 (m, 2 H), 7.24 (m, 1
H), 5.34 (dd, J = 5.8, 0.8 Hz, 1 H), 3.30 (s, 3 H), 2.77 (ddd, J = 17.3, 9.3,
9.3 Hz, 1 H), 2.50 (ddd, J = 17.3, 9.5, 2.5 Hz, 1 H), 2.35–2.20 (m, 1 H),
2.20–2.09 (m, 1 H).
13C NMR (CDCl3, 75 MHz):  = 174.5, 137.9, 129.0, 126.1, 123.2, 92.0,
53.6, 30.0, 24.4.
1h
Rf = 0.28 (EtOAc/cyclohexane 50:50); []D20 –61.7 (c 1, CH2Cl2)
IR (neat): 2963, 2877, 1739, 1669, 1436, 1243, 1199, 1175, 803 cm–1
1H NMR (CDCl3, 300 MHz):  = 7.14 (dt, J = 6.0, 1.8 Hz, 1 H), 6.15 (dt,
J = 6.0, 1.8 Hz, 1 H), 4.56 (d, J = 10.2 Hz, 1 H), 4.33 (dt, J = 20.6, 1.7 Hz,
1 H), 3.99 (dt, J = 20.6, 1.7 Hz, 1 H), 3.68 (s, 3 H), 2.2 (m, 1 H), 0.97 (d,
J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C11H14NO2: 192.1025; found:
192.1017.
1-Benzyl-5-methoxypyrrolidin-2-one (9c)20
13C NMR (CDCl3, 75 MHz):  = 171.8, 171.6, 144.1, 126.9, 59.4, 51.9,
Following the general procedure on crude 1c (138 mg, 0.8 mmol) and
after purification by column chromatography on silica gel, compound
9c was obtained as a pale yellow oil; yield: 107 mg (65%); Rf = 0.65
(EtOAc).
50.2, 29.3, 19.3, 19.0.
HRMS (ESI): m/z [M + H]+ calcd for C10H16NO3: 198.1125; found:
198.1126.
IR (neat): 2933, 2828, 1691, 1442, 1417, 1244, 1171, 1073, 703 cm–1
.
Methyl (S)-3-Methyl-2-(2-oxo-2,3-dihydro-1H-pyrrol-1-yl)buta-
noate (2h)
1H NMR (CDCl3, 300 MHz):  = 7.40–7.24 (m, 5 H), 4.96 (d, J = 14.7 Hz,
1 H), 4.74 (dd, J = 6.1, 1.5 Hz, 1 H), 4.03 (d, J = 14.7 Hz, 1 H), 3.23 (s, 3
H), 2.59 (ddd, J = 17.2, 8.8, 8.8 Hz, 1 H), 2.39 (ddd, J = 17.2, 9.5, 3.5 Hz,
1 H), 2.17–1.93 (m, 2 H).
13C NMR (CDCl3, 75 MHz):  = 23.7, 29.0, 43.8, 53.0, 89.0, 127.6, 128.4,
128.7, 136.4, 174.9.
Rf = 0.57 (EtOAc/cyclohexane 50:50).
1H NMR (CDCl3, 300 MHz):  = 6.76 (dt, J = 4.6, 2.1 Hz, 1 H), 5.35 (q, J =
2.5 Hz, 1 H), 4.58 (d, J = 9.4 Hz, 1 H), 3.77 (s, 3 H), 3.13 (m, 2 H), 2.25
(m, 1 H), 1.03 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H).
13C NMR (CDCl3, 75 MHz):  = 177.0, 171.2, 131.0, 104.0, 59.0, 52.1,
36.9, 30.4, 19.2, 18.8.
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HRMS (ESI): m/z [M + H]+ calcd for C12H16NO2: 206.1181; found:
2061187.
126.7 (minor), 126.8 (major), 128.5, 128.9, 129.1, 136.8 (minor),
137.7 (major), 170.7 (major), 171.0 (minor), 174.9 (minor), 175.0
(major).
5-Methoxy-1-[(S)-1-phenylethyl]pyrrolidin-2-one (9d)11b
HRMS (ESI): m/z [M + Na]+ calcd for C15H19NO4Na: 300.1206; found:
300.1205.
Following the general procedure on purified 1d (280 mg, 1.5 mmol)
and after purification by column chromatography on silica gel, com-
pound 9d was obtained as a yellow oil; yield: 243 mg (74%); two dia-
stereoisomers (dr 33:67); Rf = 0.53 (major), 0.44 (minor) (EtOAc/
cyclohexane 70:30).
Methyl (2S)-2-(2-Methoxy-5-oxopyrrolidin-1-yl)-3-methylbuta-
noate (9h)
Following the general procedure on purified 1h (1.26 g, 6.4 mmol)
and after purification by column chromatography on silica gel, com-
pound 9h was obtained as a yellow oil; yield: 1.08 g (70%); two dias-
tereoisomers (dr 60:40); Rf = 0.32 (major), 0.41 (minor), (EtOAc/cyclo-
hexane 50:50).
IR (neat): 2935, 2828, 1691, 1462, 1425, 1244, 1182, 1078, 745 cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.46–7.17 (m, 5 H), 5.35 (q, J = 7.2 Hz,
0.7 H, major), 5.12 (q, J = 7.2 Hz, 0.3 H, minor), 5.03 (dd, J = 6.2, 1.1 Hz,
0.3 H, minor), 4.46 (m, 0.7 H, major), 3.13 (s, 2 H, minor), 2.94 (s, 1 H,
minor), 2.6–2.46 (m, 1 H), 2.22–2.36 (m, 1 H), 2.17–1.94 (m, 0.6 H,
minor), 1.94–1.82 (m, 1.4 H, major), 1.65 (d, J = 7.2 Hz, 1 H, minor),
1.61 (d, J = 7.2 Hz, 2 H, major).
13C NMR (CDCl3, 75 MHz):  = 175.0 (minor), 174.8 (major), 141.4
(minor), 139.9 (major), 128.6 (major), 127.7 (major + minor), 128.1
(minor), 127.4 (major), 127.2 (minor), 89.1 (major), 88.9 (minor), 52.6
(major), 52.1 (minor), 51.3 (minor), 50.5 (major), 29.5 (minor), 29.2
(major), 24.2 (minor), 24.0 (major), 18.1 (major), 17.6 (minor).
IR (neat): 2955, 2829, 1740, 1699, 1415, 1243, 1192, 1174, 1072 cm–1
.
1H NMR (CDCl3, 300 MHz): 4.81 (m, 0.6 H, major), 4.81 (m, 0.34 H, mi-
nor), 4.43 (d, J = 10.9 Hz, 0.34 H, minor), 4.31 (d, J = 9.4 Hz, 0.6 H, ma-
jor), 3.71 (s, 1.1 H, minor), 3.68 (s, 1.9 H, major), 3.31 (s, 1.1 H, minor),
3.20 (s, 1.9 H, major), 2.60 (m, 1 H), 2.40–2.22 (m, 2 H), 2.09–2.00 (m,
2 H), 1.01 (d, J = 6.6 Hz, 1.9 H, major), 0.98 (d, J = 6.8 Hz, 1.1 H, minor),
0.96 (d, J = 6.8 Hz, 1.1 H, minor), 0.81 (d, J = 6.6 Hz, 1.9 H, major).
13C NMR (CDCl3, 75 MHz):  = 175.9 (minor), 175.0 (major), 171.5
(minor), 170.8 (major), 90.3 (minor), 88.5 (major), 58.3 (major), 54.2
(major), 54.0 (minor), 52.0 (major), 51.8 (minor), 29.8 (minor), 28.3
(major and minor), 27.0 (major), 24.7 (minor), 24.6 (major), 19.8 (ma-
jor), 19.7 (minor), 19.4 (minor), 18.6 (major).
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO2: 220.1337; found:
220.1341.
Methyl (2S)-6-{[(Benzyloxy)carbonyl]amino}-2-(2-methoxy-5-
oxopyrrolidin-1-yl)hexanoate (9f)
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NO4Na: 252.1206; found:
252.1207.
Following the general procedure on purified 1f (6.62 g, 18.4 mmol)
and after purification by column chromatography on silica gel, com-
pound 9f was obtained as a yellow oil; yield: 5.9 g (82%); two diaste-
reoisomers (dr 53:47); Rf = 0.4 (EtOAc/cyclohexane 70:30).
5-Allyl-1-[(S)-1-phenylethyl]pyrrolidin-2-one (11d)19,23a
Following the general procedure on 9d (110 mg, 0.5 mmol) and after
purification by column chromatography on silica gel, compound 11d
was obtained as a colorless oil; yield: 90 mg (79%); two diastereoiso-
mers (dr 77:23); Rf = 0.38 (EtOAc/cyclohexane 50:50).
IR (neat): 3339, 2948, 1693, 1243, 1075, 731, 697 cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.37 (m, 5 H) 5.12 (m, 2 H), 4.88 (br d, 1
H, NH), 4.86 (br d, J = 5.4 Hz, 0.8 H), 4.69 (dd, J = 5.3, 10.0 Hz, 0.6 H),
4.49 (dd, J = 9.1, 6.1 Hz, 0.5 H), 3.78 (s, 1.4 H, minor), 3.71 (s, 1.6 H,
major), 3.29 (s, 1.4 H, minor), 3.26 (s, 1.6 H, major), 3.19 (m, 2 H), 2.60
(m, 1 H), 2.43–2.28 (m, 1 H), 2.23–1.78 (m, 4 H), 1.66–1.26 (m, 4 H).
13C NMR (CDCl3, 75 MHz):  = 176.1, 175.1, 171.8, 171.3, 156.5, 136.6,
128.5, 128.1, 90.3, 88.9, 66.6, 54.1, 53.9, 53.5, 52.7, 52.4, 52.3, 40.6,
40.5, 30.0, 29.3, 29.2, 28.8, 28.4, 27.4, 24.5, 24.3, 23.2, 23.0.
IR (neat): 2974, 2935, 1675, 1411, 1260, 1026, 699 cm–1
.
1H NMR (CDCl3, 300 MHz):  = 7.45–7.23 (m, 5 H), 5.70–5.38 (m, 2 H),
5.11–4.85 (m, 2 H), 3.79 (tt, J = 8.2, 3.2 Hz, 0.77 H, major), 3.34 (tt, J =
8.2, 3.1 Hz, 0.23 H, minor), 2.59–2.44 (m, 1 H), 2.41–2.27 (m, 1 H),
2.17–2.01 (m, 1 H), 1.98–1.85 (m, 1 H), 1.83–1.67 (m, 2 H), 1.66 (d, J =
7.1 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C20H28NO6Na: 415.1840; found:
415.1838.
13C NMR (CDCl3, 75 MHz):  = 175.4 (major), 175.3 (minor), 141.9
(major), 139.7 (minor), 133.3 (major), 133.2 (minor), 128.6 (minor),
128.4 (major), 127.6 (minor), 127.4 (major), 127.2 (major), 118.2
(major), 56.5 (minor), 56.2 (major), 50.6 (minor), 49.4 (major), 39.6
(minor), 38.8 (major), 30.3, 23.9 (major), 23.7 (minor), 18.3 (minor),
16.3 (major).
Methyl (2S)-2-(2-Methoxy-5-oxopyrrolidin-1-yl)-3-phenylpropa-
noate (9g)
Following the general procedure on purified 1g (1.54 g, 6.3 mmol)
and after purification by column chromatography on silica gel, com-
pound 9g was obtained as a yellow oil; yield: 1.41 g (81%); two diaste-
reoisomers dr 57:43; Rf = 0.3 (EtOAc/cyclohexane 40:60).
HRMS (ESI): m/z [M + H]+ calcd for C15H20NO: 230.1545; found:
230.1548.
Methyl (2S)-2-(2-Allyl-5-oxopyrrolidin-1-yl)-3-methylbutanoate
(11h)
IR (neat): 2950, 1739, 1694, 1436, 1416, 1240, 1194, 1169, 1075, 749,
699 cm–1
.
Following the general procedure on 9h (115 mg, 0.5 mmol) and after
purification by column chromatography on silica gel, compound 11h
was obtained as a colorless oil; yield: 102 mg (85%); two diastereoiso-
mers (dr 70:30); Rf = 0.5 (EtOAc/cyclohexane 50:50).
1H NMR (CDCl3, 300 MHz):  = 7.18–7.36 (m, 5 H)), 4.92 (m, 0.83 H,
minor), 4.50 (dd, J = 9.5, 6.5 Hz, 0.58 H, major), 4.41 (t, J = 3.7 Hz, 0.58
H, major), 3.75 (s, 1.7 H, major), 3.71 (s, 1.3 H, minor), 3.27–3.47 (m, 2
H), 3.22 (s, 1.7 H, major), 3.16 (s, 1.3 H, minor), 2.46–2.62 (m, 1 H),
2.17–2.35 (m, 1 H), 1.89–2.02 (m, 2 H).
IR (neat): 2965, 2875, 1739, 1686, 1412, 1252, 1203, 1008, 916 cm–1
.
13C NMR (CDCl3, 75 MHz):  = 23.9 (minor), 24.0 (major), 28.7 minor),
28.8 (major), 34.1 (minor), 35.7 (major), 52.4 (minor), 52.5 (major),
52.5 (major), 53.7 (minor), 56.6 (major), 88.7 (minor), 90.6 (major),
1H NMR (CDCl3, 300 MHz):  = 5.84–5.62 (m, 1 H), 5.21–5.10 (m, 2 H),
4.36 (d, J = 10.7 Hz, 0.3 H, minor), 4.10 (d, J = 10.2 Hz, 0.7 H, major),
3.74 (s, 2.1 H, major), 3.72 (s, 1.0 H, minor), 3.77–3.71 (m, 0.3 H, mi-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
nor), 3.70–3.60 (m, 0.7 H, major), 2.70–2.60 (m, 0.7 H, major), 2.54–
2.03 (m, 5.6 H), 1.92–1.76 (m, 1 H), 1.05 (d, J = 6.6 Hz, 0.9 H, minor),
1.04 (d, J = 6.6 Hz, 2.1 H, major), 0.96 (d, J = 6.6 Hz, 2.1 H, major), 0.88
(d, J = 6.6 Hz, 0.9 H, minor).
Funding Information
Financial support of this work by Université de Paris (grant to Sébas-
tien Thueillon).()
13C NMR (CDCl3, 75 MHz):  = 176.0 (minor), 175.6 (major), 171.7
(minor), 170.5 (major), 133.4 (major), 133.3 (minor), 118.6 (minor),
118.5 (major), 61.6 (major), 59.8 (minor), 59.1 (major), 56.3 (minor),
51.9, 38.5 (major), 37.8 (minor), 29.6 (major), 29.5 (minor), 29.1 (ma-
jor), 26.7 (minor), 24.2 (minor), 24.0 (major), 20.5 (major), 20.1 (mi-
nor), 19.3 (minor), 19.2 (major).
Acknowledgment
The authors wish to thank Dr. Jean-François Betzer (ICSN, CNRS) for
fruitful scientific discussions during the preparation of this manu-
script.
HRMS (ESI): m/z [M + H]+ calcd for C13H22NO3: 240.1594; found:
240.1596.
Supporting Information
8,9-Dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3(2H)-one (12)8b,25,26
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707886.
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Following the general procedure on purified 1e (124 mg, 0.5 mmol)
and after purification by column chromatography on silica gel, com-
pound 12 was obtained as a brown solid; yield: 72 mg (60%); mp 100–
104 °C; Rf = 0.22 (EtOAc).
References
(1) Present address: (a) Université Paris-Saclay, CNRS, Institut de
Chimie Moléculaire et des Matériaux d’Orsay, Laboratoire de
Catalyse Moléculaire, Bâtiment 420, 91405 Orsay, France.
(b) NOVECAL, 86 rue de Paris, 91400 Orsay, France.
(2) Baussanne, I.; Dudot, B.; Perard-Viret, J.; Planas, L.; Royer, J.
ARKIVOC 2006, (vii), 57.
(3) Toffano, M.; Dudot, B.; Zaparucha, A.; Royer, J.; Sevrin, M.;
George, P.; Chiaroni, A. Tetrahedron: Asymmetry 2003, 14, 3365.
(4) (a) Wu, P.; Nielsen, T. E. Chem. Rev. 2017, 117, 7811.
(b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817.
IR (neat): 2937, 1674, 1513, 1417, 1253, 1229, 1117, 1027, 1005, 861,
766 cm–1
.
1H NMR (CDCl3, 300 MHz):  = 6.60 (s, 1 H), 4.76 (t, J = 7.5 Hz, 1 H),
4.33 (dd, J = 12.2, 5.1 Hz, 1 H), 3.90 (s, 3 H), 6.65 (s, 1 H), 3.89 (s, 3 H),
3.04 (ddd, J = 11.9, 11.9, 4.4 Hz, 1 H), 2.90 (ddd, J = 11.4, 11.4, 5.5 Hz, 1
H), 2.77–2.43 (m, 4 H), 1.86 (m, 1 H).
13C NMR (CDCl3, 75 MHz):  = 173.2, 148.1, 147.9, 129.3, 125.5, 111.7,
107.6, 56.6, 56.1, 55.9, 37.1, 31.8, 28.1, 27.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H18NO3: 248.1281; found:
248.1283.
(5) (a) Planas, L.; Pérard-Viret, J.; Royer, J. J. Org. Chem. 2004, 69,
3087. (b) Yoritate, M.; Takahashi, Y.; Tajima, H.; Ogihara, C.;
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1970, 26, 4073.
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K.; Planchat, A.; Amri, H.; Mathé-Allainmat, M.; Lebreton, J. Syn-
thesis 2016, 48, 1502. (c) del Corte, X.; de Marigorta, E. M.;
Palacios, F.; Vicario, J. Molecules 2019, 24, 2951.
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Trans. 1 1985, 2389. (b) Curti, C.; Ranieri, B.; Battistini, L.; Rassu,
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(±)-Crispine A (13)27
Under an argon atmosphere, LiAlH4 (50 mg, 1.3 mmol) was dissolved
in anhyd THF (7 mL) and the solution cooled to 0 °C. Compound 12
(60 mg, 0.24 mmol) dissolved in anhyd THF (3 mL) was added drop-
wise to the hydride solution at 0 °C, then the resulting solution heat-
ed under reflux for 3 h and stirred for a further 18 h at rt. Et2O (3 mL)
was added and the reaction was quenched by careful addition of sat.
aq sodium potassium tartrate (0.5 mL). The mixture was stirred for a
further 1 h before the addition of anhyd MgSO4 prior to filtration on a
Büchner funnel. The filtrate was evaporated under reduced pressure
and the resultant yellow solid was purified by column chromatogra-
phy on silica gel using 10:1.5 CH2Cl2/MeOH as eluent. Compound 13
was obtained as a white solid; yield: 42 mg (75%); mp 86 °C (Lit.27 mp
88–89 °C); Rf = 0.5 (CH2Cl2/MeOH 10:1.5).
IR (neat): 2936, 2789, 1607, 1508, 1372, 1211, 1135, 1014, 856, 761
cm–1
.
1H NMR (CDCl3, 300 MHz):  = 6.65 (s, 1 H), 6.61 (s, 1 H), 3.89 (s, 3 H),
3.88 (s, 3 H), 3.44 (t, J = 8.2 Hz, 1 H), 3.26–3.17 (m, 1 H), 3.17–2.99 (m,
2 H), 2.82–2.52 (m, 3 H), 2.42–2.29 (m, 1 H), 2.07–1.84 (m, 2 H), 1.84–
1.68 (m, 1 H).
13C NMR (CDCl3, 75 MHz):  = 147.3, 147.2, 131.0, 126.2, 111.3, 108.8,
63.0, 56.0, 55.9, 53.2, 48.4, 30.5, 28.1, 22.2.
(10) Zhukovsky, D.; Dar’in, D.; Kantin, G.; Krasavin, M. Eur. J. Org.
Chem. 2019, 2397.
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Giambastiani, G.; Reginato, G. Tetrahedron 1998, 54, 10403.
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erocycles 2006, 68, 2471. (f) Alves, J. C. F. J. Braz. Chem. Soc. 2007,
18, 855.
HRMS (ESI): m/z [M + H]+ calcd for C14H20NO2: 234.1488; found:
234.1493.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
F. Souquet et al.
PSP
Synthesis
(13) Integration area at 5.7 and 6.0 ppm accounts for 3.6 protons
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was incorporated. A HSQC spectrum (see Supporting Informa-
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N--ethoxylated derivatives and in MeCN to obtain the
N--hydroxylated derivatives with less efficiency.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I