A straightforward synthesis of functionalized cis-perhydroisoquinolin-1-ones

Article abstract of DOI:10.3390/molecules24030557

Base-catalyzed annulation reactions of 5,6-dihydro-2(1H)-pyridones with Nazarov-type reagents are reported. The effect of the solvent polarity and the concentration of the reagents is studied. The process involves two successive Michael additions and stereoselectively provides functionalized cis-perhydroisoquinolin-1-ones.

Full text of DOI:10.3390/molecules24030557

molecules
Article
A Straightforward Synthesis of Functionalized
cis-Perhydroisoquinolin-1-ones
Federica Arioli 1, Maria Pérez 2 , Celeste Are 1, Elies Molins 3 , Joan Bosch 1 and
Mercedes Amat 1,
*
1
Laboratory of Organic Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of
Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain; fede.arioli@hotmail.it (F.A.);
cele.are@ub.edu (C.A.); joanbosch@ub.edu (J.B.)
Department of Nutrition, Food Sciences and Gastronomy, Faculty of Pharmacy and Food Sciences,
and Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08921 Santa Coloma de
Gramanet, Spain; mariaperez@ub.edu
2
3
Institut de Ciència de Materials de Barcelona (ICMAB-CSIC), Campus UAB, 08193 Cerdanyola, Spain;
elies.molins@icmab.es
*
Correspondence: amat@ub.edu; Tel.: +34-93-402-4540
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editors: David Díez and María Ángeles Castro
Received: 15 January 2019; Accepted: 30 January 2019; Published: 3 February 2019
Abstract: Base-catalyzed annulation reactions of 5,6-dihydro-2(1H)-pyridones with Nazarov-type
reagents are reported. The effect of the solvent polarity and the concentration of the reagents is
studied. The process involves two successive Michael additions and stereoselectively provides
functionalized cis-perhydroisoquinolin-1-ones.
Keywords: 5,6-dihydro-2(1H)-pyridone; Nazarov reagents; perhydroisoquinoline; Michael addition;
stereoselectivity
1. Introduction
Nitrogen heterocycles exhibit a broad range of significant biological and pharmacological activities,
and many of them have been developed as therapeutic drugs [1,2].
In particular, the partially or totally reduced isoquinoline ring system is present in a large number
of biologically active natural products (such as the alkaloids of the yohimbine [
and madangamine [ ] groups) and medicinally useful synthetic compounds (e.g., the HIV protease
inhibitors saquinavir and nelfinavir [ ], the antimigraine drugs tezampanel and LY466195 [ ], and the
3,4], manzamine [5],
6
7,
8
9
antiobesity agent AMG 076 [10]) (Figure 1).
Together with the intramolecular Diels
the most straightforward approaches for the construction of the hydroisoquinoline ring system
involves the generation of the carbocyclic ring by an annulation reaction from appropriate
5,6-dihydro-2(1H)-pyridone derivatives. The latter strategy was developed some years ago in our
−
Alder cyclization of suitable azatrienes [11,12], one of
laboratory using the classical Diels
mind that Nazarov reagents ( -unsaturated
addition reactions with -unsaturated carbonyl derivatives, we envisaged an alternative annulation
procedure to directly access functionalized hydroisoquinolines from 5,6-dihydro-2(1H)-pyridones.
−
Alder methodology with a variety of dienes [13]. Bearing in
γ
,
δ
β-keto esters) are able to participate in double Michael
α,β
Molecules 2019, 24, 557; doi:10.3390/molecules24030557
www.mdpi.com/journal/molecules

Molecules 2019, 24, 557
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N
N
H
N
N
H
H
H
N
H
H
OH
N
N
MeO2C
OH
N
Yohimbine
Manzamine A
Madangamine D
H
CO2H
N
H
N
N
H
N
OH
N
HO2C
Tezampanel
LY466195
N
N
R =
CH2
OH
H
H
F
O
CH3
Me
t-BuHNOC
N
F
H
SC6H5
H
R =
H
H
CF3
HO2C
N
R
H
Nelfinavir
AMG 076
Figure 1. Hydroisoquinoline-containing bioactive natural products and synthetic compounds.
Nazarov reagents are versatile annulating agents, extensively used in a variety of Robinson-type
and double Michael addition annulations [14 16]. In the former, the reagent sequentially acts as
–
an electrophilic Michael acceptor and as a nucleophile to promote an aldol condensation. In the
latter, however, it successively acts as a nucleophilic Michael donor and an electrophilic Michael
acceptor, a reactivity pattern that has been successfully applied to assemble pentacyclic yohimbine-type
derivatives from unsaturated indolo[2,3-a]quinolizidine-derived lactams [17–19].
2. Results and Discussion
Compounds 6a,b,c and 8, which incorporate an additional phenylsulfonyl or ethoxycarbonyl
activating electron-withdrawing group conjugated to the carbon-carbon double bond, were selected as
the starting dihydropyridones.
Lactams 6a
overall yield from 2-piperidone (1a) by bis-sulfenylation, followed by reaction with either (Boc)2O
or MeI, and subsequent stepwise m-CPBA oxidation of the resulting N-substituted piperidones 3a
via unsaturated sulfenyl and sulfinyl derivatives 4a and 5a . A similar reaction sequence from
N-tosyl-2-piperidone 3c led to unsaturated lactam 6c in low overall yield. Due to their instability,
lactams 6a were used in the annulation step without purification. In turn, ethoxycarbonyl lactam
was prepared in high yield from N-Boc-2-piperidone (1b) via seleno derivative , as outlined in
Scheme 1.
,b, bearing an easily removable phenylsulfonyl group, were prepared in acceptable
,b
,b
,b
,b,c
8
7
Scheme 1. Preparation of the starting unsaturated lactams.

Molecules 2019, 24, 557
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To study the annulation reactions, we initially used unsaturated lactam 6a and the Nazarov
reagent 14], which incorporates a methyl group at the terminal olefinic carbon, in the presence of
Cs2CO3, the most commonly used base for the generation of Nazarov enolates [20]. Reagent has
been used extensively by Deslongchamps to generate cis-decalin derivatives [20 21]. The reaction
9
[
9
,
was carried out at room temperature, using an excess (6 equiv.) of Cs2CO3 in CH2Cl2 at different
concentrations (from 50 mM to 5 mM). In all cases, the double Michael addition reaction occurred
satisfactorily, although with only moderate stereoselectivity, to give 3:1 C-8 stereoisomeric mixtures of
cis-hydroisoquinolones 10a (cis Me/SO2Ph) and 10b (trans Me/SO2Ph), the chemical yield increasing
(79% yield at 5 mM) with the dilution (Table 1, entries 1–3). Trace amounts of the monoaddition
product 11 were detected by NMR, indicating that the annulation involves two successive Michael
addition reactions. In contrast, when acetonitrile was used as the solvent the yield was very low (entry
4). Remarkably, the use of KF as the base in a polar solvent such as methanol (entry 5) resulted in
a reversal of the stereoselectivity, leading to a mixture of bicyclic lactams 10a and 10b, in which the
trans Me/SO2Ph isomer predominated (56% yield, ratio 1:2). The influence of the solvent polarity on
the stereoselectivity of annulation reactions of
9 with β-keto esters has previously been observed [21].
The facial selectivity when using Cs2CO3 as the base can be attributed to the coordination of the Cs+
cation to the oxygen atoms of both the Nazarov reagent and the starting lactam [19].
Table 1. Reaction of unsaturated lactam 6a with Nazarov reagent 9.
O
O
Boc
N
Boc
N
Boc
N
O
OMe
O
Boc
N
O
9
SO2Ph
Me
SO2Ph
Me
O
SO2Ph
(3 equiv.)
H
H
base (6 equiv.)
SO2Ph
MeO2C
MeO2C
MeO2C
6a
from 0 ºC to rt
overnight
OH
10b
OH
10a
O
11
Entry
Base
Solvent
Concentration (mM)
Yield (%)
a/b Ratio
1
2
3
4
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KF
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeOH
50
25
5
5
5
47
56
79
10
56
3:1
3:1
3:1
–
1:2
The relative Me/SO2Ph cis configuration of bicyclic lactam 10a was unambiguously established
by X-ray crystallographic analysis (Figure 2).
Figure 2. ORTEP plot of the X-ray structure of bicyclic lactam 10a.
Unsaturated lactam 6b behaved similarly to lactam 6a in the annulation reaction with Nazarov
reagent 9, although the yields were slightly lower, probably due to the lower electrophilicity of the

Molecules 2019, 24, 557
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Michael acceptor as a consequence of the absence of an electron-withdrawing group on the piperidone
nitrogen. cis-Hydroisoquinolone 12a, with a cis Me/SO2Ph relationship, was stereo-selectively formed
(4:1 12a/12b ratio) when the reaction was performed in CH2Cl2 solution using Cs2CO3 as the base
(Table 2, entries 1 and 2), the yield once again being higher with increasing dilution (40% yield at
5 mM). As before, a reversal of the stereoselectivity was observed and the trans Me/SO2Ph isomer
predominated when using polar solvents, either MeOH in the presence of KF (1:4 ratio; entry 3) or
DMF in the presence of Cs2CO3 (1:5 ratio; entry 4). The Me/SO2Ph cis relationship of the adducts 10a
and 12a was maintained unchanged after an additional treatment (20 h, rt) with Cs2CO3 in CH2Cl2 or
KF in MeOH, thus suggesting the non-reversibility of the cyclization step.
Table 2. Reaction of unsaturated lactam 6b with Nazarov reagent 9.
Me
Me
Me
Base
N
O
N
O
N
O
O
O
SO2Ph
Me
from 0 ºC to rt, overnight
SO2Ph
Me
+
OMe
SO2Ph
H
H
9
6b
MeO2C
MeO2C
OH
OH
12a
12b
Entry
Base
Equiv Base
Equiv (9)
Solvent Concentration (mM)
Yield (%)
a/b Ratio
1
2
3
4
Cs2CO3
Cs2CO3
KF
6
6
6
4
3
3
3
2
CH2Cl2
CH2Cl2
MeOH
DMF
100
5
5
28
40
51
45
4:1
4:1
1:4
1:5
Cs2CO3
5
The relative configuration of both hydroisoquinolones, 12a and 12b, was unambiguously
established by X-ray crystallographic analysis (Figure 3).
Figure 3. ORTEP plots of the X-ray structures of bicyclic lactams 12a and 12b.
The activating phenylsulfonyl group of bicyclic lactams 10a
removed, with retention of configuration, by treatment with sodium amalgam [22] to give the
respective cis-hydroisoquinolones 13a 14a, and 14b (Scheme 2). Alternatively, removal of the N-Boc
, 12a, and 12b was stereoselectively
,
protecting group of hydroisoquionolones 10a and 13a quantitatively afforded the potentially useful
N-unsubstituted derivatives 15 and 16, respectively. The cis ring function was evident from the
observation of a positive NOE effect between the 4a and 8a methine protons.
To expand the scope of the methodology and access hydroisoquinolones lacking the methyl
substituent on the B ring, we decided to study double Michael annulations using the silylated Nazarov
reagent 17 [17], which constitutes a stable synthetic equivalent of the original Nazarov reagent (methyl
or ethyl 3-oxo-4-pentenoate) [15] that avoids the polymerization problems associated with the latter
under basic conditions.

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Me
N
R
R
N
Me
N
O
H
N
O
O
H
O
SO2Ph
Me
SO2Ph
Me
Na-Hg
−78 °C, MeOH
8a
4a
8a
4a
Na-Hg
−78 °C, MeOH
Me
Me
H
H
H
H
MeO2C
MeO2C
MeO2C
62%
MeO2C
13a 87%; 14a 76%
OH
14b
OH
OH
OH
12b
13a R = Boc
14a
10a R = Boc
TFA, CH2Cl2
rt, 30 min
98%
TFA, CH2Cl2
rt, 30 min
99%
12a
15
R = Me
16 R = H
R = Me
R = H
Scheme 2. Desulfonylation reactions and removal of the N-Boc protecting group.
As expected, the Cs2CO3-promoted annulation of the Nazarov reagent 17 with unsaturated lactam
6a under the usual reaction conditions (5 mM in CH2Cl2 as the solvent) stereoselectively afforded
cis-hydroisoquinolone 18a, in which protodesilylation had occurred, in acceptable yield (Table 3,
entry 1). The yield was not improved by increasing the excess of reagent and base (entry 2) and was
lower when operating at a higher concentration (entry 3) or when using KF in MeOH as the solvent
(entry 4). Similar moderate yields were obtained in the generation of cis-hydroisoquinolones 18b and
18c from lactams 6b (entries 5–7) and 6c (entry 8) under a variety of conditions.
Table 3. Reactions of unsaturated lactams 6a-c with Nazarov reagent 17.
Unsaturated
Lactam
Equiv
Base
Equiv
(15)
Concentration
(mM)
Entry
Base
Solvent
Product
Yield (%)
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6b
6b
6b
6c
Cs2CO3
Cs2CO3
Cs2CO3
KF
Cs2CO3
Cs2CO3
KF
6
10
6
6
6
6
6
6
3
5
3
3
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
5
5
20
5
5
100
5
18a
18a
18a
18a
18b
18b
18b
18c
47
47
20
20
35
21
20
32
Cs2CO3
5
Remarkably, the yield of the annulation with the silylated Navarov reagent 17 was higher when
using unsaturated lactam , which incorporates an ester group as an additional activating substituent.
8
Operating under the previously optimized reaction conditions, cis-hydroisoquinolone 19 was obtained
in 60% yield (Scheme 3).
Scheme 3. Reaction of unsaturated lactam 8 with the silylated Nazarov reagent 17.
In conclusion, base-promoted annulation reactions of Nazarov reagents
5,6-dihydro-2(1H)-pyridones bearing an additional activating electron-withdrawing group
lactam carbonyl constitute a straightforward procedure for the stereoselective synthesis of highly
substituted cis-hydroisoquinolin-2-ones. In the reactions with the methyl-substituted reagent , leading
9
and 17 with
α
to the
9

Molecules 2019, 24, 557
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to 8-substituted derivatives, the use of Cs2CO3 in CH2Cl2 leads to cis-hydroisoquinolones with a cis
8-Me/8a-SO2Ph relationship as the major stereoisomers. The stereoselectivity is reversed in a polar
solvent such as DMF or when the annulation is performed using KF in MeOH.
The methodology developed here provides access to polyfunctionalized bicyclic scaffolds
with potential use as precursors of bioactive hydroisoquinoline-containing natural products and
synthetic derivatives.
3. Materials and Methods
3.1. General Information
All air sensitive manipulations were carried out under a dry argon or nitrogen atmosphere.
THF and CH2Cl2 were dried using a column solvent purification system. Analytical thin-layer
chromatography was performed on SiO2 (silica gel 60A 35–70 µm, Carlo Erba, Val de Reuil Cedex,
France), and the spots were located with 1% aqueous KMnO4. Chromatography refers to flash
chromatography and was carried out on SiO2 (SDS silica gel 60 ACC, 35–75 mm, 230-240 mesh
ASTM). NMR spectra were recorded at 300 or 400 MHz (1H) and 100.6 MHz (13C), and chemical
shifts are reported in
δ values downfield from TMS or relative to residual chloroform (7.26 ppm,
77.0 ppm) as an internal standard. Data are reported in the following manner: chemical shift,
multiplicity, coupling constant (J) in hertz (Hz), integrated intensity, and assignment (when possible).
Assignments and stereochemical determinations are given only when they are derived from definitive
two-dimensional NMR experiments (HSQC-COSY). IR spectra were performed in an Avatar 320 FT-IR
spectrophotometer (Thermo Nicolet, Madison, WI, USA) and only noteworthy IR absorptions (cm−1
)
are listed. High resolution mass spectra (HMRS; LC/MSD TOF, Agilent Technologies, Santa Clara, CA,
USA) were performed by Centres Científics i Tecnològics de la Universitat de Barcelona.
3.2. Preparation of the Starting Unsaturated Lactams
3,3-Bis(phenylthio)-2-piperidone (
added under an argon atmosphere at
anhydrous THF (100 mL). The solution was stirred for 30 minutes, and then TMSCl (5.2 mL, 40.8 mmol)
was added. The solution was stirred at room temperature for 30 minutes, and then re-cooled to
2
). n-BuLi (25.5 mL of a 1.6 M solution in hexane, 40.8 mmol) was
−
78 ◦C to a solution of
δ
-valerolactam (1a, 4 g, 40.82 mmol) in
−
78 ◦C. LDA (45 mL, 2 M solution in THF/heptane/ethylbenzene, 89.8 mmol) was added, and the
solution was stirred for 30 minutes. Then, PhSSPh (19.5 g, 89.8 mmol) in anhydrous THF (50 mL) was
added, and the resulting solution was stirred at room temperature for 1 h. After this time, NH4Cl was
added, and the organic layer was extracted with EtOAc. The combined organic extracts were dried
over anhydrous MgSO4, filtered, and concentrated under reduced pressure. Flash chromatography
(9:1 hexane-EtOAc) of the residue gave lactam
2
(6.61 g, 51% yield): IR (ATR Pike)
ν
(cm−1): 3260
1
(NH), 1661 (CO); H-NMR (400 MHz, CDCl3):
δ = 1.72-1.90 (m, 2H, H-5), 1.97 (t, J = 6.2 Hz, 2H,
H-4), 3.18 (dt, J = 2.4, 6.0 Hz, 2H, H-6), 6.26 (br. s, 1H, NH), 7.32–7.34 (m, 6H, HAR), 7.63–7.65 (m,
4H, HAR); HRMS (ESI) calcd for [C17H18NOS2 + H+]: 316.0824, found: 316.062714b (detailed data in
supplementary materials).
3,3-Bis(phenylthio)-1-(tert-butoxycarbonyl)-2-piperidone (3a). n-BuLi (6.1 mL of a 1.4 M solution in hexane,
◦
8.54 mmol) was added under an argon atmosphere at
−
78 C to a solution of lactam
2
(2.25 g,
7.12 mmol) in anhydrous THF (100 mL), and the resulting solution was◦stirred for 1 h. Then, Boc2O
(2.30 g, 10.68 mmol) was added, and the mixture was stirred at
−
78 C for 1 h. After this time,
saturated NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic
extracts were dried over Na2SO4 and filtered, and the solvent was removed under reduced pressure.
Flash chromatography (9:1 hexane-EtOAc) of the residue gave N-Boc derivative 3a (2.92 g, 99% yield):
IR (ATR Pike)
2H, H-5), 2.05 (m, 2H, H-4), 3.60 (t, J = 6.1 Hz, 2H, H-6), 7.33–7.42 (m, 6H, HAR), 7.68 (m, 4H, HAR);
13C-NMR (400 MHz, CDCl3):
= 20.1 (C-5), 28.0 [(CH3)3C], 35.1 (C-4), 46.7 (C-6), 68.6 (C-3), 83.2
ν δ = 1.53 [s, 9H, (CH3)3C], 1.94 (m,
(cm−1): 1717 (CO); 1H-NMR (400 MHz, CDCl3):
δ

Molecules 2019, 24, 557
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[(CH3)3C], 128.7 (4CHAR), 129.6 (2CHAR), 130.9 (2CAR), 136.8 (4CHAR), 153.8 (CO), 168.3 (CO); HRMS
(ESI) calcd for [C22H25NO3S2 + Na+]: 438.1168, found: 438.117.
3,3-Bis(phenylthio)-1-methyl-2-piperidone (3b). n-BuLi (8.54 mL of a 1.6 M solution in hexane, 13.67 mmol)
was added under an argon atmosphere at
anhydrous THF (200 mL), and the resulting mixture was stirred at
−
78 ◦C to a solution of lactam
2
(3.60 g, 11.39 mmol) in
◦
−
78 C for 1 h. Then, MeI (1.06 mL,
17.09 mmol) was added, and the solution was stirred at room temperature for 1 h. The reaction was
quenched by addition of saturated NH4Cl, and the mixture was extracted with EtOAc. The combined
organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash
chromatography (9:1 hexane-EtOAc) of the residue afforded N-methyl derivative 3b (3.7 g, 98% yield):
IR (ATR Pike)
(m, 2H, H-4), 2.92 (s, 3H, CH3), 3.16 (t, J = 6.4 Hz, 2H, H-6), 7.31–7.38 (m, 6H, HAR), 7.63–7.65 (m,
ν δ = 1.86–1.91 (m, 2H, H-5), 1.97–1.99
(cm−1): 1642 (NCO); 1H-NMR (400 MHz, CDCl3):
4H, HAR); 13C-NMR (100.6 MHz, CDCl3):
δ = 19.6 (C-5), 34.0 (C-4), 35.8 (CH3), 50.1 (C-6), 66.0 (C-3),
128.6 (4CHAR), 129.3 (2CHAR), 131.6 (2CAR), 136.6 (4CHAR); HRMS (ESI) calcd for [C18H19NOS2 + H+]:
330.0981, found: 330.0977.
3,3-Bis(phenylthio)-1-(p-toluenesulfonyl)-2-piperidone (3c). n-BuLi (1.2 mL of a 1.6 M solution in hexane,
◦
1.9 mmol) was added at
−
78 C to a solution of lactam
2
(500 mg, 1.58 mmol) in anhydrous THF (25 mL),
and the resulting mixture was stirred at
−
78 ◦C for 1 h. Then, TsCl (452 mg, 2.37 mmol) was added,
and the solution was stirred at room temperature overnight. The reaction was quenched by addition
of saturated NH4Cl, and the mixture was extracted with EtOAc. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography (9:1
hexane-EtOAc) afforded N-tosyl derivative 3c (264 mg, 52% yield): IR (ATR Pike)
(NCO), 1169 (SO2); 1H-NMR (400 MHz, CDCl3):
= 1.55 (s, 2H, H-5), 2.02 (s, 2H, H-4), 2.49 (s, 3H,
ν
(cm−1): 1683
δ
CH3), 3.46 (br. s, 2H, H-6), 7.19–7.40 (m, 12H, HAR), 7.93 (d, J = 8.4 Hz, 2H, HAR).
1-(tert-Butoxycarbonyl)-3-(phenylthio)-5,6-dihydro-2(1H)-pyridone (4a). m-Chloroperbenzoic acid (1.09 g,
technical grade 70%, 766 mg pure oxidant, 6.33 mmol) in CH2Cl2 (100 mL) was added to a solution
◦
of lactam 3a (2.64 g, 6.33 mmol) in CH2Cl2 (200 mL) at
−
78 C. The solution was stirred at this
temperature for 2 h and then for 30 minutes at room temperature. After this time, a saturated solution
of NaHCO3 was added, the mixture was extracted with CH2Cl2, and the organic solvent was removed
under reduced pressure. The crude product was purified by flash chromatography (95:5 hexane-EtOAc)
to afford unsaturated lactam 4a (1.88 g, 97% yield): IR (ATR Pike)
1H-NMR (300 MHz, CDCl3):
= 1.54 [s, 9H, (CH3)3C], 2.39 (td, J = 6.6, 4.8 Hz, 2H, H-5), 3.84 (t,
J = 6.6 Hz, 2H, H-6), 6.08 (t, J = 4.8 Hz, 1H, H-4), 7.33–7.41 (m, 2H, HAR), 7.47–7.50 (m, 2H, HAR),
7.66–7.70 (m, 1H, HAR); 13C-NMR (100.6 MHz, CDCl3):
= 25.3 (C-5), 28.0 [(CH3)3C], 43.7 (C-6), 83.4
ν
(cm−1): 1762 (CO), 1715 (CO);
δ
δ
[(CH3)3C], 128.8 (CHAR), 129.5 (2CHAR), 131.0 (C-3, CAR), 134.8 (2CHAR), 135.5 (C-4), 152.8 (CO), 161.7
(CO); HRMS (ESI) calcd for [C16H19NO3S + Na+]: 328.0978, found: 328.0975.
1-Methyl-3-(phenylthio)-5,6-dihydro-2(1H)-pyridone (4b). Operating as described for the preparation of
compound 4a, from a solution of lactam 3b (280 mg, 0.85 mmol) in CH2Cl2 (20 mL) and m-CPBA
(210 mg, technical grade 70%, 0.85 mmol) in CH2Cl2 (20 mL), unsaturated lactam 4b was obtained
1
(160 mg, 86% yield) as a yellow foam: H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
δ
= 2.34 (td, J = 7.2,
4.8 Hz, 2H, H-5), 3.04 (s, 1H, CH3), 3.40 (t, J = 7.2 Hz, 2H, H-6), 5.81 (t, J = 4.8 Hz, 1H, H-4), 7.35–7.39
(m, 3H, HAR), 7.48–7.50 (m, 2H, HAR); 13C-NMR (100.6 MHz, CDCl3):
δ
= 24.6 (C-5), 34.9 (CH3), 47.6
(C-6), 128.5 (CHAR), 129.4 (2CHAR), 130.8 (C-4), 132.0, 134.4 (C-3, CAR), 134.6 (2CHAR), 162.9 (CO).
3-(Phenylthio)-1-(p-toluenesulfonyl)-5,6-dihydro-2(1H)-pyridone (4c). Operating as described for the
preparation of compound 4a, from a solution of lactam 3c (264 mg, 0.58 mmol) in CH2Cl2 (15 mL)
and m-CPBA (142 mg, technical grade 70%, 0.58 mmol) in CH2Cl2 (15 mL), unsaturated lactam 4c
was obtained (123 mg, 61% yield) as a yellow foam: IR (ATR Pike)
1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
= 2.43 (s, 3H, CH3), 2.48 (td, J = 6.3, 4.8 Hz, 2H, H-5),
4.04 (t, J = 6.3 Hz, 2H, H-6), 6.08 (t, J = 4.8 Hz, 1H, H-4), 7.30–7.37 (m, 7H, HAR), 7.93 (d, J = 8.4 Hz,
ν
(cm−1): 1683 (CO), 1166 (SO2);
δ

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2H, HAR); 13C-NMR (100.6 MHz, CDCl3):
δ
= 21.6 (CH3), 25.9 (C-5), 44.1 (C-6), 128.7 (CHAR), 128.9
(CHAR), 129.4 (CHAR), 129.6 (CHAR), 130.7 (CAR), 134.5 (CHAR), 135.6 (C-3, CAR), 136.2 (C-4), 144.9
(CHAR), 161.1 (NCO); HRMS (ESI) calcd for [C18H17NO3S2 + H+]: 360.0723, found: 360.0720.
1-(tert-Butoxycarbonyl)-3-(phenylsulfinyl)-5,6-dihydro-2(1H)-pyridone (5a). m-Chloroperbenzoic acid
(1.51 g, technical grade 70%, 1.06 g pure oxidant, 6.14 mmol) in CH2Cl2 (100 mL◦) was added to
a solution of phenylthio derivative 4a (1.884 g, 6.14 mmol) in CH2Cl2 (200 mL) at
−
78 C. The solution
was stirred at this temperature for 1.5 h. Then, a saturated solution of NaHCO3 was added, the mixture
was extracted with CH2Cl2, and the organic solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (95:5 hexane-EtOAc) to afford sulfinyl derivative 5a
(1.39 g, 70% yield): IR (ATR Pike)
CDCl3, COSY, g-HSQC): = 1.51 [s, 9H, (CH3)3C], 2.55–2.75 (m, 2H, H-5), 3.59 (ddd, J = 13.2, 10.4,
5.2 Hz, 1H, H-6), 4.05 (dtd, J = 13.2, 5.2, 1.1 Hz, H-6), 7.45-7.47 (m, 3H, HAR), 7.57 (td, J = 3.6, 1.2 Hz,
1H, H-4), 7.79–7.81 (m, 2H, HAR); 13C-NMR (100.6 MHz, CDCl3):
= 24.9 (C-5), 27.9 [(CH3)3C], 43.2
ν
(cm−1): 1762 (CO), 1719 (CO), 1099, 1049 (SO); 1H-NMR (400 MHz,
δ
δ
(C-6), 83.8 [(CH3)3C)], 125.6 (2CHAR), 129.1 (2CHAR), 131.3 (CHAR), 142.3 (C-4), 142.6, 143.7 (CAR, C-3),
151.9 (CO), 160.2 (CO); HRMS (ESI) calcd for [C16H19NO4S + Na+]: 344.0927, found: 344.0927.
1-(Methyl)-3-(phenylsulfinyl)-5,6-dihydro-2(1H)-pyridone (5b). Operating as described for the preparation
of compound 5a, from a solution of phenylthio derivative 4b (163 mg, 0.74 mmol) in CH2Cl2 (15 mL)
and m-CPBA (183 mg, technical grade 70%, 0.74 mmol) in CH2Cl2 (20 mL), sulfinyl derivative 5b was
1
obtained (100 mg, 57% yield): IR (ATR Pike)
CDCl3, COSY, g-HSQC):
2H, H-6), 7.31 (t, J = 4.8 Hz, 1H, H-4), 7.44–7.45 (m, 3H, HAR), 7.78–7.81 (m, 2H, HAR); 13C-NMR
ν
(cm−1): 1652 (CO), 1043 (SO); H-NMR (400 MHz,
δ
= 2.53–2.74 (2m, 2H, H-5), 2.90 (s, 3H, CH3), 3.38–3.46 (dd, J = 8.8, 6.8 Hz,
(100.6 MHz, CDCl3):
δ = 24.0 (C-5), 33.7 (CH3), 46.8 (C-6), 125.5 (2CHAR), 128.8 (2CHAR), 131.0 (CHAR),
138.1 (C-4), 140.6, 143.8 (CAR, C-3), 160.1 (NCO); HRMS (ESI) calcd for [C12H13NO2S + H+]: 236.074,
found: 236.0741.
3-(Phenylsulfinyl)-1-(p-toluenesulfonyl)-5,6-dihydro-2(1H)-pyridone (5c). Operating as described for the
preparation of compound 5a, from a solution of phenylthio derivative 4c (55 mg, 0.12 mmol) in CH2Cl2
(3 mL) and m-CPBA (30 mg, technical grade 70%, 0.12 mmol) in CH2Cl2 (3 mL), sulfinyl derivative 5c
was obtained. This compound was used in the next step without further purification: IR (ATR Pike)
ν
(cm−1): 1683, (NCO), 1362 (SO2), 1170 (SO); 1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
δ
= 2.43 (s,
3H, CH3), 2.67-2.81 (m, 2H, H-5), 3.78–3.86 (m, 1H, H-6), 4.11–4.20 (m, 1H, H-6), 7.27 (d, J = 7.6 Hz,
2H, HAR), 7.36–7.41 (m, 3H, HAR), 7.52 (dd, J = 4.4, 3.6 Hz, 1H, H-4), 7.63–7.66 (m, 2H, HAR), 7.82
(d, J = 8.0 Hz, 2H, HAR); 13C-NMR (100.6 MHz, CDCl3):
δ = 21.6 (CH3), 25.3 (C-5), 43.8 (C-6), 125.1
(2CHAR), 128.3 (2CHAR), 129.1 (2CHAR), 129.4 (2CHAR), 131.3 (CHAR), 135.1 (CAR), 142.8 (C-4), 143.2,
145.1 (CAR, C-3), 159.7 (NCO).
1-(tert-Butoxycarbonyl)-3-(phenylsulfonyl)-5,6-dihydro-2(1H)-pyridone (6a). m-Chloroperbenzoic acid
(1.06 mg, technical grade 70%, 745 mg pure oxidant, 4.32 mmol) in CH2Cl2 (150 mL) was added
to a solution of sulfinyl derivative 5a (1.39 g, 4.32 mmol) in CH2Cl2 (60 mL) at
was stirred at room temperature for 6 h. Then, a saturated solution of NaHCO3 was added, the mixture
was extracted with CH2Cl2, and the organic solvent was removed under reduced pressure to afford
sulfonyl derivative 6a, which was used in the next step without purification: IR (ATR Pike)
1721 (CO), 1689 (CO), 1446 (SO2), 1143 (SO2); 1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
−
78 ◦C. The solution
ν
(cm−1):
= 1.49 [s,
δ
9H, (CH3)3C], 2.67 (td, J = 6.0, 4.0 Hz, 2H, H-5), 3.87 (t, J = 6.8 Hz, 2H, H-6), 7.51–7.53 (m, 2H, HAR),
7.60 (t, J = 7.6 Hz, 1H, HAR), 8.05 (dm, J = 7.2 Hz, 2H, HAR), 8.08 (t, J = 4.4 Hz, 1H, H-4); 13C-NMR
(100.6 MHz, CDCl3):
δ = 25.0 (C-5), 27.9 [(CH3)3C], 42.9 (C-6), 84.2 [(CH3)3C], 128.7 (2CHAR), 129.3
(2CHAR), 133.5 (CHAR), 138.7, 139.5 (C-3, CAR), 151.4 (CO), 152.2 (C-4), 157.8 (CO); HRMS (ESI) calcd
for [C16H19NO5S + H+]: 338.1057, found: 338.1066.

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1-Methyl-3-(phenylsulfonyl)-5,6-dihydro-2(1H)-pyridone (6b). Operating as described for the preparation
of compound 6a (reaction time 20 h), from a solution of sulfinyl derivative 5b (100 mg, 0.42 mmol) in
CH2Cl2 (10 mL) and m-CPBA (104 mg, technical grade 70%, 0.42 mmol) in CH2Cl2 (10 mL), sulfonyl
derivative 6b was obtained. This compound was used in the next step without purification: IR (ATR
1
Pike)
ν
(cm−1): 1662 (NCO), 1306 (SO2), 1151 (SO2); H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
δ
= 2.67 (td, J = 7.2, 4.4 Hz, 2H, H-5), 2.93 (s, 3H, CH3), 3.46 (t, J = 7.2 Hz, 2H, H-6), 7.51 (tm, J = 7.6 Hz,
2H, HAR), 7.57 (m, 1H, HAR), 7.87 (t, J = 4.4 Hz, 1H, H-4), 8.05 (dm, J = 7.6 Hz, 2H, HAR); 13C-NMR
(100.6 MHz, CDCl3):
δ = 24.3 (C-5), 34.4 (CH3), 46.6 (C-6), 128.6 (2CHAR), 129.1 (2CHAR), 133.4
(CHAR), 140.0 (C-3, CAR), 148.4 (C-4), 159.0 (CO); HRMS (ESI) calcd for [C12H13NO3S + H+]: 252.0689,
found: 252.0679.
3-(Phenylsulfonyl)-1-(p-toluenesulfonyl)-5,6-dihydro-2(1H)-pyridone (6c). Operating as described for the
preparation of compound 6a (reaction time 20 h), from a solution of sulfinyl derivative 5c (45 mg,
0.12 mmol) in CH2Cl2 (6 mL) and m-CPBA (30 mg, technical grade 70%; 21 mg pure oxidant, 0.12 mmol)
in CH2Cl2 (6 mL), sulfonyl derivative 6c was obtained. This compound was used in the next step
without purification: IR (ATR Pike)
CDCl3, COSY, g-HSQC): = 2.42 (s, 1H, CH3), 2.79 (td, J = 6.4, 4.4 Hz, 2H, H-5), 4.04 (t, J = 6.0 Hz, 2H,
ν
(cm−1): 1695 (NCO), 1362 (SO2), 1157 (SO2); 1H-NMR (400 MHz,
δ
H-6), 7.29 (d, J = 8.0 Hz, 2H, HAR), 7.47–7.51 (m, 2H, HAR), 7.57 (tt, J = 7.6, 1.2 Hz, 1H, HAR), 7.85 (d,
J = 8.0 Hz, 2H, HAR), 7.96 (d, J = 8.0 Hz, 2H, HAR), 8.06 (t, J = 4.4 Hz, 1H, H-4); 13C-NMR (100.6 MHz,
CDCl3):
δ = 21.6 (CH3), 25.7 (C-5), 43.5 (C-6), 128.4 (2CHAR), 128.8 (2CHAR), 129.1 (2CHAR), 129.6
(2CHAR), 133.7 (CHAR), 134.9 (CAR), 137.8 (CHAR), 139.0 (C-3), 145.3 (CAR), 153.2 (C-4), 157.2 (NCO).
1-(tert-Butoxycarbonyl)-3-(ethoxycarbonyl)-3-(phenylselenyl)-2-piperidone (
silyl)amide (11.1 mL of a 1 M solution in THF, 11.1 mmol) was slowly added at
7
). Lithium bis(◦trimethyl
−
78 C under
an argon atmosphere to a solution of lactam 1b (1.0 g, 5.05 mmol) in anhydrous THF (100 mL), and the
solution was stirred for 1 h. Then, ethyl chloroformate (532 l, 5.56 mmol) and, after 1 h of continuous
stirring at
78 ◦C, a solution of PhSeCl (1.48 g, 7.58 mmol) in anhydrous THF (10 mL) were added
µ
−
to the solution. The mixture was stirred for a further 1 h and poured into saturated aqueous NH4Cl.
The resulting mixture was extracted with EtOAc, and the combined organic extracts were dried,
filtered, and concentrated under reduced pressure. Flash chromatography (8:2 hexane-EtOAc) of the
resulting oil gave the seleno derivative
1718 (CO); 1H-NMR (300 MHz, CDCl3):
7
δ
(1.79 g, 83% yield) as a yellow foam: IR (ATR Pike)
= 1.27 (t, J = 7.2 Hz, 3H, CH2CH3), 1.54 [s, 9H, (CH3)3C], 1.73
ν
(cm−1):
(m, 1H, H-5), 1.84 (m, 1H, H-5), 2.01 (ddd, J = 13.8, 10.2, 5.7 Hz, 1H, H-4), 2.28 (dt, J = 13.8, 6.0 Hz, 1H,
H-4), 3.52 (m, 1H, H-6), 3.61 (ddd, J = 13.2, 8.4, 5.4 Hz, 1H, H-6), 4.22 (qd, J = 7.2, 3.3 Hz, 2H, CH2CH3),
7.31 (t, J = 7.2, 2H, HAR), 7.41 (t, J = 7.2 Hz, 1H, HAR), 7.65 (t, J = 7.2 Hz, 2H, HAR); HRMS (ESI) calcd
for [C19H25NO5Se + Na+]: 450.0787, found: 450.0788.
1-(tert-Butoxycarbonyl)-3-(ethoxycarbonyl)-5,6-dihydro-2(1H)-pyridone (
8). H2O2 (900
µl, 29.35 mmol) and
pyridine (405 l, 5.03 mmol) were added at room temperature to a solution of seleno lactam
µ
7
(1.79 g,
4.19 mmol) in CH2Cl2 (300 mL), and the resulting solution was stirred at room temperature for 30
minutes. Water was then added, and the mixture was extracted with CH2Cl2. The combined organic
extracts were dried, filtered, and concentrated under reduced pressure. Flash chromatography (8:2
hexane-EtOAc) of the resulting oil gave unsaturated lactam
(ATR Pike)
(cm−1): 1715 (CO); 1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
3H, CH2CH3), 1.54 [s, 9H, (CH3)3C], 2.52 (td, J = 6.4, 4.4 Hz, 2H, H-5), 3.88 (t, J = 6.4 Hz, 2H, H-6),
4.29 (q, J = 6.8 Hz, 2H, CH2CH3), 7.48 (t, J =.4 Hz, 1H, H-4); 13C-NMR (100.6 MHz, CDCl3):
= 14.1
8
(981 mg, 87% yield) as a yellow foam: IR
ν
δ
= 1.33 (t, J = 6.8 Hz,
δ
(CH2CH3), 24.7 (C-5), 28.0 [(CH3)3C], 43.0 (C-6), 61.5 (CH2CH3), 83.6 [(CH3)3C], 130.9 (C-3), 148.5 (C-4),
160.0 (CO), 164.0 (CO); HRMS (ESI) calcd for [C13H19NO5 + Na+]: 292.1155, found: 292.1166.
3.3. General Procedure for the Double Michael Addition Reactions
A solution of unsaturated lactam 6a
,
b
,
c
or
8
(1 equiv.) in anhydrous CH2Cl2, MeCN or MeOH was
or 15) and Cs2CO3
added at 0 ◦C under an argon atmosphere to a solution of the Nazarov reagent (
9

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or KF in anhydrous CH2Cl2, MeCN or MeOH, and the resulting mixture was allowed to warm slowly
to room temperature. After 20 h of stirring at room temperature, the mixture was concentrated under
reduced pressure. Flash chromatography (9:1 hexane-EtOAc) of the residue afforded the corresponding
adduct/s (10a,b, 12a,b, 16a,b,c or 17) as yellow foams (detailed data in supplementary materials).
cis-2-(tert-Butoxycarbonyl)-6-hydroxy-5-(methoxycarbonyl)-8-methyl-1-oxo-8a-(phenylsulfonyl)-1,2,3,4,4a,
7,8,8a-octahydroisoquinolines 10a and 10b. Operating as described above in the general procedure, from
unsaturated lactam 6a (800 mg, 2.28 mmol) in anhydrous CH2Cl2 (200 mL), Nazarov reagent
9 (1.07 g,
7.5 mmol), and Cs2CO3 (4.9 g, 15 mmol) in anhydrous CH2Cl2 (250 mL), cis-hydroisoquinolones
10a (cis Me/SO2Ph isomer) and 10b (trans Me/SO2Ph isomer) were obtained (ratio 3:1, 890 mg, 79%
yield). Compound 10a: IR (ATR Pike)
COSY, g-HSQC): = 1.08 (d, J = 6.4 Hz, 3H, CH3), 1.50 [s, 9H, (CH3)3C], 1.89 (m, 1H, H-7), 2.32 (dm,
ν
(cm−1): 1727 (CO), 1654 (CO); 1H-NMR (400 MHz, CDCl3,
δ
J = 14.8 Hz, 1H, H-4), 2.40 (m, 2H, H-8, H-7), 2.70 (dddd, J = 14.8, 13.6, 5.2, 3.6 Hz, 1H, H-4), 3.23 (td,
J = 12.8, 4.0 Hz, 1H, H-3), 3.74 (dm, J = 12.8 Hz, 1H, H-3), 3.82 (s, 3H, CH3O) 3.92 (br. s, 1H, H-4a),
7.49 (td, J = 7.6, 2.0 Hz, 2H, HAR), 7.63 (td, J = 7.6, 1.2 Hz, 1H, HAR), 7.96–7.99 (dd, J = 7.6, 1.2 Hz,
2H, HAR); 13C-NMR (100.6 MHz, CDCl3):
δ = 14.0 (CH3), 23.3 (C-4), 27.8 [(CH3)3C], 29.3 (C-4a), 30.8
(C-8), 35.0 (C-7), 42.9 (C-3), 51.8 (CH3O), 77.4 (C-8a), 83.6 [(CH3)3C], 96.6 (C-5), 128.3 (2CHAR), 130.9
(2CHAR), 134.1 (CHAR), 137.0 (CAR), 151.8 (CO), 167.1 (CO), 171.5, 171.6 (CO, C-6); HRMS (ESI) calcd
1
for [C23H29NO8S + Na+]: 502.1506, found: 502.1511. Compound 10b: H-NMR (400 MHz, CDCl3,
COSY, g-HSQC): δ = 1.06 (d, J = 6.8 Hz, 3H, CH3), 1.53 [s, 9H, (CH3)3C], 1.69 (ddd, J = 13.2, 3.6, 1H,
H-4), 2.17 (d, J = 18.4 Hz, 1H, H-7), 2.44 (dd, J = 14.0, 2.8 Hz, 1H, H-4), 2.79 (m, 1H, H-8), 3.15 (dd,
J = 18.0, 6.0 Hz, 1H, H-7), 3.39 (td, J = 12.8, 3.2 Hz, 1H, H-3), 3.71 (dd, J = 12.8, 1.2, 1H, H-4a), 3.86 (s, 3H,
CH3O) 3.94 (dt, J = 12.4, 2.4 Hz, H-3), 7.54 (t, J = 7.2 Hz, 2H, HAR), 7.68 (td, J = 8.0, 1.2 Hz, 1H, HAR),
7.89 (d, J = 8.0 Hz, 2H, HAR); 13C-NMR (100.6 MHz, CDCl3):
δ = 20.4 (CH3), 27.7 (C-4), 27.9 [(CH3)3C],
30.1 (C-8), 33.2 (C-7), 33.2 (C-4a), 45.7 (C-3), 51.8 (CH3O), 77.9 (C-8a), 83.5 [(CH3)3C], 96.8 (C-5), 128.5
(2CHAR), 131.0 (2CHAR), 134.3 (CHAR), 134.9 (CAR), 151.5 (CO), 166.3 (CO), 171.0, 171.8 (CO, C-6).
cis-6-Hydroxy-5-(methoxycarbonyl)-2,8-dimethyl-1-oxo-8a-(phenylsulfonyl)-1,2,3,4,4a,7,8,8a-octahydroiso-
quinolines 12a and 12b. Operating as described in the general procedure, from unsaturated lactam 6b
(220 mg, 0.87 mmol) in anhydrous MeOH (160 mL), Nazarov reagent 9 (372 mg, 2.62 mmol), and KF
(304 mg, 5.24 mmol) in anhydrous MeOH (10 mL), cis-hydroisoquinolones 12a (cis Me/SO2Ph isomer)
and 12b (trans Me/SO2Ph isomer) were obtained (ratio 1:5, 175 mg, 51% yield). Compound 12a: IR
(ATR Pike)
ν δ = 1.09 (d, J = 6.8 Hz,
(cm−1): 1646 (CO); 1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
3H, CH3), 1.90 (dd, J = 18.5, 2.0 Hz, 1H, H-7), 2.30 (dq, J = 17.6, 2.4 Hz, 1H, H-4), 2.39 (dm, J = 18.5 Hz,
1H, H-7), 2.48 (m, 1H, H-8), 2.67-2.73 (m, 1H, H-4), 2.96 (s, 3H, CH3N), 3.21 (m, 2H, H-3), 3.84 (s, 3H,
CH3O), 7.53 (t, J = 7.6 Hz, 2H, HAR), 7.65 (t, J = 7.2 Hz, 1H, HAR), 8.07 (dd, J = 7.6 Hz, 1H, HAR), 12.34
(s, 1H, OH); 13C-NMR (100.6 MHz, CDCl3):
δ = 13.8 (CH3), 23.0 (C-4), 29.6 (C-4a), 30.5 (C-8), 35.3 (C-7),
35.8 (NCH3), 46.3 (C-3), 51.8 (CH3O), 75.5 (C-8a), 96.6 (C-5), 128.3 (2CHAR), 131.0 (2CHAR), 133.9
(CHAR), 138.0, (CAR), 165.0 (CO), 171.9 (C-6, CO); HRMS (ESI) calcd for [C19H23NO6S + H+]: 394.1319,
1
found: 394.1323. Compound 12b: H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
δ
= 1.02 (d, J = 7.2 Hz,
3H, CH3), 1.69 (qd, J = 12.8, 4.4 Hz, 1H, H-4), 2.16 (dd, J = 18.0, 1.6 Hz, 1H, H-7), 2.32 (dm, J = 12.8 Hz,
1H, H-4), 2.77 (s, 3H, CH3N), 3.04 (t, J = 6.8 Hz, 1H, H-8), 3.04–3.10 (m, 2H, H-7, H-3), 3.25 (td, J = 13.2,
4.0 Hz, 1H, H-3), 3.60 (dd, J = 12.8, 4.0 Hz, 1H, H-4a), 3.81 (s, 3H, CH3O), 7.51 (t, J = 7.6 Hz, 2H, HAR),
7.62 (t, J = 7.2 Hz, 1H, HAR), 7.90 (t, J = 7.2 Hz, 1H, HAR), 12.2 (s, 1H, OH); 13C-NMR (100.6 MHz,
CDCl3):
δ = 20.6 (CH3), 28.1 (C-4), 29.7 (C-8), 33.2 (C-7), 33.9 (C-4a), 35.8 (CH3N), 48.8 (C-3), 51.8
(CH3O), 75.8 (C-8a), 97.4 (C-5), 128.3 (CHAR), 130.8 (CHAR), 133.9 (C-3), 136.7, (CAR), 164.9 (CO), 171.1
(C-6), 171.9 (CO).
cis-2-(tert-Butoxycarbonyl)-6-hydroxy-5-(methoxycarbonyl)-1-oxo-8a-(phenylsulfonyl)-1,2,3,4,4a,7,8,8a-
octahydroisoquinoline (18a). Operating as described in the general procedure, from unsaturated lactam
6a (150 mg, 0.44 mmol) in anhydrous CH2Cl2 (65 mL), Nazarov reagent 17 (268 mg, 1.33 mmol),
and Cs2CO3 (865 mg, 2.66 mmol) in anhydrous CH2Cl2 (20 mL), cis-hydroisoquinolone 18a was

Molecules 2019, 24, 557
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obtained (96 mg, 47% yield): IR (ATR Pike)
ν
(cm−1): 1733 (C=O), 1653 (NCO); 1H-NMR (400 MHz,
CDCl3, COSY, g-HSQC):
δ = 1.55 [s, 9H, (CH3)3C)], 1.64 (m, 1H, H-4), 2.12–2.21 (m, 3H, 2H-7, H-8),
2.46-2.54 (m, 2H, H-8, H-4), 3.62-3.74 (m, 2H, 2H-3), 3.85 (s, 3H, CH3O), 3.96 (dd, J = 9.6, 3.6 Hz,
H-4a), 7.53 (t, J = 7.6 Hz, 2H, HAR), 7.68 (t, J = 7.6, 1.2 Hz, 1H, HAR), 7.86 (d, J = 7.6, 1.2 Hz, 2H,
HAR), 12.34 (s, 1H, OH); 13C-NMR (100.6 MHz, CDCl3):
δ = 25.8 (C-8), 26.4 (C-7), 27.9 [(CH3)3C], 28.3
(C-4), 32.6 (C-4a), 44.3 (C-3), 51.9 (CH3O), 74.1 (C-8a), 83.6 [(CH3)3C], 98.4 (C-5), 128.5 (2CHAR), 130.8
(2CHAR), 134.3 (CHAR), 135.0 (CAR), 151.8 (CO), 166.7 (CO), 171.5, 173.9 (CO, C-6); HRMS (ESI) calcd
for [C22H27NO8S + NH4+]: 483.1796, found: 483.1789.
cis-6-Hydroxy-5-(methoxycarbonyl)-2-methyl-1-oxo-8a-(phenylsulfonyl)-1,2,3,4,4a,7,8,8a-octahydroisoqui-
noline (18b). Operating as described in the general procedure, from unsaturated lactam 6b (60 mg,
0.24 mmol) in anhydrous CH2Cl2 (35 mL), Nazarov reagent 17 (144 mg, 0.71 mmol), and Cs2CO3
(469 mg, 1.44 mmol) in anhydrous CH2Cl2 (15 mL), cis-hydroisoquinolone 18b was obtained (32 mg,
35% yield): IR (ATR Pike)
ν δ = 1.97
(cm−1): 1653 (CO); 1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
(m, 1H, H-4), 2.00-2.15 (m, 3H, H-7, 2H-8), 2.35 (m, 1H, H-7), 2.46-2.54 (ddt, J = 13.8, 8.8, 4.2 Hz, 1H,
H-4), 2.93 (s, 3H, CH3N), 3.17 (ddt, J = 12.8, 9.4, 3.8 Hz, 1H, H-3), 3.27 (m, 1H, H-3), 3.84 (s, 3H, CH3O),
4.01 (dd, J = 6.4, 3.6 Hz, H-4a), 7.51 (t, J = 7.6, Hz, 2H, HAR), 7.64 (t, J = 7.6 Hz, 1H, HAR), 7.88 (d, J = 7.6
Hz, 2H, HAR), 12.40 (s, 1H, OH); 13C-NMR (100.6 MHz, CDCl3):
δ = 26.1 (C-7), 26.2 (C-4), 27.2 (C-8),
32.1 (C-4a), 35.8 (CH3N), 46.9 (C-3), 51.8 (CH3O), 71.6 (C-8a), 97.7 (C-5), 128.6 (2CHAR), 130.1 (2CHAR),
133.8 (CHAR), 136.7 (CAR), 164.5 (CO), 171.8, 172.9 (CO, C-6); HRMS calcd for [C18H21NO6S + H+]:
380.1162, found: 380.1158.
cis-6-Hydroxy-5-(methoxycarbonyl)-1-oxo-8a-(phenylsulfonyl)-2-(p-toluenesulfonyl)-1,2,3,4,4a,7,8,8a-octa-
hydroisoquinoline (18c). Operating as described in the general procedure, from unsaturated lactam
6c (50 mg, 0.12 mmol) in anhydrous CH2Cl2 (20 mL), Nazarov reagent 17 (73 mg, 0.36 mmol) and
Cs2CO3 (234 mg, 0.72 mmol) in anhydrous CH2Cl2 (5 mL), cis-hydroisoquinolone 18c was obtained
(20 mg, 32% overall yield for the three steps). IR (ATR Pike)
CDCl3, COSY, g-HSQC): = 1.85 1.93 (m, 2H, H-4, H-7), 1.99-2.04 (m, 2H, H-7, H-8), 2.29-2.35 (m, 1H,
ν
(cm−1): 1653 (CO); 1H-NMR (400 MHz,
δ
−
H-8), 2.50 (s, 3H, CH3), 2.75-2.70 (m, 1H, H-4), 3.84 (s, 3H, CH3O) 3.91 (m, 1H, H-3), 4.01 (m, 1H, H-3),
7.22 -7.34 (m, 6H, HAR), 7.60 (td, J = 7.2, 1.2 Hz, 1H, HAR), 7.91 (d, J = 8.8 Hz, 2H, HAR), 12.34 (s, 1H,
OH); 13C-NMR (100.6 MHz, CDCl3):
δ = 21.7 (CH3), 25.7 (C-8), 27.0 (C-7), 28.3 (C-4), 31.9 (C-4a), 43.8
(C-3), 52.0 (CH3O), 73.1 (C-8a), 97.8 (C-5), 128.3-130.7 (CHAR), 134.3 (CHAR), 134.6, 135.2 (CAR, CHAR),
145.1 (CAR), 165.5 (CO), 171.4, 172.9 (CO, C-6); HRMS (ESI) calcd for [C24H25NO8S2 + H+]: 520.1094,
found: 520.1108.
cis-2-(tert-Butoxycarbonyl)-8a-(ethoxycarbonyl)-6-hydroxy-5-(methoxycarbonyl)-1-oxo-1,2,3,4,4a,7,8,8a-
octahydroisoquinoline (19). Operating as described in the general procedure, from unsaturated lactam
8
(90 mg, 0.33 mmol) in anhydrous CH2Cl2 (60 mL), Nazarov reagent 17 (202 mg, 1 mmol), and Cs2CO3
(652 mg, 2 mmol) in anhydrous CH2Cl2 (5 mL), cis-hydroisoquinolone 19 was obtained (87 mg, 60%
yield): IR (ATR Pike)
= 1.09 (d, J = 7.2 Hz, 3H, CH2CH3), 1.36 [s, 9H, CH3)3C], 1.51 (ddd, J = 14.0, 12.0, 4.8 Hz, 1H, H-4),
ν
(cm−1): 1725 (CO), 1654 (CO); 1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
δ
1.90 (ddd, J = 14.0, 11.2, 7.2 Hz, 1H, H-8), 2.03 (dq, J = 14.0, 3.6 Hz, 1H, H-4), 2.18 (ddd, J = 18.4, 7.2, 2.0
Hz, 1H, H-7), 2.32 (dd, J = 14.0, 7.2 Hz, 1H, H-8), 2.63 (ddd, J = 18.4, 10.4, 8.0 Hz, 1H, H-7), 3.31 (dd,
J = 11.6, 3.2 Hz, 1H, H-4a), 3.40 (td, J = 12.4, 3.6 Hz, 1H, H-3), 3.64 (s, 3H, CH3O), 3.66 (ddd, J = 12.4,
4.8, 3.2 Hz, 1H, H-3), 4.05 (qd, J = 7.2, 2.4 Hz, 2H, CH2CH3), 12.18 (s, 1H, OH); 13C-NMR (100.6 MHz,
CDCl3):
δ = 13.9 (CH2CH3), 24.6 (C-8), 26.3 (C-7), 27.5 (C-4), 27.9 [(CH3)3C], 34.7 (C-4a), 45.7 (C-3), 51.7
(CH3O), 56.1 (C-8a), 61.7 (CH2CH3), 83.4 [(CH3)3C], 98.0 (C-5), 152.7 (C-6), 170.4 (CO), 170.5 (CO),
171.9 (CO), 172.7 (CO); HRMS (ESI) calcd for [C19H27NO8 + Na+]: 420.1629, found: 420.1645.
3.4. General Procedure for the Desulfonylation Reactions
Na2HPO4 (50 equiv.) and sodium amalgam (25 equiv.) were added at
−
78 ◦C under an argon
atmosphere to a solution of the sulfonyl derivative 10a 12a or 12b (1 equiv.) in anhydrous methanol
,

Molecules 2019, 24, 557
12 of 14
(0.025 M), and the mixture was stirred at
−
78 ◦C for 2 h. The solution was then filtered and quenched
with H2O at low temperature. The mixture was concentrated under reduced pressure, and the resulting
aqueous solution was extracted with EtOAc. The combined organic extracts were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. Flash chromatography (9:1 hexane-EtOAc)
of the residue afforded the desulfurated compounds 13a, 14a or 14b (detailed data in supplementary
materials).
cis-2-(tert-Butoxycarbonyl)-6-hydroxy-5-(methoxycarbonyl)-8-methyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroiso-
quinoline (H-8/H-8a trans, 13a). Operating as described in the above general desulfonylation procedure,
from a solution of sulfonyl derivative 10a (580 mg, 1.21 mmol) in anhydrous methanol (50 mL),
Na2HPO4 (8.60 g, 60.6 mmol), and sodium amalgam (6.77 g, 30.3 mmol), compound 13a was obtained
1
(357 mg, 87% yield): H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
δ
= 1.05 (d, J = 6.0 Hz, 3H, CH3),
1.53 [s, 9H, (CH3)3C], 1.79 (dddd, J = 19.2, 12.8, 11.2, 4.8 Hz, 1H, H-4), 2.04 (m, 1H, H-7), 2.10 (m,
1H, H-4), 2.30 (m, 2H, H-8, H-8a), 2,46 (dd, J = 19.2, 4.8 Hz, 1H, H-7), 2.98 (dt, J = 11.2, 4.0 Hz, 1H,
H-4a), 3.41 (td, J = 12.8, 4.0 Hz, 1H, H-3), 3.70-3.75 (m, 1H, H-3), 3.79 (s, 3H, CH3O), 12.23 (s, 1H, OH);
13C-NMR (100.6 MHz, CDCl3):
δ = 18.8 (CH3), 26.9 (C-8), 27.1 (C-4), 27.9 [(CH3)3C], 32.0 (C-4a), 36.8
(C-7), 45.2 (C-3), 50.5 (C-8a), 51.6 (CH3O), 82.7 [(CH3)3C], 99.3 (C-5), 153.3 (CO), 169.0 (CO), 172.2,
173.1 (CO, C-6); HRMS (ESI) calcd for [C17H25NO6 + Na+]: 362.1574, found: 362.1579.
cis-6-Hydroxy-5-(methoxycarbonyl)-2-methyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline (H-8/H-8a trans,
14a). Operating as described in the general desulfonylation procedure, from a solution of sulfone
12a (100 mg, 0.25 mmol) in anhydrous MeOH (10 mL), Na2HPO4 (1.81 g, 12.7 mmol), and sodium
amalgam (1.42 g, 6.36 mmol), compound 14a was obtained (48 mg, 76% yield) as a white foam: IR
(ATR Pike)
ν δ = 1.09 (d, J = 7.2 Hz,
(cm−1): 1645 (CO); 1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
3H, CH3), 1.90 (m, 1H, H-4), 1.94–2.10 (m, 2H, H-4, H-7), 2.24 (m, 2H, H-8, H-8a), 2.38 (d, J = 18.4,
4.4 Hz, 1H, H-7), 2.90 (m, 1H, H-4a), 2.92 (s, 3H, CH3N), 3.21–3.25 (m, 2H, H-3), 3.79 (s, 3H, CH3O),
12.30 (s, 1H, OH); 13C-NMR (100.6 MHz, CDCl3):
δ = 19.2 (CH3), 26.5 (C-4), 27.4 (C-8a), 31.3 (C-4a),
34.8 (CH3N), 37.1 (C-7), 47.2 (C-8), 48.8 (C-3), 51.5 (CH3O), 99.1 (C-5), 170.7 (CO), 172.3 (C-6), 172.6
(CO); HRMS (ESI) calcd for [C13H20NO4 + H+]: 254.1387, found: 254.1387.
cis-6-Hydroxy-5-(methoxycarbonyl)-2-methyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline (H-8/H-8a cis,
14b). Operating as described in the general desulfonylation procedure, from a solution of sulfone
12b (340 mg, 0.87 mmol) in anhydrous MeOH (10 mL), Na2HPO4 (6.134 g, 43.2 mmol), and sodium
amalgam (4.836 g, 21.6 mmol), compound 14b was obtained (137 mg, 62% yield) as a white foam:
1H-NMR (400 MHz, CDCl3, COSY, g-HSQC):
δ = 1.05 (d, J = 7.2 Hz, 3H, CH3), 1.86 (qd, J = 12.0, 5.2,
1H, H-4), 2.10 (dm, J = 12.0 Hz, 1H, H-4), 2.19 (dd, J = 18.0, 2.0 Hz, 1H, H-7), 2.657-2.64 (m, 12H, H-8,
H-7), 2.67 (m, 1H, H-8a), 2.85–2.90 (m, 1H, H-4a), 3.00 (s, 3H, NCH3), 3.24 (dq, J = 12.0, 3.2 Hz, 1H,
H-3), 3.39 (td, J = 12.0, 4.4 Hz, 1H, H-3), 3.79 (s, 3H, CH3O), 12.48 (s, 1H, OH); 13C-NMR (100.6 MHz,
CDCl3):
δ = 18.8 (CH3), 26.6 (C-4), 29.4 (C-8a), 31.9 (C-4a), 34.9 (CH3N), 36.1 (C-7), 43.6 (C-8), 49.2 (C-3),
51.5 (CH3O), 98.0 (C-5), 171.2 (CO), 172.6 (C-6, CO).
3.5. General Procedure for the Removal of the N-Boc Substituent
TFA (1:3 TFA/CH2Cl2 ratio) was added to a solution of the N-Boc derivative 10a or 13a in
anhydrous CH2Cl2 (0.05-0.06 M), and the mixture was stirred for 30 minutes at room temperature.
Toluene (1 mL) was added to the resulting solution, and the mixture was concentrated under
reduced pressure. After a second addition of toluene (1 mL) and concentration of the mixture, flash
chromatography (7:3 to 3:7 hexane-EtOAc) of the residue afforded the deprotected compound 15 or 16
.
cis-6-Hydroxy-5-(methoxycarbonyl)-8-methyl-1-oxo-8a-(phenylsulfonyl)-1,2,3,4,4a,7,8,8a-octahydroisoqui-
noline (Me/SO2Ph cis, 15). Operating as described in the above general procedure, from a solution of the
N-Boc derivative 10a (23 mg, 0.048 mmol) in anhydrous CH2Cl2 (750 L) and TFA (250 L), compound
15 was obtained (18 mg, 98% yield): IR (ATR Pike)
(cm−1): 3352 (NH), 1668 (CO); 1H-NMR (400
µ
µ
ν

Molecules 2019, 24, 557
13 of 14
MHz, CDCl3, COSY, g-HSQC):
δ
= 1.11 (d, J = 6.8 Hz, 3H, CH3), 1.94 (dd, J = 17.6, 2.0 Hz, H-7), 2.32
(dm, J = 14.8 Hz, 1H, H-4), 2.45 (m, 1H, H-8), 2.50 (dm, J = 17.6 Hz, 1H, H-7), 2.65 (dddd, J = 14.8, 12.4,
5.6, 3.6 Hz, 1H, H-4), 3.16 (td, J = 12.4, 4.4 Hz, 1H, H-3), 3.27 (m, 1H, H-3), 3.85 (s, 3H, CH3O), 3.97
(br.s, 1H, H-4a), 6.29 (br.s, 1H, NH), 7.53 (t, J = 7.2, Hz, 2H, HAR), 7.65 (t, J = 7.2 Hz, 1H, HAR), 8.06
(d, J = 7.2 Hz, 2H, HAR), 12.33 (s, 1H, OH); 13C-NMR (100.6 MHz, CDCl3):
δ = 13.7 (CH3), 22.4 (C-4),
29.2 (C-4a), 30.1 (C-8), 35.2 (C-7), 38.7 (C-3), 51.8 (CH3O), 75.1 (C-8a), 96.5 (C-5), 128.3 (2CHAR), 130.6
(2CHAR), 134.0 (CHAR), 137.7 (CAR), 167.0 (CO), 171.6, 171.8 (CO, C-6); HRMS calcd for [C18H21NO6S
+ H+]: 380.1162, found: 380.1164.
cis-6-Hydroxy-5-(methoxycarbonyl)-8-methyl-1-oxo-1,2,3,4,4a,7,8,8a-octahydroisoquinoline (H-8/H-8a trans,
16). Operating as described in the above general procedure, from a solution of the N-Boc derivative
13a (10 mg, 0.03 mmol) in anhydrous CH2Cl2 (600
(7 mg, 99% yield): IR (ATR Pike)
(cm−1): 3340 (NH), 1659 (CO); 1H-NMR (400 MHz, CDCl3, COSY,
g-HSQC): = 1.12 (d, J = 6.8 Hz, 3H, CH3), 1.83 (m, 1H, H-4), 1.98 (dd, J = 13.6, 3.6 Hz, 1H, H-4), 2.06
µL) and TFA (200 µL), compound 16 was obtained
ν
δ
(dd, J = 18.4, 8.8 Hz, H-7), 2.23 (m, 2H, H-8, H-8a), 2.42 (dd, J = 18.4, 4.8 Hz, 1H, H-7), 2.93 (m, 1H,
H-4a), 3.23-3.40 (m, 2H, H-3), 3.79 (s, 3H, CH3O), 6.22 (br.s, 1H, NH), 12.29 (s, 1H, OH); 13C-NMR (100.6
MHz, CDCl3):
δ = 19.1 (CH3), 25.7 (C-4), 27.3 (C-8, C-8a), 31.0 (C-4a), 37.1 (C-7), 41.1 (C-3), 51.6 (CH3O),
99.1 (C-5), 172.2, 172.4 (CO, C-6); HRMS calcd for [C12H17NO4 + H+]: 240.1230, found: 240.1232.
Supplementary Materials: The following are available online. Copies of 1H, 13C, and NOE NMR spectra,
and crystallographic data for 10a (CCDC 1890851), 12a (CCDC 1890850), and 12b (CCDC 1890852). CCDC
1890850-1890852 contains the supplementary crystallographic data for this paper. These data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
Author Contributions: M.A. designed and planned the research; M.P. supervised the experimental work; F.A.
and C.A. performed the experimental work and characterized the compounds; E.M. carried out the X-ray analysis;
J.B. discussed the results and prepared the manuscript for publication.
Funding: This research was funded by the MINECO/FEDER, Spain (Project CTQ2015-65384-R).
Acknowledgments: Financial support from the MINECO/FEDER, Spain (Project CTQ2015-65384-R) is gratefully
acknowledged. Thanks are also due to the MINECO (Spain) for a fellowship to F. A. (AP2010-1663). We also
acknowledge the networking contribution from the COST Action CM1407.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).