Catalytic Asymmetric 1,3-Dipolar Cycloaddition/Hydroamination Sequence: Expeditious Access to Enantioenriched Pyrroloisoquinoline Derivatives

Article abstract of DOI:10.1021/acs.joc.7b01927

A three-step reaction sequence has been developed to prepare a variety of enantioenriched pyrroloisoquinoline derivatives. The process involves a catalytic asymmetric azomethine ylide 1,3-dipolar cycloaddition followed by an intramolecular Au^I-catalyzed alkyne hydroamination and enamine reduction.

Full text of DOI:10.1021/acs.joc.7b01927

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Note
Catalytic Asymmetric 1,3-Dipolar Cycloaddition/hydroamination Sequence:
Expeditious Access to Enantioenriched Pyrroloisoquinoline Derivatives
Alba Molina, Ana Pascual-Escudero, Javier Adrio, and Juan C. Carretero
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01927 • Publication Date (Web): 21 Sep 2017
Downloaded from http://pubs.acs.org on September 21, 2017
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The Journal of Organic Chemistry
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Catalytic Asymmetric 1,3ꢀDipolar
Cycloaddition/hydroamination Sequence: Expeditious
Access to Enantioenriched Pyrroloisoquinoline
Derivatives
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Alba Molina,a Ana Pascual-Escudero,a Javier Adrio,a,b* and Juan C. Carreteroa,b *
aDepartamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid,
Cantoblanco, 28049 Madrid, Spain
bInstitute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid,
28049 Madrid, Spain
javier.adrio@uam.es, juancarlos.carretero@uam.es
ABSTRACT: A three step reaction sequence has been developed to prepare a variety of
enantioenriched pyrroloisoquinoline derivatives. The process involves a catalytic asymmetric
azomethine ylide 1,3ꢀdipolar cycloaddition followed by an intramolecular AuI catalyzed alkyne
hydroamination and enamine reduction.
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Nitrogen containing heterocycles are present in countless natural products and have been used as
privileged structures in the search of novel therapeutic agents based in small molecules.1 Consequently,
the development of processes that allow the concise construction of structurally diverse azaꢀheterocycles
is a central synthetic goal that is currently intensively investigated. The pyrroloisoquinoline unit is an
important motif, present in a family of natural occurring alkaloids with relevant biological activities. For
example, Crispine A2, displays important cytotoxic properties, Harmicine3 shows strong antiꢀleishmania
activity, Erysotramidine4 exhibits hypotensive, sedative and anticonvulsive properties, and Lamellarins,
a family of marine natural products,5 possess promising antitumor activities (Figure 1). Furthermore,
some unnatural derivatives containing this heterocyclic system also display potential pharmacological
properties.6
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Figure 1. Selected natural products containing the pyrroloisoquinoline scaffold
The interest of this kind of compounds has encouraged the search of effective approaches for the
construction of this skeleton, and several powerful methods for their synthesis have been established.
Among them, the 1,3ꢀdipolar cycloaddition has played a prevalent role due to its versatility and high
atom economy. More specifically, several efficient procedures for the synthesis of racemic
pyrrolidinoisoquinoline derivatives by cycloaddition of cyclic azomethine ylides and activated alkenes
have been reported. These approaches involve different methods for the formation of the required
isoquinoline derived dipole, which can be generated by inter7 or intramolecular8 Nꢀalkylation of imines
(Scheme 1, eq. 1 and eq. 2), via metal catalyzed 6ꢀexo cyclization of alkynyliminoesters9 (Scheme 1, eq.
3) or by metal or photocatalyzed oxidation of the corresponding tetrahydroisoquinoline precursor
(Scheme 1, eq. 4).10
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However, to the best of our knowledge, catalytic asymmetric procedures to the synthesis of
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enantioenriched pyrroloisoquinolines have not been yet developed using this general cycloaddition
approach, despite of the catalytic asymmetric 1,3ꢀdipolar cycloaddition of azomethine ylides is one of
the most straightforward methods for the preparation of enantioenriched pyrrolidines.11
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Scheme 1. Synthesis of pyrroisoquinoline derivatives by 1,3ꢀdipolar cycloaddition of azomethine ylides.
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Previous work: non enantioselective procedures
+
Cl
CO2Et
(eq.1)
(eq.2)
N
R1
R1
N
CO2R
R1
Z
Z
N
CO2Et
N
CO2Et
(eq.3)
N
CO2Et
Z
Z
Br
H2N
references 7-10
CO2Et
+
(eq.4)
CHO
This work: catalytic asymmetric procedure
RO
Z
CO2Et
R1
N
CO2R
NH
O
R1
Z
Z
R1
CO2R
N
R1
[Cu]
[Cu+]
L*
Z
N
1) [Au+]
2) [H-]
(eq. 5)
Z
Z
In connection with our previous work in metalꢀcatalyzed asymmetric [3+2] cycloadditions of
azomethine ylides,12 we set out to explore the application of this methodology to the enantioselective
synthesis of pyrroloisoquinolines. Taking into account that the excellent enantioinduction obtained in
this reaction relays on the formation of a five membered metallacycle by coordination of the oxygen and
nitrogen atoms of the iminoester to the chiral metal complex, we postulated that a catalytic asymmetric
1,3ꢀdipolar cycloaddition/hydroamination sequence from an orthoꢀalkynylaryl αꢀiminoester (Scheme 1,
eq. 5) may enable the enantioselective preparation of the challenging pyrroloisoquinoline motif. We
report herein the development of this approach by means of an asymmetric CuI catalyzed 1,3ꢀdipolar
cycloaddition followed by AuI catalyzed intramolecular alkyne hydroamination as key steps.
To explore the viability of this strategy, we selected as model reaction the cycloaddition between the
iminoester 1a (prepared by Sonogashira reaction of 2ꢀbromobenzaldehyde with 1ꢀhexyne followed by
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condensation with methyl glycinate) and Nꢀmethylmaleimide (2) (Table 1). As starting point we used
the conditions previously reported by our research group [Cu(CH3CN)4PF6 as metal source, (R)ꢀ
Fesulphos as ligand, Et3N as base and THF as solvent].13 This reaction afforded the expected adduct
endoꢀ3a with nearly complete diastereoselectivity (endo/exo = >20/1) and excellent enantiocontrol14
(98% ee) albeit modest isolated yield (56%, Table 1, Entry 1). The use of AgOAc as metal source
improved the yield but at the expense of the enantioselectivity (Entry 2). Other combinations of chiral
ligands, solvents and bases were also tested in the reaction although with less satisfactory results (see
Supporting Information for details). Kobayashi and coꢀworkers have recently described a highly
reactive catalyst system for a related 1,3ꢀdipolar cycloaddition based on the generation of a chiral
copper amide/Fesulphos complex.15 Gratifyingly, using Kobayashi´s conditions the yield increased to
77% as well as preserving an excellent enantioselectivity (Entry 3). The reaction can be also performed
using a lower catalyst loading (5 mol% instead of 10 mol%) albeit with lower chemical efficiency and
enantiocontrol (Entry 4).
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Table 1: Optimization experiments for the model 1,3ꢀdipolar cycloaddition with (R)ꢀFesulphos as
ligand.
Entry
1
[M]
Base
Et3N
Yield (%)a,b
56
ee (%)c
d
CuPF6
98
2
3
AgOAc
CuOTfe
CuOTfe
Et3N
70
77
52
88
≥ 99
90
KHMDS
KHMDS
4f
aIsolated yield after chromatographic purification. bOnly the endo adduct was observed by 1H-
c
e
NMR in the crude mixtures. ee determined by HPLC. dCu(CH3CN)4PF6. CuOTf = CuOTf. 0.5
toluene complex. f5 mol% of catalyst.
Next, we focus our attention to the subsequent intramolecular alkyne hydroamination. This process
has been widely applied for the construction of nitrogen containing heterocycles and many metal
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catalysts has showed activity in this reaction.16 After a survey of metal salts and ligands, we found that
the desired enamine product 6a was cleanly formed using commercialy available cationic gold complex
JohnPhosAu 5 as catalyst.17 However, the silicaꢀgel chromatographic purification of this tetracyclic
enamine 6a was problematic due to its instability. Thus, it was stereoselectively transformed into the
corresponding tetrahydroisoquinoline 7a by “in situ” reduction of the enamine moiety with NaBH3CN
under acid conditions (HCl 5%, MeOH), providing 7a in 65% isolated overall yield, preserving as
expected the high enantioselectivity (≥99 % ee, Scheme 2).
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Scheme 2. Hidroamination/enamine reduction sequence.
With this optimal reaction conditions in hands, we studied the scope of the process with regard to the
substitution at the azomethine precursor. As summarized in Scheme 3, iminoesters 1bꢀj with different
substituents at the alkyne and the aromatic ring were investigated. The cyclohexylethynyl and
phenylethynyl derivatives 1b and 1c furnished the corresponding pyrrolidines (endoꢀ3b and endoꢀ3c) in
high yield and excellent enantioselectivity. The cycloaddition of iminoesters (1dꢀe) bearing electron rich
aromatic alkyne substituents proceeded similarly giving rise the desired endoꢀpyrrolidines 3d and 3e as
the only detectable isomers with excellent enantiocontrol (96% and ꢀ≥99% ee, respectively). The
presence of a heteroaromatic substituent such as thiophenyl unit is also well tolerated albeit with
incomplete endoꢀselectivity (adduct 3f, endo/exo 88/12).18
Electronically diverse substrates having different substituents at the aromatic ring such as Me, OMe or
F also provided the corresponding adducts (3gꢀi) with good enantioselectivity under the reaction
conditions. The procedure can be also applied to alanineꢀbased dipoles (R4= Me, endoꢀ3j) with good
enantioselectivity (89% ee).
The subsequent intramolecular one pot goldꢀcatalyzed hydroamination/reduction reaction sequence
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took place generally with reasonable yields (45ꢀ76% yield) providing the desired highly enantioenriched
pyrroloisoquinoline derivatives (7bꢀi) with very high cisꢀdiastereoselectivities. On the other hand, the
reaction of pyrrolidine 3j with a quaternary stereocenter at Cꢀ2 proved less diastereoselective.19
The relative and absolute configuration of the adducts endoꢀ3 was established based on the results
previously obtained by our research group using the CuI/(R)ꢀFesulphos catalytic system,13,14 while the
relative configuration of products 7 having five stereogenic centres was unequivocally established by Xꢀ
ray diffraction analysis of 7d.20
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Scheme 3. Scope of the cycloaddition/hydroamination/reduction sequence. a,b
Me
N
Me
N
Me
N
O
O
N
O
O
O
O
a) 5 (10 mol%)
THF, rt, 18 h
CuOTf/KHMDS
(10 mol%)
R4
R4
R3
R2
R4
2
R3
R2
CO2Me
L* (11 mol%)
CO2Me
b) NaBH3CN
R3
R2
N
N
H
CO Me
THF, rt, 18 h
2
HCl 5%/MeOH
0ºC, 1h
R1
L* = (R)-Fesulphos
R1
7b-j
R1
endo-3b-j
1b-j
b
aIsolated yield after chromatographic purification. ee determined by HPLC for adducts
3 (products 7 are assumed to have the same ee than the corresponding precursor 3).
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Next, we extended the scope of this asymmetric [3+2] cycloaddition/hydroamination sequence to the
use of transꢀbissulfonylethylene 8 as dipolarophile. The reaction of iminoester 1a (R= Me) or 1k (R=
tBu) under the optimized conditions afforded efficiently the corresponding bissulfonyl pyrrolidine 9
with high exoꢀdiastereoselectivity13b and enantioselectivity (96% and 89% ee, respectively, Scheme 4).
However, the intramolecular one pot hydroamination/reduction sequence did not afford the desired
pyrroloisoquinolines due to the formation of a complex mixture of products after isolation and analysis
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by HꢀNMR. Assuming a low stability of the expected pyrroloisoquinoline 11, DBU was added to the
reaction mixture after the reduction step in order to promote the in situ basic elimination of the sulfonyl
groups. Under these conditions the pyrroloisoquinoline 12a was obtained in 55% yield but with low
enantioselectivity (34% ee, Scheme 4), showing that the reduction of the enamine moiety in
intermediate 10a was much less cisꢀdiatereoselctive than in the case of the maleimide adducts.
Replacing the methyl ester with the more sterically demanding tꢀbutyl ester resulted in a significant
improvement in the enantioselectivity (product 12k, 65% ee).
Scheme 4. Reactions with transꢀbissulfonylethylene.
In conclusion, a practical procedure for the enantioselective synthesis of pyrroloisoquinoline derivatives
has been developed using the catalytic asymmetric 1,3ꢀdipolar cycloaddition of alkynyl substituted
azomethine ylides as key step. In the presence of CuI/(R)ꢀFesulphos as catalyst system the pyrrolidine
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adducts were obtained with very high diastereoselectivity and excellent enantioselectivity. The
subsequent one pot gold catalyzed hydroamination/reduction sequence provided the desired
enantioenriched pyrroisoquinoline scaffolds in a straightforward manner.
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Experimental Section
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General procedures.
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All airꢀ and moistureꢀsensitive manipulations were carried out in anhydrous solvents and under argon
atmosphere. Dichloromethane, toluene, tetrahydrofuran and acetonitrile were dried over the PureSolv
MD purification system. Reactions were monitored by thinꢀlayer chromatography carried out on 0.25
mm silica gel plates (230ꢀ400 mesh). Flash column chromatographies were performed using silica gel
(230ꢀ400 mesh). NMR spectra were recorded on 300 or 500 MHz spectrometers and calibrated using
residual undeuterated solvent (CDCl3) as internal reference (δH = 7.26 ppm, δC = 77.16 ppm). HRMS
spectra were measured on a TOF mass spectrometer with electrospray ionization (ESI) as the ionization
source. αꢀIminoesters 1aꢀk were prepared by condensation of methyl glycinate hydrochloride and the
corresponding aldehydes.13 Aldehydes were prepared by Sonogashira coupling between 2ꢀ
bromobenzaldehyde and the corresponding alkyne, according to literature procedures.21 Due to their
lability, all αꢀiminoesters once isolated were immediately used in the 1,3ꢀdipolar cycloaddition without
further purification.
2ꢀ(Hexꢀ1ꢀynꢀ1ꢀyl)ꢀ4,5ꢀdimethoxybenzaldehyde: To a solution of Pd(CH3CN)2Cl2 (19.45 mg, 0.15
mmol), PPh3 (39.3 mg, 0.30 mmol), CuI (23.8 mg, 0.25 mmol) and 6ꢀbromoveratraldehyde (1.23 g, 5.0
mmol) in THF (6 mL) under nitrogen atmosphere, 1ꢀhexyne (0.48 mL, 246 mg, 6.0 mmol) and Et3N
(1.4 ml, 1.0 g, 10.0 mmol) were added and the resulting mixture was stirred for 12h at 50ºC. The
solution was filtered over Celite® and purified by silica gel flash chromatography (cyclohexaneꢀEtOAc
100:1) to afford 2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ4,5ꢀdimethoxybenzaldehyde (900.6 mg, 73%, brown oil, ) which was
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isolated together with 5% of the starting aldehyde. H NMR (300 MHz, CDCl3): δ 10.17 (s, 1H), 7.13
(s, 1H), 6.71 (s, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 2.28 (t, J = 7.0 Hz, 2H), 1.50 – 1.36 (m, 2H), 1.36 – 1.23
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13
(m, 2H), 0.77 (t, J = 7.2 Hz, 3H). C NMR (75 MHz, CDCl3): δ 190.5, 153.5, 149.0, 130.0, 122.5,
114.3, 107.8, 96.3, 76.0, 56.0, 55.82, 30.5, 22.0, 19.1, 13.5. HRMS (FB+): Calculated for C15H19O3,
247.1334; found, 247.1342 ([M+H], 20).
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Typical procedure for the synthesis of αꢀiminoesters. Methyl (E)ꢀNꢀ[(2ꢀ(hexꢀ1ꢀynꢀ1ꢀ
yl)phenyl)methylene]glycinate (1a): A suspension of methyl glycinate hydrochloride (1.60 g, 18.0
mmol), MgSO4 (2.17 g, 18.0 mmol) and Et3N (2.5 mL, 18.0 mmol) in dry dichloromethane (8 mL) was
stirred at room temperature for 30 minutes and 2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)benzaldehyde (1.78 g, 9.0 mmol) in
dichloromethane (2 mL) was added. After stirring 12h at room temperature the mixture was filtered and
water (10 mL) was added. The organic layer was separated and the aqueous phase was extracted with
dichloromethane (15 mL). The combined organic layers were washed with brine, dried over MgSO4,
filtered and evaporated under reduced pressure to afford 1a (1.49 g, 64%, brown oil), used without
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further purification in the next reaction step. H NMR (300 MHz, CDCl3): δ 8.70 (s, 1H), 7.97 (d, J =
7.8 Hz, 1H), 7.41 – 7.23 (m, 3H), 4.41 (s, 2H), 3.72 (s, 3H), 2.44 (t, J = 6.9 Hz, 2H), 1.62 – 1.49 (m,
2H), 1.49 – 1.37 (m, 2H), 0.97 – 0.85 (m, 3H).
Methyl (E)ꢀNꢀ[(2ꢀ(cyclohexylethynyl)phenyl)methylene]glycinate (1b): Following the typical
procedure, the reaction of methyl glycinate hydrochloride (239 mg, 1.9 mmol), MgSO4 (228 mg, 1.9
mmol), Et3N (0.26 mL, 1.9 mmol) and 2ꢀ(cyclohexylethynyl)benzaldehyde (201.9 mg, 0.95 mmol) in
dry dichloromethane (3 mL) afforded 1b (262 mg, 93%, yellow oil). 1H NMR (300 MHz, CDCl3): δ
8.81 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.45 – 7.27 (m, 3H), 4.45 (s, 2H), 3.79 (s, 3H), 2.72 – 2.58 (m,
1H), 1.97 – 1.83 (m, 2H), 1.82 – 1.69 (m, 2H), 1.64 – 1.49 (m, 3H), 1.45 – 1.31 (m, 3H).
Methyl (E)ꢀNꢀ[(2ꢀ(phenylethynyl)phenyl)methylene]glycinate (1c): Following the typical procedure,
the reaction of methyl glycinate hydrochloride (258 mg, 2.90 mmol), MgSO4 (349 mg, 2.90 mmol),
Et3N (404 µL, 2.90 mmol) and 2ꢀ(phenylethynyl)benzaldehyde (300 mg, 1.45 mmol) in dry
dichloromethane (3 mL) afforded 1c (242 mg, 87%, brown oil). 1H NMR (300 MHz, CDCl3): δ 8.94 (s,
1H), 8.19 (d, J = 7.0 Hz, 1H), 7.68 – 7.59 (m, 3H), 7.52 – 7.37 (m, 5H), 4.56 (s, 2H), 3.83 (s, 3H).
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Methyl (E)ꢀNꢀ[(2ꢀ(4ꢀtert-butylphenylethynyl)phenyl)methylene]glycinate (1d): Following the
typical procedure, the reaction of methyl glycinate hydrochloride (445 mg, 5.0 mmol), MgSO4 (601 mg,
5.0 mmol), Et3N (0.7 mL, 5.0 mmol) and 2ꢀ(4ꢀtertꢀbutylphenylethynyl)benzaldehyde (656 mg, 2.5
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8
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mmol) in dry dichloromethane (5 mL) afforded 1d (805 mg, 97%, brown oil). H NMR (300 MHz,
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CDCl3): δ 8.94 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 7.65 – 7.38 (m, 7H), 4.55 (s, 2H), 3.84 (s, 3H), 1.39 (s,
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9H).
Methyl (E)ꢀNꢀ[(2ꢀ(4ꢀmethoxyphenylethynyl)phenyl)methylene]glycinate (1e): Following the typical
procedure, the reaction of methyl glycinate hydrochloride (39.2 mg, 0.44 mmol), MgSO4 (53.0 mg, 0.44
mmol), Et3N (61.3µL, 0.44 mmol) and 2ꢀ(4ꢀmethoxyphenylethynyl)benzaldehyde (52.0 mg, 0.22 mmol)
1
in dry dichloromethane (1 mL) afforded 1e (60.8 mg, 90%, brown oil). H NMR (300 MHz, CDCl3): δ
8.94 (s, 1H), 8.23 – 8.12 (m, 1H), 7.62 – 7.37 (m, 5H), 6.99 – 6.92 (m, 2H), 4.53 (s, 2H), 3.87 (s, 3H),
3.83 (s, 3H).
Methyl (E)ꢀNꢀ[(2ꢀ(tiofenꢀ2ꢀylethynyl)phenyl)methylene]glycinate (1f): Following the typical
procedure, the reaction of methyl glycinate hydrochloride (89.1 mg, 1.0 mmol), MgSO4 (120.3 mg, 1.0
mmol), Et3N (139 µL, 1.0 mmol) and 2ꢀ(tiofenꢀ2ꢀylethynyl)benzaldehyde (106 mg, 0.5 mmol) in dry
dichloromethane (3 mL) afforded 1f (122 mg, 86%, brown oil). 1H NMR (300 MHz, CDCl3): δ 8.75 (s,
1H), 8.05 (d, J = 6.8 Hz, 1H), 7.57 – 7.24 (m, 5H), 7.03 – 6.93 (m, 1H), 4.43 (s, 2H), 3.72 (s, 3H).
Methyl (E)ꢀNꢀ[(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ5ꢀmethylphenyl)methylene]glycinate (1g): Following the typical
procedure, the reaction of methyl glycinate hydrochloride (57.0 mg, 0.64 mmol), MgSO4 (77.0 mg, 0.64
mmol), Et3N (89 µL, 0.64 mmol) and 2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ5ꢀmethylbenzaldehyde (64.0 mg, 0.32 mmol) in
1
dry dichloromethane (1 mL) afforded 1g (72.4 mg, 83%, brown oil). H NMR (300 MHz, CDCl3): δ
8.66 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.19 – 7.08 (m, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.35 (s, 2H), 3.69
(s, 3H), 2.43 – 2.33 (m, 2H), 2.24 (s, 3H), 1.59 – 1.30 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).
Methyl (E)ꢀNꢀ[(5ꢀfluoroꢀ2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)phenyl)methylene]glycinate (1h): Following the typical
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procedure, the reaction of methyl glycinate hydrochloride (133.6 mg, 1.5 mmol), MgSO4 (210 mg, 1.8
mmol), Et3N (209 µL, 1.5 mmol) and 5ꢀfluoroꢀ2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)benzaldehyde (204 mg, 1.0 mmol) in
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dry dichloromethane (3 mL) afforded 1h (274 mg, 99%, brown oil). H NMR (300 MHz, CDCl3): δ
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8
8.71 (s, 1H), 7.74 (dd, J = 9.5, 2.5 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.05 (td, J = 8.3, 2.6 Hz, 1H), 4.45 (s,
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2H), 3.78 (s, 3H), 2.55 – 2.40 (m, 2H), 1.67 – 1.36 (m, 4H), 1.01 – 0.86 (m, 3H).
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Methyl (E)ꢀNꢀ[(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ4,5ꢀdimethoxyphenyl)methylene]glycinate (1i): Following the
general procedure, the reaction of methyl glycinate hydrochloride (0.4 g, 5.0 mmol), MgSO4 (0.60 g, 5.0
mmol), Et3N (0.7 mL, 5.0 mmol) and 2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ4,5ꢀdimethoxybenzaldehyde (0.6 g, 2.5 mmol)
in dry dichloromethane (5 mL) afforded 1i (0.7 g, 91%, brown oil). 1H NMR (300 MHz, CDCl3): δ 8.68
(s, 1H), 7.53 (s, 1H), 6.85 (s, 1H), 4.41 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.76 (s, 3H), 2.43 (t, J = 7.0
Hz, 2H), 1.65 – 1.40 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H).
Methyl (E)ꢀNꢀ[(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)phenyl)methylene]alaninate (1j): Following the typical procedure,
the reaction of methyl alaninate hydrochloride (0.30 g, 2.2 mmol), MgSO4 (0.26 g, 2.2 mmol), Et3N (0.3
mL, 2.2 mmol) and 2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀbenzaldehyde (0.20 g, 1.1 mmol) in dry dichloromethane (5 mL)
afforded 1j (0.27 g, 92%, brown oil). 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1H), 8.21 – 7.94 (m, 1H),
7.47 – 7.39 (m, 1H), 7.40 – 7.28 (m, 2H), 4.23 (q, J = 6.8 Hz, 1H), 3.78 (s, 3H), 2.50 (t, J = 6.9 Hz, 2H),
1.74 – 1.44 (m, 7H), 0.99 (t, J = 7.2 Hz, 3H).
tertꢀButyl (E)ꢀNꢀ[(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)phenyl)methylene]glycinate (1k): Following the typical
procedure, the reaction of tertꢀbutyl glycinate hydrochloride (0.36 g, 2.2 mmol), MgSO4 (0.26 g, 2.2
mmol), Et3N (0.3 mL, 2.2 mmol) and 2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀbenzaldehyde (0.2 g, 1.1 mmol) in dry
1
dichloromethane (5 mL) afforded 1k (0.27 g, 89%, brown oil). H NMR (300 MHz, CDCl3): δ 8.77 (s,
1H), 8.08 (d, J = 7.1 Hz, 1H), 7.41 (d, J = 7.0 Hz, 1H), 7.37 – 7.24 (m, 2H), 4.35 (s, 2H), 2.46 (t, J = 6.9
Hz, 2H), 1.70 – 1.52 (m, 4H), 1.50 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H).
Typical procedure for the asymmetric [3+2] cycloaddition of azomethine ylides with Nꢀ
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methylmaleimide.
(1S,3R,3aS,6aR)ꢀ
Methyl
3ꢀ(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)phenyl)ꢀ5ꢀmethylꢀ4,6ꢀ
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dioxooctahydropyrrolo [3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3a): A suspension of (R)ꢀFesulphos (5.04
mg, 0.011 mmol), CuOTf. 0.5 toluene complex (5.17 mg, 0.01 mmol) and KHMDS (1.99 mg, 0.01
mmol) in THF (1 mL) under argon atmosphere was heated at 40ºC for 1h (Kobayashi´s conditions15).
The resulting mixture was cooled to room temperature and solutions of 1a (33.5 mg, 0.13 mmol) in THF
(1 mL) and Nꢀmethylmaleimide (11.1 mg, 0.10 mmol) in THF (1 mL) were successively added. After
18h at room temperature, the mixture was diluted with dichloromethane and filtered over Celite®. The
crude was concentrated under reduced pressure and purified by silica gel flash chromatography
(cyclohexaneꢀEtOAc 3:1) to afford endoꢀ3a (28.7 mg, 77%, brown oil). [α]D20: ꢀ 65.7 (c = 0.10, CHCl3),
≥ 99% ee. HPLC: Daicel Chiralpak ASꢀH, hexaneꢀisopropanol 80ꢀ20, flow rate 0.7 mL/min (λ = 254
nm), tR: 18.6 min (1S,3R,3aS,6aR)ꢀ3a and 28.9 min (1R,3S,3aR,6aS)ꢀ3a. 1H NMR (300 MHz, CDCl3): δ
7.52 – 7.48 (m, 1H), 7.48 – 7.43 (m, 1H), 7.33 – 7.27 (m, 2H), 4.89 (d, J = 8.2 Hz, 1H), 4.12 (d, J = 6.7
Hz, 1H), 3.93 (s, 3H), 3.72 (t, J = 8.0 Hz, 1H), 3.62 (t, J = 7.3 Hz, 1H), 2.89 (s, 3H), 2.51 (t, J = 6.9 Hz,
2H), 1.73 – 1.46 (m, 4H), 1.01 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 176.2, 174.6, 170.3,
138.4, 132.4, 127.9, 127.8, 125.7, 123.1, 95.7, 78.7, 62.2, 61.8, 52.4, 48.2, 47.7, 31.0, 25.1, 22.2, 19.4,
13.7. HRMS (ESI+): Calculated for C21H25N2O4, 369.1808; found, 369.1798 ([M+H], 100).
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(1S,3R,3aS,6aR)ꢀ Methyl 3ꢀ(2ꢀ(cyclohexylethynyl)phenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxooctahydro pyrrolo
[3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3b): Following the typical procedure, the reaction of Nꢀ
methylmaleimide (11.1 mg, 0.10 mmol) and 1b (36.8 mg, 0.13 mmol) afforded, after purification by
silica gel flash chromatography (cyclohexaneꢀEtOAc 4:1), the cycloadduct endoꢀ3b (37.5 mg, 95%,
brown oil). [α]D20:+8.4 (c=0.89, CHCl3), ≥ 99% ee. HPLC: Daicel Chiralpak IB, hexaneꢀisopropanol
80ꢀ20, flow rate 0.7 mL/min (λ = 254 nm), tR:17.8 min (1R,3S,3aR,6aS)ꢀ3b and 19.9 min
(1S,3R,3aS,6aR)ꢀ3b. 1H NMR (300 MHz, CDCl3): δ 7.49 – 7.34 (m, 2H), 7.29 – 7.18 (m, 2H), 4.85 (dd,
J = 7.6, 5.2 Hz, 1H), 4.12 – 3.96 (m, 1H), 3.87 (s, 3H), 3.68 (t, J = 8.0 Hz, 1H), 3.56 (t, J = 7.3 Hz, 1H),
2.83 (s, 3H), 2.72 – 2.56 (m, 1H), 2.47 – 2.30 (m, 1H), 2.00 – 1.83 (m, 2H), 1.82 – 1.73 (m, 2H), 1.59 –
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1.50 (m, 3H), 1.41 – 1.30 (m, 2H). C NMR (75 MHz, CDCl3): δ 176.1, 174.5, 170.3, 138.4, 132.2,
127.8, 127.7, 125.6, 123.1, 99.6, 78.6, 62.1, 61.7, 52.3, 48.0, 47.5, 32.9, 32.8, 29.9, 25.9, 25.0. HRMS
(ESI+): Calculated for C23H27N2O4, 395.1965; found, 395.1948 ([M+H], 100).
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(1S,3R,3aS,6aR)ꢀ Methyl 3ꢀ(2ꢀ(phenylethynyl)phenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxooctahydropyrrolo [3,4ꢀ
c]pyrroleꢀ1ꢀcarboxylate (endoꢀ3c): Following the typical procedure, the reaction of Nꢀ
methylmaleimide (11.1 mg, 0.10 mmol) and 1c (36.1 mg, 0.13 mmol) afforded, after purification by
silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), the cycloadduct endoꢀ3c (36.9 mg, 95%,
brown oil). [α]D20:+18.7 (c=1.03, CHCl3), 99% ee. HPLC: Daicel Chiralpak ASꢀH, hexaneꢀisopropanol
80ꢀ20, flow rate 0.7 mL/min (λ = 254 nm), tR: 31.2 min (1S,3R,3aS,6aR)ꢀ3c and 41.9 min
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(1R,3S,3aR,6aS)ꢀ3c. H NMR (300 MHz, CDCl3): δ 7.61 – 7.56 (m, 1H), 7.55 – 7.46 (m, 3H), 7.40 –
7.29 (m, 5H), 4.93 (d, J = 8.3 Hz, 1H), 4.09 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 3.73 (t, J = 8.0 Hz, 1H),
3.57 (t, J = 7.3 Hz, 1H), 2.83 (s, 3H), 2.47 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 175.7, 174.2, 169.9,
138.4, 132.0, 131.2, 128.4, 128.3, 128.2, 127.5, 125.5, 122.7, 121.8, 93.9, 86.9, 61.7, 61.3, 52.0, 47.6,
47.3, 24.7. HRMS (ESI+): Calculated for C23H21N2O4, 389.1495; found, 389.1478 ([M+H], 100).
(1S,3R,3aS,6aR)ꢀ
Methyl
3ꢀ(2ꢀ(4ꢀtert-butylphenylethynyl)phenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxo
octahydropyrrolo [3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3d): Following the typical procedure, the
reaction of Nꢀmethylmaleimide (11.1 mg, 0.10 mmol) and 1d (43.3 mg, 0.13 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 4:1), the cycloadduct endoꢀ3d
(40.5 mg, 91%, brown solid). [α]D20:+46.9 (c=0.22, CHCl3), 96% ee. Mp 117ꢀ119 ºC. HPLC: Daicel
Chiralpak IA, hexaneꢀisopropanol 80ꢀ20, flow rate 0.7 mL/min (λ = 254 nm), tR: 36.8 min
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(1S,3R,3aS,6aR)ꢀ3d and 54.7 min (1R,3S,3aR,6aS)ꢀ3d. H NMR (300 MHz, CDCl3): δ 7.60 – 7.54 (m,
1H), 7.49 – 7.43 (m, 3H), 7.42 – 7.35 (m, 2H), 7.32 – 7.27 (m, 2H), 4.92 (d, J = 8.4 Hz, 1H), 4.07 (d, J
= 7.0 Hz, 1H), 3.87 (s, 3H), 3.73 (t, J = 8.1 Hz, 1H), 3.55 (t, J = 7.4 Hz, 1H), 2.83 (s, 3H), 1.34 (s, 9H).
13C NMR (75 MHz, CDCl3): δ 176.1, 174.6, 170.3, 152.1, 138.8, 132.3, 131.3, 128.6, 127.9, 125.9,
125.6, 122.4, 120.1, 94.5, 86.7, 62.2, 61.7, 52.4, 48.1, 47.7, 34.9, 31.3, 25.1. HRMS (ESI+): Calculated
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for C27H29N2O4, 445.2121; found, 445.2117 ([M+H], 100).
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(1S,3R,3aS,6aR)ꢀ
Methyl
3ꢀ(2ꢀ(4ꢀmethoxyphenylethynyl)phenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxo
5
6
7
8
octahydropyrrolo [3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3e): Following the typical procedure, the
reaction of Nꢀmethylmaleimide (11.1 mg, 0.10 mmol) and 1e (40.0 mg, 0.13 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), the cycloadduct endoꢀ3e
(39.8 mg, 95%, brown oil). [α]D20:+53.3 (c=0.17, CHCl3), ≥99% ee. HPLC: Daicel Chiralpak IB,
hexaneꢀisopropanol 70ꢀ30, flow rate 0.7 mL/min (λ = 254 nm), tR: 36.8 min (1R,3S,3aR,6aS)ꢀ3e and
54.7min (1S,3R,3aS,6aR)ꢀ3e. 1H NMR (300 MHz, CDCl3): δ 7.65 – 7.50 (m, 1H), 7.51 – 7.41 (m, 3H),
7.35 – 7.06 (m, 2H), 7.01 – 6.69 (m, 2H), 4.90 (d, J = 8.5 Hz, 1H), 4.08 (d, J = 7.0 Hz, 1H), 3.87 (s,
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3H), 3.83 (s, 3H), 3.72 (t, J = 8.1 Hz, 1H), 3.57 (t, J = 7.3 Hz, 1H), 2.82 (s, 3H). C NMR (75 MHz,
CDCl3): δ 176.1, 174.6, 170.3, 159.9, 138.5, 133.0, 132.2, 128.4, 127.8, 125.9, 122.5, 115.1, 114.2,
94.4, 86.0, 62.1, 61.7, 55.4, 52.3, 48.0, 47.7, 25.0. HRMS (ESI+): Calculated for C24H23N2O5,
419.1601; found, 419.1583 ([M+H], 100).
(1S,3R,3aS,6aR)ꢀ Methyl 3ꢀ(2ꢀ(tiophenꢀ2ꢀylethynyl)phenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxooctahydro pyrrolo
[3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3f): Following the typical procedure, the reaction of Nꢀ
methylmaleimide (11.1 mg, 0.10 mmol) and 1f (36.8 mg, 0.13 mmol) afforded, after purification by
silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), the cycloadduct endoꢀ3f (24.9 mg, 63%,
brown oil). [α]D20:+3.3 (c=0.12, CHCl3), ≥99% ee. HPLC: Daicel Chiralpak IB, hexaneꢀisopropanol
70ꢀ30, flow rate 0.7 mL/min (λ = 254 nm), tR: 36.8 min (1R,3S,3aR,6aS)ꢀ3f and 54.7min
(1S,3R,3aS,6aR)ꢀ3f. 1H NMR (300 MHz, CDCl3): 7.58 – 7.53 (m, 1H), 7.51 – 7.45 (m, 1H), 7.34 – 7.27
(m, 4H), 7.03 (dd, J = 5.1, 3.7 Hz, 1H), 4.89 (d, J = 8.1 Hz, 1H), 4.11 (d, J = 7.0 Hz, 1H), 3.88 (s, 3H),
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3.76 – 3.67 (m, 1H), 3.64 – 3.55 (m, 1H), 2.83 (s, 3H). C NMR (75 MHz, CDCl3): δ 176.1, 174.6,
170.3, 138.8, 132.3, 132.1, 129.1, 128.0, 127.8, 127.4, 126.0, 123.1, 122.0, 91.1, 87.6, 62.1, 61.8, 52.5,
48.1, 47.8, 25.2. HRMS (ESI+): Calculated for C21H17N2O5S, 409.0852; found, 409.0850 ([M+H], 70).
(1S,3R,3aS,6aR)ꢀ
Methyl
3ꢀ(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ5ꢀmethylphenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxo
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octahydropyrrolo [3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3g): Following the typical procedure, the
reaction of Nꢀmethylmaleimide (11.1 mg, 0.10 mmol) and 1g (35.3 mg, 0.13 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 4:1), the cycloadduct endoꢀ3g
(36.7 mg, 96%, yellow oil). Mp 88ꢀ90 ºC. [α]D20:+85.5 (c=0.8, CHCl3), 81% ee. HPLC: Daicel
Chiralpak IB, hexaneꢀisopropanol 80ꢀ20, flow rate 0.7 mL/min (λ = 210 nm), tR: 44.0 min
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(1R,3S,3aR,6aS)ꢀ3g and 59.2 min (1S,3R,3aS,6aR)ꢀ3g. H NMR (300 MHz, CDCl3): δ 7.37 – 7.16 (m,
2H), 7.14 – 6.97 (m, 1H), 4.80 (d, J = 7.7 Hz, 1H), 4.07 (d, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.76 – 3.42
(m, 2H), 2.85 (s, 3H), 2.46 (t, J = 6.8 Hz, 2H), 2.30 (s, 3H), 1.66 – 1.39 (m, 4H), 0.96 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 176.3, 174.8, 170.4, 137.4, 135.2, 133.1, 128.9, 125.7, 122.8, 95.2,
78.7, 62.8, 61.8, 52.4, 48.2, 47.8, 31.0, 25.1, 22.2, 21.1, 19.4, 13.8. HRMS (ESI+): Calculated for
C`22H27N2O4, 383.1965; found, 383.1963 ([M+H], 100).
(1S,3R,3aS,6aR)ꢀ
Methyl
3ꢀ(5ꢀfluoroꢀ2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)phenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxo
octahydropyrrolo [3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3h): Following the typical procedure, the
reaction of Nꢀmethylmaleimide (11.1 mg, 0.10 mmol) and 1h (35.8 mg, 0.13 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 4:1), the cycloadduct endoꢀ3h
(26.6 mg, 93%, yellow oil). [α]D20:+40.9 (c=0.10, CHCl3), 96% ee. HPLC: Daicel Chiralpak ASꢀH,
hexaneꢀisopropanol 80ꢀ20, flow rate 0.7 mL/min (λ = 254 nm), tR: 18.7 min (1S,3R,3aS,6aR)ꢀ3h and
31.7min (1R,3S,3aR,6aS)ꢀ3h. 1H NMR (300 MHz, CDCl3): δ 7.40 (dd, J = 8.4, 5.6 Hz, 1H), 7.16 (dd, J
= 9.8, 2.6 Hz, 1H), 6.97 – 6.83 (m, 1H), 4.78 (d, J = 8.2 Hz, 1H), 4.05 (d, J = 6.8 Hz, 1H), 3.86 (s, 3H),
3.65 (t, J = 8.0 Hz, 1H), 3.55 (t, J = 7.3 Hz, 1H), 2.83 (s, 3H), 2.43 (t, J = 7.0 Hz, 2H), 1.71 – 1.37 (m,
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4H), 0.94 (t, J = 7.2 Hz, 3H). C NMR (75 MHz, CDCl3): δ 176.0, 174.4, 170.1, 162.3 (d, J = 248.7
Hz), 141.5 (d, J = 7.7 Hz), 134.0 (d, J = 8.2 Hz), 119.1 (d, J = 3.3 Hz), 114.9 (d, J = 22.0 Hz), 113.2 (d,
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J = 24.0 Hz), 95.2, 77.7, 77.4, 77.2, 61.6, 61.6, 52.4, 47.7, 47.3, 30.9, 25.1, 22.2, 19.4, 13.7. F NMR
(282 MHz, CDCl3): δ ꢀ110.85. HRMS (ESI+): Calculated for C21H24FN2O4, 387.1714; found, 387.1699
([M+H], 100).
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(1S,3R,3aS,6aR)ꢀ
Methyl
3ꢀ(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ4,5ꢀdimethoxyphenyl)ꢀ5ꢀmethylꢀ4,6ꢀdioxo
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octahydropyrrolo [3,4ꢀc]pyrroleꢀ1ꢀcarboxylate (endoꢀ3i): Following the typical procedure, the
reaction of Nꢀmethylmaleimide (11.1 mg, 0.10 mmol) and 1i (41.3 mg, 0.13 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 2:1) an inseparable mixture (93:7)
of the cycloadducts endoꢀ3i and exoꢀ3i. (32.6 mg, 76%, brown oil) [α]D20:+94.7 (c=0.80, CHCl3), 90%
ee (endo). HPLC: Daicel Chiralpak IA, hexaneꢀisopropanol 70ꢀ30, flow rate 0.7 mL/min (λ = 254 nm),
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tR: 24.3 min (1R,3S,3aR,6aS)ꢀ3i and 35.5min (1S,3R,3aS,6aR)ꢀ3i. H NMR (300 MHz, CDCl3): δ 6.92
(s, 1H), 6.86 (s, 1H), 4.79 (dd, J = 7.4, 4.1 Hz, 1H), 4.07 – 4.01 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.80
(s, 3H), 3.62 – 3.50 (m, 2H), 2.84 (s, 3H), 2.44 (t, J = 7.0 Hz, 3H), 1.68 – 1.38 (m, 4H), 0.95 (t, J = 7.2
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 176.1, 174.5, 170.1, 148.8, 147.9, 131.4, 114.96, 114.5, 108.6,
93.9, 78.2, 61.7, 61.4, 56.0, 55.7, 52.1, 47.7, 47.3, 30.9, 24.6, 22.1, 19.2, 13.56. HRMS (ESI+):
Calculated for C23H29N2O6, 429.2020; found, 429.2016 ([M+H], 100).
(1S,3R,3aS,6aR)ꢀ Methyl 3ꢀ(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)phenyl)ꢀ1,5ꢀdimethylꢀ4,6ꢀdioxooctahydropyrrolo[3,4ꢀ
c]pyrroleꢀ1ꢀcarboxylate (3j): Following the typical procedure, the reaction of Nꢀmethylmaleimide
(11.1 mg, 0.10 mmol) and 1j (32.6 mg, 0.13 mmol) afforded, after purification by silica gel flash
20
chromatography (cyclohexaneꢀEtOAc 4:1), the cycloadduct endoꢀ3j (23.6 mg, 63%, brown oil).[α]D
:
+39.3 (c = 0.06, CHCl3), 89% ee. HPLC: Daicel Chiralpak AD, hexaneꢀisopropanol 80ꢀ20, flow rate
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0.7 mL/min (λ = 254 nm), tR: 18.6 min (1R,3S,3aR,6asS)ꢀ3j and 12.60 min (1S,3R,3aS,6aR)ꢀ3j. H
NMR (300 MHz, CDCl3): δ 7.48 – 7.42 (m, 1H), 7.40 – 7.28 (m, 1H), 7.28 – 7.19 (m, 2H), 5.24 – 5.02
(m, 1H), 3.87 (s, 3H), 3.73 (t, J = 8.2 Hz, 1H), 3.26 (d, J = 7.5 Hz, 1H), 2.78 (s, 3H), 2.67 (bs, 1H), 2.48
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(t, J = 6.8 Hz, 2H), 1.63 (s, 3H), 1.60 – 1.44 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H). C NMR (75 MHz,
CDCl3): δ 176.0, 174.5, 172.9, 138.4, 132.4, 127.9, 127.7, 125.3, 123.4, 95.7, 78.7, 67.3, 60.2, 55.5,
52.7, 48.6, 30.9, 24.9, 23.8, 22.2, 19.4, 13.7. HRMS (FB+): Calculated for C22H27N2O4, 383.1971;
found, 383.1976 ([M+H], 100).
Typical procedure for catalytic asymmetric [3+2] cycloaddition of azomethine ylides with
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bis(phenylsulfonyl)ethylene
(2R,3S,4S,5S)ꢀ
Methyl
5ꢀ(2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)phenyl)ꢀ3,4ꢀ
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bis(phenylsulfonyl)pyrrolidineꢀ2ꢀcarboxylate (exoꢀ9a): A suspension of (R)ꢀFesulphos (5.04 mg,
0.011 mmol), CuOTf 0.5 toluene complex (5.17 mg, 0.01 mmol) and KHMDS (1.99 mg, 0.01 mmol) in
THF (1 mL) under argon atmosphere was heated at 40ºC for 1h. The resulting mixture was cooled to
room temperature and solutions of 1a (33.5 mg, 0.13 mmol) in THF (1 mL) and transꢀ1,2ꢀ
bis(phenylsulfonyl)ethylene (30.1 mg, 0.10 mmol) in THF (1 mL) were successively added. After 18h at
room temperature, the mixture was diluted with dichloromethane and filtered over Celite®. The crude
was concentrated under reduced pressure and purified by silica gel flash chromatography (cyclohexaneꢀ
EtOAc 3:1) to afford exoꢀ9a (60.3 mg, 82%, brown oil).[α]D20: +17.6 (c = 0.15, CHCl3), 96% ee.
HPLC: Daicel Chiralpak IB, hexaneꢀisopropanol 80ꢀ20, flow rate 0.7 mL/min (λ = 254 nm), tR: 17.4
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min (2S,3R,4R,5R)ꢀ9a and 20.8 min (2R,3S,4S,5S)ꢀ9a. H NMR (300 MHz, CDCl3): δ 7.85 (d, J = 7.9
Hz, 2H), 7.75 – 7.56 (m, 5H), 7.54 – 7.40 (m, 2H), 7.35 – 7.04 (m, 5H), 5.20 (d, J = 7.2 Hz, 1H), 4.62
(dd, J = 6.2, 3.0 Hz, 1H), 4.53 (dd, J = 7.2, 3.0 Hz, 1H), 4.26 (d, J = 6.2 Hz, 1H), 3.66 (s, 3H), 2.49 (t, J
= 7.0 Hz, 2H), 1.73 – 1.42 (m, 4H), 0.96 (t, J = 7.2 Hz, 2H).13C NMR (75 MHz, CDCl3): δ 167.6,
138.7, 138.6, 137.2, 134.5, 134.1, 132.5, 129.5, 129.2, 128.7, 128.5, 128.5, 128.2, 126.5, 124.8, 96.2,
78.3, 71.0, 67.6, 64.7, 61.6, 52.7, 30.8, 22.2, 19.5, 13.8. HRMS (ESI+): Calculated for C30H32NO6S2,
566.1665; found, 566.1646 ([M+H], 100).
(2R,3S,4S,5S)ꢀtertꢀButyl
5ꢀ(2ꢀ(heptꢀ1ꢀynꢀ1ꢀyl)phenyl)ꢀ3,4ꢀbis(phenylsulfonyl)pyrrolidineꢀ2ꢀ
carboxylate (exoꢀ9k): Following the typical procedure, the reaction of transꢀ1,2ꢀ
bis(phenylsulfonyl)ethylene (30.8 mg, 0.10 mmol) and 1k (44.9 mg, 0.15 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), a 92:8 mixture of exoꢀ9k and
endoꢀ9k (56.5 mg, 93%, yellow oil). [α]D20: +22.4 (c = 0.98, CHCl3), 89% ee (exo). HPLC: Daicel
Chiralpak AD, hexaneꢀisopropanol 80ꢀ20, flow rate 0.7 mL/min (λ = 254 nm), tR: 14.2 min
(2R,3S,4S,5S)ꢀ9k and 17.8 min (2S,3R,4R,5R)ꢀ9k. 1H NMR (300 MHz, CDCl3): δ 7.90 – 7.84 (m, 2H),
7.74 – 7.66 (m, 1H), 7.62 – 7.53 (m, 3H), 7.50 – 7.38 (m, 2H), 7.34 – 7.03 (m, 6H), 5.16 (d, J = 7.4 Hz,
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1H), 4.61 (dd, J = 6.4, 3.1 Hz, 1H), 4.45 (dd, J = 7.3, 3.1 Hz, 1H), 4.22 (d, J = 6.3 Hz, 1H), 2.49 (t, J =
7.1 Hz, 2H), 1.73 – 1.41 (m, 13H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 166.1,
139.0, 137.2, 134.4, 134.0, 132.6, 129.5, 129.1, 128.7, 128.5, 128.3, 128.2, 127.8, 126.6, 124.6, 83.4,
78.4, 71.5, 67.4, 66.0, 61.6, 30.8, 28.1, 22.3, 19.6, 13.8. HRMS (FAB+): Calculated for C33H38NO6S2,
608.2141; found, 608.2155 ([M+H], 85).
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Typical procedure for the hydroamination/reduction sequence.
(6S,8S,8aR,11aS,11bR)ꢀ Methyl 6ꢀbutylꢀ10ꢀmethylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,11a,11bꢀoctahydroꢀ
6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7a): A solution of endoꢀ3a (31.8 mg,
0.08 mmol) in dichloromethane (1 mL) was added to a solution of JohnPhosAuMeCN SbF6 (6.7 mg,
8·10ꢀ3 mmol) in dichloromethane (1 mL) under argon atmosphere at room temperature. After 18h the
solution was cooled to 0ºC and MeOH (0.4 mL), HCl 5% (0.17 mL) and NaBH3CN (10.6 mg) were
successively added. The mixture was stirred for 1h at 0ºC, diluted with dichloromethane (5 mL) and
washed with 5 mL of saturated NaHCO3 solution, water (2 x 5 mL) and brine (2 x 5 mL). The organic
layer was separated, dried (Mg2SO4), concentrated under reduced pressure and purified by silica gel
flash chromatography (cyclohexaneꢀEtOAc 3:1) to afford 7a (20.0 mg, 65%, white solid), ≥99% ee.
HPLC: Daicel Chiralpak IB, hexaneꢀisopropanol 70ꢀ30, flow rate 0.7 mL/min (λ = 254 nm), tR: 23.5
min (6S,8S,8aR,11aS,11bR)ꢀ7a and 34.2 min (6R,8R,8aS,11aR,11bS)ꢀ7a. Mp 157ꢀ159 ºC. [α]D20: +6.1
(c=0.54, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.51 – 7.42 (m, 1H), 7.25 – 7.15 (m, 2H), 7.12 – 7.03
(m, 1H), 3.95 (d, J = 6.2 Hz, 1H), 3.75 (s, 3H), 3.71 (d, J = 6.7 Hz, 1H), 3.60 – 3.48 (m, 2H), 2.96 –
2.70 (m, 5H), 2.52 (dd, J = 12.0, 8.1 Hz, 1H), 1.53 – 1.11 (m, 6H), 0.89 (t, J = 7.0 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 176.1, 174.9, 171.6, 134.8, 132.1, 128.5, 127.3, 127.2, 125.1, 68.5, 67.5, 62.0,
52.5, 46.8, 45.5, 35.9, 33.7, 28.4, 25.2, 22.9, 14.0. HRMS (ESI+): Calculated for C21H27N2O4,
371.1965; found, 371.1967 ([M+H], 100).
(6R,8S,8aR,11aS,11bR)ꢀ
Methyl
6ꢀcyclohexylꢀ10ꢀmethylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,11a,11bꢀ
octahydroꢀ6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7b): Following the
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typical procedure, the hydroamination/reduction of endoꢀ3b (43.6 mg, 0.11 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), 7b (19.5 mg, 45%, white
solid). Mp 212ꢀ214 ºC. [α]D20:+187.2 (c=0.20, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.55 – 7.36 (m,
1H), 7.25 – 7.16 (m, Hz, 2H), 7.16 – 7.01 (m, 1H), 3.90 (d, J = 7.3 Hz, 1H), 3.78 – 3.68 (m, 4H), 3.63 –
3.43 (m, 2H), 3.16 – 2.95 (m, 1H), 2.90 (s, 3H), 2.69 – 2.60 (m, 1H), 2.51 – 2.36 (m, 1H), 1.97 – 1.55
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(m, 6H), 1.53 – 1.38 (m, 2H), 1.06 – 0.77 (m, 3H). C NMR (75 MHz, CDCl3): δ 176.3, 175.1, 170.8,
135.0, 132.0, 128.4, 127.2, 126.9, 125.1, 69.4, 68.4, 68.3, 52.4, 46.8, 45.5, 41.1, 32.5, 30.9, 27.4, 27.3,
26.8, 26.5, 25.1. HRMS (ESI+): Calculated for C23H29N2O4, 397.2121; found, 397.2118 ([M+H], 100).
(6R,8S,8aR,11aS,11bR)ꢀ Methyl 10ꢀmethylꢀ6ꢀphenylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,11a,11bꢀoctahydroꢀ
6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7c): Following the typical procedure,
the hydroamination/reduction of endoꢀ3c (20.1 mg, 0.05 mmol) afforded, after purification by silica gel
flash chromatography (cyclohexaneꢀEtOAc 3:1), 7c (11.0 mg, 56%, yellow solid). Mp 157ꢀ159 ºC.
[α]D20:+6.1 (c=0.54, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.57 – 7.51 (m, 1H), 7.39 – 7.20 (m, 7H),
7.16 – 7.10 (m, 1H), 4.07 (d, J = 6.0 Hz, 1H), 3.83 – 3.72 (m, 1H), 3.64 – 3.54 (m, 2H), 3.53 – 3.38 (m,
2H), 3.11 (s, 3H), 3.00 – 2.83 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 175.9, 175.0, 169.5, 138.6,
134.8, 131.9, 130.3, 128.8, 128.3, 128.1, 127.4, 127.2, 125.4, 69.0, 68.6, 67.4, 51.6, 46.6, 45.5, 37.8,
25.1. HRMS (ESI+): Calculated for C23H23N2O4, 391.1652; found, 391.1647 ([M+H], 100).
(6R,8S,8aR,11aS,11bR)ꢀMethyl
6ꢀ(4ꢀtertꢀbutylphenyl)ꢀ10ꢀmethylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,
11a,11bꢀoctahydroꢀ6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7d): Following
the typical procedure, the hydroamination/reduction of endoꢀ3d (53.5 mg, 0.12 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), 7d (27.3 mg, 51%, white
solid). Mp 238ꢀ240 ºC. [α]D20:+118.9 (c=0.35, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.60 – 7.49 (m,
1H), 7.40 – 7.22 (m, 6H), 7.19 – 7.10 (m, 1H), 4.09 (d, J = 6.0 Hz, 1H), 3.83 – 3.74 (m, 1H), 3.66 – 3.54
(m, 2H), 3.52 – 3.39 (m, 2H), 3.11 (s, 3H), 2.99 – 2.80 (m, 4H), 1.34 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 176.0, 175.1, 169.6, 151.7, 135.5, 135.0, 131.9, 130.0, 128.4, 127.3, 127.2, 125.4, 124.9,
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68.9, 68.4, 66.9, 51.6, 46.6, 45.5, 37.6, 34.7, 31.4, 25.1. HRMS (ESI+): Calculated for C27H31N2O4,
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447.2278; found, 447.2261 ([M+H], 100).
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(6R,8S,8aR,11aS,11bR)ꢀMethyl
6ꢀ(4ꢀmethoxyphenyl)ꢀ10ꢀmethylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,
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11a,11bꢀoctahydroꢀ6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7e): Following
the typical procedure, the hydroamination/reduction of endoꢀ3e (53.6 mg, 0.13 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), 7e (28.8 mg, 53%, brown
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solid). Mp 250ꢀ252 ºC. [α]D20:+90.7 (c=0.17, CHCl3). H NMR (300 MHz, CDCl3): δ 7.52 (d, J = 7.2
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Hz, 1H), 7.35 – 7.18 (m, 4H), 7.13 (d, J = 7.1 Hz, 1H), 6.82 (t, J = 5.6 Hz, 2H), 4.05 (d, J = 5.9 Hz, 1H),
3.75 – 3.85 (m, 4H), 3.56 – 3.53 (m, 2H), 3.44 (d, J = 3.7 Hz, 2H), 3.16 (s, 3H), 2.93 – 2.84 (m, 4H).
13C NMR (75 MHz, CDCl3): δ 176.0, 175.1, 169.6, 159.9, 135.0, 131.9, 131.4, 130.8, 128.4, 127.3,
127.2, 125.4, 113.4, 69.0, 68.6, 66.6, 55.4, 51.7, 46.6, 45.6, 37.9, 25.1. HRMS (ESI+): Calculated for
C24H25N2O5, 421.1757; found, 421.1755 ([M+H], 100).
(6R,8S,8aR,11aS,11bR)ꢀMethyl 6ꢀ(tiophenꢀ2ꢀyl)ꢀ10ꢀmethylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,11a, 11bꢀ
octahydroꢀ6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7f): Following the typical
procedure, the hydroamination/reduction of endoꢀ3f (36.8 mg, 0.10 mmol) afforded, after purification
by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), 7f (28.32 mg, 76%, white solid). Mp 180ꢀ
182 ºC. [α]D20:+102.8 (c=0.48, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.58 – 7.46 (m, 1H), 7.34 – 7.20
(m, 3H), 7.19 – 7.10 (m, 1H), 7.06 – 7.01 (m, 1H), 6.94 (dd, J = 5.0, 3.6 Hz, 1H), 4.10 (d, J = 6.5 Hz,
1H), 3.93 (dd, J = 11.6, 3.4 Hz, 1H), 3.83 – 3.72 (m, 1H), 3.67 – 3.53 (m, 2H), 3.54 – 3.43 (m, 1H), 3.27
(s, 3H), 3.07 (dd, J = 16.1, 3.1 Hz, 1H), 2.87 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 175.7, 174.9,
169.2, 142.4, 134.4, 131.7, 128.8, 128.3, 127.4, 127.3, 126.4, 126.2, 125.6, 68.7, 68.3, 61.0, 51.9, 46.5,
45.5, 38.9, 25.2. HRMS (ESI+): Calculated for C21H21N2O4S, 397.1216; found, 397.1212 ([M+H],
100).
(6S,8S,8aR,11aS,11bR)ꢀMethyl
6ꢀbutylꢀ2,10ꢀdimethylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,11a,11bꢀ
octahydroꢀ6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7g): Following the
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typical procedure, the hydroamination/reduction of endoꢀ3g (34.4 mg, 0.09 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), 7g (20.7 mg, 60%, brown
oil). [α]D20:+118.9 (c=0.35, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.36 (d, J = 7.8 Hz, 1H), 7.04 (d, J
= 8.0 Hz, 1H), 6.91 (s, 1H), 3.95 (d, J = 6.2 Hz, 1H), 3.75 (s, 3H), 3.71 (d, J = 6.7 Hz, 1H), 3.60 – 3.48
(m, 2H), 2.88 (s, 3H), 2.82 – 2.74 (m, 2H), 2.51 – 2.47 (m, 1H), 2.30 (s, 3H), 1.53 – 1.11 (m, 6H), 0.89
(t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 176.1, 175.0, 171.7, 136.7, 134.6, 129.1, 129.0,
127.1, 126.0, 68.3, 67.5, 62.0, 52.4, 46.8, 45.6, 35.8, 33.6, 28.4, 25.2, 22.8, 21.3, 14.0. HRMS (ESI+):
Calculated for C22H29N2O4, 385.2121; found, 385.2113 ([M+H], 100).
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(6S,8S,8aR,11aS,11bR)ꢀMethyl 6ꢀbutylꢀ2ꢀfluoroꢀ10ꢀmethylꢀ9,11ꢀdioxoꢀ5,8,8a,9,10,11,11a, 11bꢀ
octahydroꢀ6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7h): Following the
typical procedure, the hydroamination/reduction of endoꢀ3h (26.3 mg, 0.07 mmol) afforded, after
purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), 7h (17.67 mg, 65%, orange
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solid). Mp 185ꢀ187 ºC. [α]D20:+173.2 (c=0.87, CHCl3). H NMR (300 MHz, CDCl3): δ 7.17 (dd, J =
9.7, 2.3 Hz, 1H), 7.12 – 7.00 (m, 1H), 6.90 (m, 1H), 3.96 – 3.86 (m, 1H), 3.75 (s, 3H), 3.67 (t, J = 6.4
Hz, 1H), 3.61 – 3.50 (m, 2H), 2.90 (s, 3H), 2.87 – 2.81 (m, 1H), 2.78 – 2.66 (m, 1H), 2.57 – 2.44 (m,
1H), 1.52 – 1.11 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 175.9, 174.7, 171.5,
160.4 (d, J = 243.2 Hz), 133.8 (d, J = 7.5 Hz), 130.3 (d, J = 3.1 Hz), 129.8 (d, J = 7.9 Hz), 114.5 (d, J =
21.4 Hz), 114.0 (d, J = 22.5 Hz), 68.2, 67.4, 62.0, 52.5, 46.6, 45.4, 35.2, 33.6, 28.4, 25.3, 22.9, 14.0.
HRMS (ESI+): Calculated for C21H26N2O4F, 389.1871; found, 389.1871 ([M+H], 100).
(6S,8S,8aR,11aS,11bR)ꢀMethyl
10ꢀmethylꢀ2,3ꢀdimethoxyꢀ6ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)ꢀ9,11ꢀdioxoꢀ
5,8,8a,9,10,11,11a, 11bꢀoctahydroꢀ6Hꢀpyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate
(7i): Following the typical procedure, the hydroamination/reduction of endoꢀ3i (40.3 mg, 0.09 mmol)
afforded, after purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 2:1), 7i (24.4 mg,
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63%, yellow solid). Mp 90ꢀ92 ºC. [α]D20:+70.2 (c=0.13, CHCl3). H NMR (300 MHz, CDCl3): δ 6.96
(s, 1H), 6.57 (s, 1H), 3.91 (s, 3H), 3.88 (d, J = 6.9 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.68 (t, J = 6.8
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Hz, 1H), 3.61 – 3.46 (m, 2H), 2.89 (s, 3H), 2.85 – 2.64 (m, 2H), 2.54 – 2.42 (m, 1H), 1.50 – 1.39 (m,
2H), 1.34 – 1.14 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 176.0, 174.9, 171.6,
148.3, 146.6, 127.0, 124.2, 110.9, 110.8, 68.3, 67.5, 62.2, 56.3, 55.9, 52.4, 46.8, 45.7, 35.5, 33.6, 28.4,
25.3, 22.9, 14.1. HRMS (ESI+): Calculated for C23H31N2O6, 431.2176; found, 431.2167 ([M+H], 100).
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Methyl
6ꢀbutylꢀ8,10ꢀdimethylꢀ9,11ꢀdioxoꢀ6,8,8a,9,10,11,11a,11bꢀoctahydroꢀ5Hꢀ
pyrrolo[3',4':3,4]pyrrolo[2,1ꢀa]isoquinolineꢀ8ꢀcarboxylate (7j): Following the typical procedure, the
hydroamination/reduction of endoꢀ3j (47.2 mg, 0.12 mmol) afforded, after purification by silica gel
flash chromatography (cyclohexaneꢀEtOAc 3:1), the adduct cisꢀ7j (18.2 mg, 40%, yellow oil) and transꢀ
7j (9.8 mg, 23%, yellow oil).
(6S,8S,8aR,11aS,11bR)ꢀcisꢀ7j: [α]D20: +25.7 (c = 0.31, CHCl3), 90% ee. 1H NMR (300 MHz, CDCl3):
δ 7.44 – 7.37 (m, 1H), 7.32 – 7.21 (m, 2H), 7.12 (d, J = 6.5 Hz, 1H), 5.00 (d, J = 3.6 Hz, 1H), 4.45 (s,
1H), 3.70 (s, 3H), 3.34 – 3.20 (m, 2H), 2.98 (s, 3H), 1.83 – 1.63 (m, 2H), 1.41 (s, 3H), 1.31 – 1.05 (m,
6H), 0.82 (t, J = 6.5 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 177.6, 176.2, 172.4, 143.1, 141.8, 127.8,
127.7, 122.3, 122.1, 71.7, 71.1, 63.5, 56.9, 52.3, 52.0, 36.3, 31.9, 25.1, 24.1, 22.5, 20.9, 14.0.HRMS
(FB+): Calculated for C22H29N2O4, 385.2121; found, 385.2127 ([M+H], 25).
(6S,8S,8aR,11aS,11bR)ꢀtransꢀ7j: [α]D20: ꢀ20.0 (c = 0.02, CHCl3), 99% ee. 1H NMR (300 MHz, CDCl3
δ 7.51 – 7.45 (m, 1H), 7.33 – 7.18 (m, 2H), 7.15 – 7.09 (m, 1H), 4.40 (d, J = 5.9 Hz, 1H), 3.77 – 3.64
(m, 4H), 3.13 – 3.06 (m, 1H), 2.99 – 2.86 (m, Hz, 4H), 2.82 – 2.66 (m, 2H), 1.57 (s, 3H), 1.52 – 1.13
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(m, 6H), 0.92 (t, J = 6.4 Hz, 3H). C NMR (75 MHz, CDCl3): δ 176.2, 175.2, 174.0, 134.2, 132.5,
128.3, 127.4, 126.7, 124.9, 69.6, 63.2 56.0, 55.3, 52.3, 45.6, 36.2, 32.7, 28.5, 25.0, 22.7, 15.5, 14.0.
HRMS (ESI+): Calculated for C22H29N2O4, 385.2121; found, 385.2098 ([M+H], 20).
Typical procedure for the hydroamination/reduction/desulfonylation sequence.
(S)ꢀMethyl 5ꢀbutylꢀ5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ3ꢀcarboxylate (12a): A solution of exoꢀ9a
(50.0 mg, 0.088 mmol) in dichloromethane (1 mL) was added to a solution of JohnPhosAuMeCN SbF6
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(6.8 mg, 8.8·10ꢀ3 mmol) in dichloromethane (0.5 mL) under argon atmosphere at room temperature.
After 18h at room temperature, the solution was cooled to 0ºC and MeOH (0.5 mL), HCl 5% (0.25 mL)
and NaBH3CN (11.2 mg, 0.18 mmol) were successively added. The mixture was stirred for 1h at 0ºC
and DBU was added to pH=8. Then, the reaction mixture was warmed to rt, diluted with
dichloromethane (5 ml) and washed with water (2 x 5 mL) and brine (2 x 5 mL). The organic layer was
separated, dried over MgSO4, filtered, concentrated under reduced pressure and purified by silica gel
flash chromatography (cyclohexaneꢀEtOAc 3:1) to afford 12a (13.7 mg, 55%, yellow oil). [α]D20: ꢀ9.7
(c = 1.10, CHCl3), 34% ee. HPLC: Daicel Chiralpak IA, CO2ꢀmethanol 99ꢀ1, flow rate 1 mL/min (λ =
230 nm), tR: 18.6 min (S)ꢀ12a and 28.9 min (R)ꢀ12a. 1H NMR (300 MHz, CDCl3): δ 7.60 (d, J = 7.2 Hz,
1H), 7.34 – 7.23 (m, 2H), 7.05 (d, J = 4.1 Hz, 1H), 6.56 (d, J = 4.1 Hz, 1H), 5.58 – 5.37 (m, 1H), 3.88
(s, 3H), 3.33 (dd, J = 15.9, 6.0 Hz, 1H), 3.00 (d, J = 15.9 Hz, 1H), 1.70 – 1.21 (m, 6H), 0.86 (t, J = 6.4
Hz, 3H).13C NMR (75 MHz, CDCl3): δ 161.7, 135.2, 130.3, 128.9, 128.3, 127.7, 127.1, 123.5, 121.3,
118.6, 104.7, 52.3, 51.2, 33.5, 32.4, 28.5, 22.6, 14.1. HRMS (FB+): Calculated for C18H21NO2,
283.1572; found, 283.1573 ([M], 100).
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(S)ꢀtertꢀButyl 5ꢀbutylꢀ5,6ꢀdihydropyrrolo[2,1ꢀa]isoquinolineꢀ3ꢀcarboxylate (12k): Following the
typical procedure, the hydroamination/reduction/desulfonylation secuence of exoꢀ9k (38.1 mg, 0.06
mmol) afforded, after purification by silica gel flash chromatography (cyclohexaneꢀEtOAc 3:1), 12k
(10.2 mg, 50%, yellow oil). Compound characterization should be performed immediately after
purification in order to minimize the formation of decomposition products. [α]D20: +11 (c = 1.30,
CHCl3), 65% ee. HPLC: Daicel Chiralpak IA, CO2ꢀmethanol 99ꢀ1, flow rate 1 mL/min (λ = 230 nm),
tR: 16.9 min (S)ꢀ12k and 18.5 min (R)ꢀ12k. 1H NMR (300 MHz, CDCl3): δ 7.70 – 7.56 (m, 1H), 7.36 –
7.21 (m, 3H), 6.99 (d, J = 4.0 Hz, 1H), 6.56 (d, J = 4.1 Hz, 1H), 5.74 – 5.24 (m, 1H), 3.43 – 3.22 (m,
1H), 2.98 (d, J = 16.1 Hz, 1H), 1.64 (s, 9H), 1.45 – 1.24 (m, 6H), 0.87 (t, J = 6.5 Hz, 3H).13C NMR (75
MHz, CDCl3): δ 160.5, 134.1, 129.8, 128.4, 128.1, 127.0, 126.6, 122.9, 117.82, 104.0, 79.9, 77.2, 51.8,
33.3, 32.3, 28.2, 22.3, 13.7. HRMS (FB+): Calculated for C21H27NO2, 325.2035; found, 325.2042 ([M],
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70).
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Supporting Information
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1H and 13C NMR spectra for all new compounds, copies of HPLC chromatograms used to determine the
enantiomeric purity and Xꢀray crystallographic data of compound endoꢀ7d in CIF format are available
free of charge via the Internet at http://pubs.acs.org
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Acknowledgments
Financial support of this work by the Ministerio de Economía, Industria y Competitividad and Fondo
Europeo de Desarrollo Regional (projects CTQ2012ꢀ35790 MINECO and CTQ2015ꢀ66954ꢀP
MINECO/FEDER, UE) are gratefully acknowledged. A. PꢀE. thanks the MICINN for a predoctoral
fellowship. We thank Takasago Company (Dr. Taichiro Touge) for the generous loans of Segphos chiral
ligands.
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