Pyrrolidine and Indolizidine Alkaloids from Chiral N - Tert -Butanesulfinyl Imines Derived from 4-Halobutanal

Article abstract of DOI:10.1055/s-0037-1610763

An efficient stereocontrolled preparation of 2-substituted pyrrolidines and 5-substituted indolizidin-7-ones, by using chiral N - tert -butanesulfinyl imines derived from 4-halobutanal as starting materials, is detailed. Addition of Grignard reagents and a decarboxylative Mannich- reaction with β-keto acids involving these chiral imines proceeded with high diastereoselectivity. The synthesis of the pyrrolidinic alkaloids (-)-bgugaine, (+)-villatamine B, (-)-norhygrine, trans -dendrochrysanine, and (-)-ruspolinone demonstrated the utility of this methodology.

Full text of DOI:10.1055/s-0037-1610763

SYNTHESIS
0
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1
1
4
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7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 1749–1759
feature
1749
Cycloadditions and Methodology: Stereo-
A. Sirvent et al.
Feature
Synthesis
Pyrrolidine and Indolizidine Alkaloids from Chiral N-tert-Butane-
sulfinyl Imines Derived from 4-Halobutanal
Ana Sirventa,b,c
O
O
Sandra Hernández-Ibáñeza,b,c
Miguel Yus*c
Francisco Foubelo*a,b,c
OMe
OMe
Me
N
N
H
Ph
O
(–)-trans-dendrochrysanine
(–)-ruspolinone
O
S
a Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
foubelo@ua.es
O
O
R1MgBr
R3CHO
N
t-Bu
Hal
HO
R2
H
b Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Me
c Centro de Innovación en Química Avanzada (ORFEO-CINQA),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
yus@ua.es
N
N
Me
O
(–)-bgugaine
Me
Me
N
N
Et
Dedicated to Professor Joaquín Plumet on the occasion of his
75th birthday
Me
O
(+)-villatamine B
Corresponding Authors
Received: 27.11.2020
Accepted after revision: 11.01.2021
Published online: 10.02.2021
countered in alkaloids, with a six-membered ring fused to
the pyrroline moiety, and these compounds could also dis-
play a wide range of biological activities.
DOI: 10.1055/s-0037-1610763; Art ID: ss-2020-z0608-fa
On the other hand, chiral N-tert-butanesulfinyl imines
have been extensively used as electrophiles in reactions
with different nucleophilic species, among them, organo-
metallic compounds. The electron-withdrawing sulfinyl
group bonded to the nitrogen atom facilitates the nucleo-
philic addition to the iminic carbon, and the configuration
of the sulfur stereocenter plays an important role in con-
trolling the stereochemical outcome of these transforma-
tions.3 Since both enantiomers of the chiral aldimines are
easily prepared from enantiopure commercially available
tert-butanesulfinamide, along with the easily removal of
the sulfinyl group under acidic conditions, and the develop-
ment of practical procedures for recycling the chiral auxil-
iary, this strategy has become a potent tool to prepare chi-
ral compounds with a nitrogen atom bonded to a stereo-
genic center, working even on large scale. Continuing our
interest in the use of N-tert-butanesulfinyl imines as elec-
trophiles,4 we envisioned a straightforward stereoselective
synthesis of 2-substituted pyrrolidines and 5-substituted
indolizidin-7-ones, based on the diastereoselective addition
of Grignard reagents and -keto acids to chiral imines de-
rived from 4-halobutanal. The initially formed haloalkyl-
amine derivatives are transformed into the corresponding
pyrrolidines upon intramolecular nucleophilic substitution
involving the nitrogen atom, with the halogen atom acting
as a leaving group (Scheme 1). As far as we know, this strat-
egy was also reported by Reddy and Prashad in the forma-
tion of 2-substituted pyrrolidines by diastereoselective ad-
dition of Grignard reagents to N-tert-butanesulfinyl imine
of 4-chlorobutanal.5 The same compounds can be accessed
by performing a diastereoselective reduction of N-tert-
butanesulfinyl -chlorobutyl ketimines.6
Abstract An efficient stereocontrolled preparation of 2-substituted
pyrrolidines and 5-substituted indolizidin-7-ones, by using chiral N-tert-
butanesulfinyl imines derived from 4-halobutanal as starting materials,
is detailed. Addition of Grignard reagents and
a decarboxylative
Mannich reaction with -keto acids involving these chiral imines pro-
ceeded with high diastereoselectivity. The synthesis of the pyrrolidinic
alkaloids (–)-bgugaine, (+)-villatamine B, (–)-norhygrine, trans-dendro-
chrysanine, and (–)-ruspolinone demonstrated the utility of this meth-
odology.
Key words chiral sulfinyl imines, diastereoselective additions, decar-
boxylative Mannich reaction, bgugaine, villatamine, norhygrine, trans-
dendrochrysanine, ruspolinone
The pyrrolidine ring is not only widely represented in
nature, but this molecular array is also found in biologically
active molecules, including approved commercial drugs. As
a consequence, the number of synthetic methodologies
which allow an expeditious access to these systems is con-
stantly increasing. Most of these approaches consist of the
formation of the five-membered ring through a cyclization
process involving the nitrogen atom of an amine derivative
and a functional group located at an appropriate position
along the hydrocarbon chain. Preparation of substituted
pyrrolidines in a stereoselective fashion is of greater inter-
est, and this can be achieved when the cyclization reactions
are carried out using enantiopure precursors. Haloamines1
and aminoalkenes2 have been used as precursors in this
type of transformations, the pyrrolidine ring being formed
in the latter case through an intramolecular hydroamina-
tion reaction. Bicyclic systems containing bridgehead nitro-
gen, such as 1-azabicyclo[4.3.0]nonanes, the so-called pyr-
rolizidines, are also structural motifs less frequently en-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1750
A. Sirvent et al.
Feature
Synthesis
Biographical Sketches
Ana Sirvent received her B.Sc.
degree in chemistry from the
University of Alicante in 2015.
She also obtained an M.Sc. de-
gree in medicinal chemistry from
the same university in 2016 un-
at Yale University in 2019, she
has been a Ph.D. student in the
group of Prof. Francisco Foubelo
and Prof. Miguel Yus.
der the supervision of Prof. Fran-
cisco Foubelo. Since then, and
after a short research stay in the
group of Prof. Jonathan A. Ellman
Sandra Hernández Ibáñez re-
ceived her B.Sc. in biochemistry
from the University of Murcia in
2016. In 2017, she received her
M.S. in Research, Development,
Control and Innovation of Drugs
from the University of Granada,
conducting research under the
supervision of Professor Rafael
Salto González. In 2018, she ob-
tained her second M.S. in bio-
medical research from the
University of Valencia, conduct-
ing research under the supervi-
sion of Professor Carles Soler
Vázquez. Currently, she is a Ph.D.
candidate in the group of Profes-
sor Francisco Foubelo at the Uni-
versity of Alicante.
Miguel Yus was born in Zarago-
za (Spain) in 1947, and received
his B.S. (1969), M.S. (1971), and
Ph.D. (1973) degrees from the
University of Zaragoza. After
spending two years as a postdoc-
toral fellow at the Max Planck In-
stitut für Kohlenforschung in
Mülheim a. d. Ruhr he returned
to Spain to the University of
Oviedo where he became an as-
sociate professor in 1977, and
was promoted to full professor in
1987 at the same university. In
1988 he moved to a chair in or-
ganic chemistry at the University
of Alicante. Professor Yus has
of 77. He has received several in-
ternational awards and has also
been named an active academi-
cian by the European Academy of
Sciences and Arts, and is an aca-
demic member of the Athens In-
stitute for Education and
Research. Professor Yus has been
on the advisory board of more
than 30 international journals
and was also the editor-in-chief
of Letters in Organic Chemistry
and Open Chemistry. Professor
been
a visiting professor at
different institutions and univer-
sities including ETH-Zürich, Ox-
ford, Harvard, Uppsala, Marseille,
Tucson, Okayama, Paris, Stras-
bourg, Bolonia, Sassari, Tokyo,
and Kyoto. He has been a co-au-
thor of more than 600 papers
(and six patents) and has super-
vised 62 doctoral students (the-
ses already presented). He has
delivered about 250 lectures,
most of them abroad. His biblio-
metric data include more than
28,000 citations and an h-index
Yus founded
a new chemical
company MEDALCHEMY S.L. to
commercialize fine chemicals.
Francisco Foubelo was born in
1961 and studied chemistry at
the University of Oviedo where
he received B.S. (1984), M.S.
(1986), and Ph.D. (1989) de-
grees, under the direction of Pro-
fessors J. Barluenga, M. Yus, and
F. J. Fañanás. He then joined the
laboratory of Professor M. F.
Semmelhack at Princeton Uni-
versity as a Fulbright postdoctor-
al fellow, and, in 1991, the group
of Professor M. Yus at the Univer-
sity of Alicante, where he be-
came an associate professor in
2002. His current research inter-
ests are focused on the develop-
ment
of
new
synthetic
methodologies involving chiral
sulfinyl imines and on metal-
promoted functionalization of
alkenes and alkynes.
1995, and
a full professor in
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759

1751
A. Sirvent et al.
Feature
Synthesis
Me
( )n
MgBr
R1
O
S
O
S
2a (n = 10)
2b (n = 12)
2c (n = 14)
N
R2
N
t-Bu
HN
t-Bu
Br
Br
PhMe
–78 to 23 °C
( )n
H
Me
1a
3a (n = 10, 74%, >95:5 dr)
3b (n = 12, 64%, >95:5 dr)
3c (n = 14, 65%, >95:5 dr)
O
S
O
R1MgBr
H
S
N
t-Bu
HN
t-Bu
S
R1
R2
Hal
Hal
N
t-Bu
H
R1
[Hal = Br]
Mg
1. 2 M HCl–Et2O
MeOH, 0 °C
2. 2 M NaOH, CH2Cl2
0 °C
O
O
O
A
(SS)-imine: Re face attack
HO
R3
t-Bu
37% CH2O–H2O
NaBH4, MeOH
O
S
R3
O
NH
O
N
R4
23 °C
( )n
( )n
Me
Me
N
N
Me
5a (n = 10, 80%, 97:3 er)
5b (–)-bgugaine (n = 12, 79%, 97:3 er)
5c (n = 14, 89%, 94:6 er)
H
[Hal = Br]
Hal
R3
[R3 = Me, Hal = Cl]
4a (n = 10, 99%)
4b (n = 12, 99%)
4c (n = 14, 99%)
R5CHO
O
O
Me
S
S
N
( )12
MgBr
HN
t-Bu
N
t-Bu
O
Br
R5
Br
( )12
Me
H
ent-1a
ent-3b (64%, >95:5 dr)
Scheme 1 Retrosynthetic analysis for the preparation of 2-substituted
pyrrolidines and 5-substituted indolizidin-7-ones from N-tert-butane-
sulfinyl imines derived from 4-halobutanal
( )12
Me
( )12
ent-4b (99%)
Me
N
N
Me
H
ent-5b (95%, 94:6 er)
The addition of Grignard reagents to N-tert-butane-
sulfinyl aldimines proceeds with high levels of diastereo-
control when the reaction is performed in non-coordinat-
ing solvents, such as dichloromethane and toluene.7 The at-
tack of the Grignard reagent occurs on the Re face of the
imine with the S configuration at the sulfur atom, a cyclic
six-membered chelated transition state A being proposed
to rationalize these experimental results (Scheme 2).7b This
model was also consistent with the observed solvent effect.
Taking into account our experience in the diastereoselective
addition of organomagnesium compounds to these imines,8
we studied first the addition of a 1 M solution of dodecyl-
magnesium bromide (2a) in diethyl ether to imine 1a de-
rived from 4-bromobutanal and (S)-tert-butanesulfinamide
in toluene. The addition was carried out at –78 °C, and, after
that, the reaction mixture was allowed to reach room tem-
perature. The reaction product 3a was obtained in 74% yield
and excellent diastereoselectivity, and the configuration
was assigned according to mechanistic model A (Scheme 2).
Similarly, the reactions of chiral imine 1a with tetradecyl-
and hexadecylmagnesium bromide (2b and 2c, respective-
ly) provided compounds 3b and 3c, respectively, with simi-
lar yields and diastereoselectivities. Organomagnesium
compounds 2 were prepared from the corresponding com-
mercially available alkyl bromides upon reaction with mag-
nesium in anhydrous diethyl ether at 23 °C for 4 hours. The
configuration of the newly created stereogenic center is de-
termined by the configuration of the sulfur atom of the chi-
ral aldimine. In this respect, the reaction of ent-1a, which
derives from (R)-tert-butanesulfinamide, with tetradecyl-
Scheme 2 Stereoselective synthesis of 2-substituted pyrrolidines from
N-tert-butanesulfinyl bromoaldimines 1a, including natural alkaloid
(–)-bgugaine (5b)
magnesium bromide led to ent-3b, the enantiomer of 3b
(Scheme 2).
Further removal of the sulfinyl group under acidic con-
ditions in methanol as solvent, and subsequent treatment
of the resulting ammonium salt under basic conditions gave
the expected 2-substituted pyrrolidines 4 in quantitative
yields (Scheme 2). Final N-methylation of these heterocy-
cles by treatment with an excess of both aqueous formalde-
hyde and sodium borohydride yielded N-methylpyrrolidine
derivatives 5. Yields were excellent, and the enantiomeric
ratios were also extremely high in this last transformation,
and were determined by using an O-aryl lactic acid deriva-
1
tive as a chiral solvating agent in H NMR analysis.9 It was
not possible to determine the enantiomeric ratio of these
compounds by means of HPLC or GC with chromatographic
columns with a chiral packing. Compound 5b is (–)-
bgugaine,10 an alkaloid isolated from the tubers of Arisarum
vulgare, which is found on the Mediterranean coasts of Mo-
rocco and Spain.11 This compound is a potent hepatotoxin
in human liver cells, and has a strong binding affinity for
DNA, displaying antibacterial and antimycotic activities.12
Taking advantage of the previously reported methodolo-
gy, the pyrrolidine alkaloid (+)-villatamine B (12) was syn-
thesized from chiral bromoaldimine ent-1a and dodeca-
3,5-dien-1-ylmagnesium bromide (10) (Scheme 3). This
Grignard reagent was prepared following the methodology
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759

1752
A. Sirvent et al.
Feature
Synthesis
OH
O
MgBr
HBr (48%)
0 to 23 °C
Mg
7
Me
( )5
Me
Br
Me
MgBr
Me
( )5
( )5
( )5
H
THF, 67 °C
THF, 0 to 23 °C
10
8 (98%)
9 (95%)
6
O
S
N
t-Bu
Br
1. 2 M HCl–Et2O
MeOH, 0 °C
H
Me
Me
ent-1a
( )5
11 (65%, >95:5 dr)
N
S
N
2. MeCHO, NaBH4
MeOH, 23 °C
PhMe, –78 to 23 °C
Et
t-Bu
O
(+)-villatamine B (12, 98%, >95:5 er)
Scheme 3 Stereoselective synthesis of (+)-villatamine B (12) from N-tert-butanesulfinyl bromoaldimine ent-1a
developed by Davies and co-workers in the synthesis of (–)-
pseudodistotimin E,13 starting from (E)-non-2-enal (6). The
addition of cyclopropylmagnesium bromide (7) to aldehyde
6 gave allylic alcohol 8 in high yield. Treatment of 8 with an
aqueous solution of hydrogen bromide (48%) led to (3E,5E)-
1-bromododeca-3,5-diene (9) as the major diastereoisomer,
with less than 10% of the (3E,5Z) and (3Z,5E) isomers also
forming. Organomagnesium compound 10 was prepared
upon reaction of alkyl bromide 9 with magnesium, in the
presence of a catalytic amount of iodine, in THF at 67 °C for
1 hour. The addition of this THF solution of compound 10 to
a solution of chiral imine ent-1a in anhydrous toluene at
–78 °C, followed by stirring the reaction mixture to reach
room temperature, produced, surprisingly, N-tert-butane-
sulfinyl pyrrolidine 11. This compound was isolated as an
almost single diastereoisomer after column chromatogra-
phy purification, considering the configuration of the new
stereocenter (only a singlet corresponding to the tert-butyl
group was observed in the 1H NMR spectrum). Apparently,
after nucleophilic addition of the Grignard reagent, the re-
sulting magnesium amide underwent intramolecular cy-
clization, leading to 11. The synthesis of (+)-villatamine B
(12)14 was finally accomplished by carrying out desulfinyla-
tion under acidic conditions, and final N-ethylation through
a reductive amination with acetaldehyde (Scheme 3). This
marine alkaloid was isolated from the depredatory flat-
worm Prostheceraeus vittatus and its tunicate prey Claveli-
na lepadiformis, and exhibited cytotoxicity against different
human cancer cell lines.15
We have found that the base-promoted decarboxyl-
ative-Mannich coupling of -keto acids and N-tert-butane-
sulfinyl imines led to -amino ketone derivatives in high
yields and in a diastereoselective manner. In this case, the
nucleophilic addition of the enolate took place to the Re
face of imine with SS configuration. Based on DFT calcula-
tions, an eight-membered cyclic transition state B was pro-
posed to rationalize the experimental results (Scheme 4).16
A straightforward synthesis of (–)-norhygrine (15) was ac-
complished by the diastereoselective coupling of 3-oxo-
butanoic acid (13a) and chiral imine 1a. The base-promot-
ed decarboxylative-Mannich coupling of these reagents led
to -amino ketone derivative 14a in 85% isolated yield. Fur-
ther removal of the sulfinyl group under acidic conditions,
followed by intramolecular N-alkylation upon treatment
with sodium bicarbonate, yielded (–)-norhygrine (15),
which was easily isolated as its hydrochloride derivative
(Scheme 4). Interestingly, N-acylation of (–)-norhygrine
(15) with cinnamyl chloride led to (–)-trans-dendrochry-
sanine (16) in 77% yield, from -amino ketone derivative
14a. This alkaloid has been isolated from the stems of
Dendrobium chrysanthum,17 and according to 1H and 13C
NMR spectra, compound 16 exists at room temperature as
O
R1
H
O
Me
O
O
N
O
O
·HCl
Ph
Cl
2 M HCl–Et2O
23 °C
t-Bu
N
S
H
O
Me
Me
norhygrine (15)
O
N
N
R2
DMAP, Et3N, CH2Cl2
0 to 23 °C
O
H
H
Li
15·HCl (79%, 2 steps)
O
O
(–)-trans-dendrochrysanine
B
(16, 77%, 2 steps, 91.5:8.5 er)
1. 2 M HCl–Et2O, MeOH, 0 °C
2. NaHCO3, H2O, 23 °C
(R1 = Me)
t-Bu
O
O
(SS)-imine: Re face attack
HO
R1
O
S
O
13a (R1 = Me)
13b [R1 = 3,4-(MeO)2C6H3]
1. 2 M HCl–Et2O
MeOH, 0 °C
S
OMe
OMe
N
t-Bu
O
NH
O
N
H
LiOEt, THF, 0 to 23 °C
2. NaHCO3, H2O, 23 °C
[R1 = 3,4-(MeO)2C6H3]
Br
Br
H
R1
1a
14a (R1 = Me, 85%, >95:5 dr)
14b [R1 = 3,4-(MeO)2C6H3,
82%, >95:5 dr]
(–)-ruspolinone (17, 92%, 98.5:1.5 er)
Scheme 4 Stereoselective synthesis of (–)-norhygrine (15), dendrochrysanine (16), and (–)-ruspolinone (17) from N-tert-butanesulfinyl bromoaldi-
mine 1a
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759

1753
A. Sirvent et al.
Feature
Synthesis
O
O
O
S
t-Bu
S
HO
Me
Me
N
t-Bu
t-Bu
O
NH
O
1. 2 M HCl–Et2O, MeOH, 0 °C
13a
N
2. R2CHO, Et3N, L-proline, EtOH, 23 °C
Cl
Cl
LiOEt, THF
0 to 23 °C
O
H
Me
Me
R2
19a (R2 = n-Pr, 57%, 98:2 er)
19b (R2 = n-C6H13, 53%, 95.5:4.5 er)
1b
18 (81%, >95:5 dr)
O
O
O
S
t-Bu
S
HO
N
O
NH
O
1. 2 M HCl–Et2O, MeOH, 0 °C
13a
N
2. R2CHO, Et3N, L-proline, EtOH, 23 °C
Cl
Cl
LiOEt, THF
0 to 23 °C
O
H
n-Pr
ent-18 (81%, >95:5 dr)
ent-1b
ent-19a (55%, 98.5:1.5 er)
(R2 = n-C6H13
)
(R2 = n-Pr)
N
N
N
Me
O
R2
Me
19a (R2 = n-Pr)
19b (R2 = n-C6H13
167B (20a)
(–)-209D (20b)
)
Scheme 5 Stereoselective synthesis of indolizidinones 19a and 19b from N-tert-butanesulfinyl chloroaldimine 1b
an interconverting 4:1 mixture of atropoisomers.1d Decar-
boxylative coupling of -keto acid 13b and N-tert-butane-
sulfinyl imine 1a led to -amino ketone derivative 14b in
82% yield, and it was transformed under the previously
mentioned reaction conditions into (–)-ruspolinone (17) in
92% yield, an alkaloid isolated from Ruspolia bypercrateri-
formis, which has been proposed as a biosynthetic precur-
sor of septicine, tylophorine, and related alkaloids (Scheme
4).18,19
and ent-1b (RS-configuration). Enantiomeric ratios of com-
pounds 19 were found to be excellent, and were deter-
mined by GC using a chromatographic column with a chiral
packing (Scheme 5). Indolizidinones 19a and 19b could be
considered direct precursors21 of dendrobatid alkaloids
167D (20a) and (–)-209D (20b),22 respectively.
In conclusion, we have developed methodologies for the
enantioselective synthesis of 2-substituted pyrrolidines and
5-substituted indolizidin-7-ones, starting from N-tert-bu-
tanesulfinyl imines derived from 4-halobutanal. The stereo-
chemical outcome of the nucleophilic addition of organo-
magnesium reagents and the decarboxylative Mannich re-
action with 3-oxoalkanoic acids is governed by the
configuration of the sulfur atom of the chiral sulfinyl unit.
The formation of the pyrrolidine ring is achieved upon re-
moval of the sulfinyl group under acidic conditions, fol-
lowed by intramolecular N-alkylation. In addition, an L-pro-
line organocatalyzed intramolecular Mannich reaction of -
amino ketone derivatives with an aldehyde led to the for-
mation of 5-substituted indolizidin-7-ones. The usefulness
of these methodologies was illustrated by the total synthe-
sis of alkaloids such as (–)-bgugaine, (+)-villatamine B, (–)-
norhygrine, trans-dendrochrysanine, (–)-ruspolinone, as
well as by the synthesis of indolizidinones 19a and 19b,
which can be considered direct precursors of dendrobatid
indolizidine alkaloids 167D and (–)-209D.
It was also possible to carry out the stereoselective syn-
thesis of the indolizidine skeleton from chiral N-tert-bu-
tanesulfinyl haloimines 1 (Scheme 5). The base-promoted
decarboxylative-Mannich coupling of 3-oxobutanoic acid
(13a) and N-tert-butanesulfinyl imine 1b, derived from 4-
chlorobutanal, gave -amino ketone derivative 18 in 81%
yield. This compound participated in an L-proline organo-
catalyzed intramolecular Mannich reaction with an alde-
hyde (R2CHO: n-butanal and n-heptanal) to give cis-2,6-
disubstituted piperidin-4-ones,20 first, followed by a subse-
quent intramolecular N-alkylation involving the carbon–
chlorine bond, leading finally to the corresponding indol-
izidine 19, in moderate yields (Scheme 5). Importantly,
when the reaction was performed with bromine derivative
14a, the expected indolizidines 19 were obtained in less
than 10% yield, and a significant amount of (–)-norhygrine
(15) was also formed. Apparently, when N-alkylation of the
resulting free amine occurs first, after removal of the
sulfinyl group, L-proline intramolecular Mannich reaction
does not take place. Since alkyl bromides are better alkylat-
ing reagents than alkyl chlorides, notably higher yields of
indolizidines 19 were obtained starting from chloro deriva-
tive 18 instead of bromo derivative 14a. Both enantiomers
of 5-propylindolizidin-7-one (19a and ent-19a) are accessi-
ble through this methodology, the configuration of the re-
action product depending on the configuration of the sulfur
atom of the starting chloroaldimine 1b (SS-configuration)
All reactions were performed in dry glassware using conventional
Schlenck techniques under a static pressure of argon, unless other-
wise stated. Reagents and solvents were purchased from commercial
suppliers and used as received. tert-Butanesulfinamides (R and S)
were a gift from Medalchemy (>99% ee by chiral HPLC on a Chiracel
AS column, 90:10 n-hexane/i-PrOH, 1.2 mL/min,  = 222 nm). TLC was
performed on silica gel 60 F254, using aluminum plates and visualized
with phosphomolybdic acid (PMA) stain. Flash chromatography was
carried out on handpacked columns of silica gel 60 (230–400 mesh).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759

1754
A. Sirvent et al.
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Melting points are uncorrected. Optical rotations were measured us-
ing a Jasco P-1030 polarimeter with a thermally jacketed 5 cm cell at
approximately 23 °C and concentrations (c) are given in g/100 mL. En-
antiomeric ratios were determined by gas liquid chromatography
(GLC) on an Agilent 6890N Network gas chromatograph equipped
with a CP-Chirasil-Dex CB column. Infrared analyses were performed
with an ATR Jasco FT/IR-4100 spectrophotometer; wave numbers are
given in cm–1. Low-resolution mass spectra (EI) were obtained with
an Agilent GC/MS5973N spectrometer at 70 eV; and fragment ions in
m/z with relative intensities (%) in parentheses. High-resolution mass
spectra (HRMS) were also carried out in the electron impact mode
(EI) at 70 eV and on a Finnigan MAT95S spectrometer equipped with
a time of flight (TOF) analyzer and the samples were ionized by ESI
techniques and introduced through an ultra-high pressure liquid
chromatography (UPLC) model. 1H NMR spectra were recorded at 300
or 400 MHz for 1H NMR and 75 or 100 MHz for 13C NMR on a Bruker
AV300 Oxford or a Bruker AV400 spectrometer, respectively, using
CDCl3 and CD3OD as solvents, and TMS as internal standard ( = 0.00).
13C NMR spectra were recorded with 1H-decoupling at 100 MHz and
are referenced to CDCl3 at  = 77.16. DEPT-135 experiments were per-
formed to assign CH, CH2, and CH3. Imines 1a23 and 1b5 were prepared
from the corresponding aldehyde and (R)- or (S)-tert-butanesulfin-
amide in THF, in the presence of titanium tetraethoxide (2 equiv).
Compounds 13 were prepared by hydrolysis of the corresponding -
keto ester.
HRMS (ESI-TOF): m/z calcd for C16H32N [M+ – C4H10BrOS]: 238.2535;
found: 238.2529.
(4R,SS)-N-(tert-Butanesulfinyl)-1-bromooctadecan-4-amine (3b)
Purification by flash column chromatography (silica gel, hexane/EtOAc,
5:1) afforded 3b as a colorless oil; yield: 0.144 g (64%); Rf = 0.46
(hexane/EtOAc, 2:1); []D20 +13.7 (c 0.94, CH2Cl2).
IR (neat): 2919, 2854, 1461, 1369, 1265, 1056, 736 cm–1
.
1H NMR (400 MHz, CDCl3):  = 3.41 (t, J = 6.6 Hz, 2 H), 3.27–3.19 (m, 1
H), 2.99 (d, J = 6.7 Hz, 1 H), 2.04–1.81 (m, 2 H), 1.77–1.49 (m, 4 H),
1.29–1,25 (m, 24 H), 1.22 (s, 9 H), 0.92–0.84 (m, 3 H).
13C NMR (75 MHz, CDCl3):  = 56.1 (CH), 56.0 (C), 36.7 (CH2), 34.2
(CH2), 33.8 (CH2), 32.1 (CH2), 29.9 (CH2), 29.85 (CH2), 29.8 (CH2), 29.75
(CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 28.9 (CH2), 25.8 (CH2), 22.8
(CH2), 14.2 (CH3).
MS (EI, 70 eV): m/z (%) = 453 (M+ + 2, 0.02), 451 (M+, 0.01), 397 (35),
395 (34), 380 (11), 378 (11), 315 (20), 274 (15), 200 (10), 198 (10),
118 (42), 97 (10), 85 (22), 83 (16), 71 (30), 70 (54), 69 (17), 57 (100),
55 (20), 43 (26), 41 (27).
HRMS (ESI-TOF): m/z calcd for C18H3879BrNOS [M+ – C4H8]: 395.1857;
found: 395.1687.
(4S,RS)-N-(tert-Butanesulfinyl)-1-bromooctadecan-4-amine (ent-
3b)
Bromoalkyl Sulfinamides 3 by Diastereoselective Addition of
Grignard Reagents 2 to Bromoaldimines 1; General Procedure
Starting from aldimine ent-1a, and after purification by flash column
chromatography (silica gel, hexane/EtOAc, 5:1) ent-3b was afforded as
a colorless oil; yield: 0.144 g (64%). Physical and spectroscopic data
were found to be the same as for 3b; []D20 –23.9 (c 1.04, CH2Cl2).
The appropriate alkyl bromide (5.00 mmol) was added dropwise to a
suspension of Mg turnings (0.180 g, 7.50 mmol, 1.5 equiv) in anhyd
Et2O (3.00 mL). Then a catalytic amount of 1,2-dibromoethane (18.0
L, 0.25 mmol, 5 mol%) was added and the solution was stirred at r.t.
for 4 h. The resulting solution of alkylmagnesium bromide (2, ~1.1 M
in Et2O, 1.20 mL, 1.25 mmol, 2.5 equiv) was slowly added to a solution
of aldimine 1a (0.127 g, 0.50 mmol) in anhyd toluene (2.50 mL) at
–78 °C. The reaction mixture was allowed to reach r.t. over 15 h. After
that, it was cooled down to 0 °C, hydrolyzed with water (10 mL) and
extracted with EtOAc (3 × 15 mL). The organic layers were successive-
ly washed with water (15 mL) and brine (10 mL), then dried (MgSO4),
and concentrated under vacuum (15 Torr). The residue was purified
by column chromatography (silica gel, hexane/EtOAc, 5:1) to yield
pure compounds 3.
(4R,SS)-N-(tert-Butanesulfinyl)-1-bromoeicosan-4-amine (3c)
Purification by flash column chromatography (silica gel, hexane/EtOAc,
5:1) afforded 3c as a colorless wax; yield: 0.155 g (65%); Rf = 0.50
(hexane/EtOAc 2:1); []D20 +18.7 (c 1.09, CH2Cl2).
IR (neat): 2923, 2854, 1461, 1369, 1253, 1052, 728 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.41 (t, J = 6.6 Hz, 2 H), 3.29–3.19 (m, 1
H), 2.99 (d, J = 6.6 Hz, 1 H), 2.02–1.87 (m, 2 H), 1.77–1.48 (m, 4 H),
1.30–1,24 (m, 28 H), 1.22 (s, 9 H), 0.91–0.84 (m, 3 H).
13C NMR (75 MHz, CDCl3):  = 56.1 (CH), 56.0 (C), 36.7 (CH2), 34.2
(CH2), 33.8 (CH2), 32.1 (CH2), 29.9 (CH2), 29.85 (CH2), 29.8 (CH2), 29.75
(CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 28.9 (CH2), 25.8 (CH2), 22.8
(CH2), 14.2 (CH3).
(4R,SS)-N-(tert-Butanesulfinyl)-1-bromohexadecan-4-amine (3a)
MS (EI, 70 eV): m/z (%) = 481 (M+ + 2, 0.02), 479 (M+, 0.01), 425 (34),
423 (33), 406 (10), 344 (11), 343 (37), 302 (13), 118 (64), 85 (21), 83
(17), 71 (31), 70 (100), 69 (19), 57 (92), 55 (22), 43 (31), 41 (26)
Purification by flash column chromatography (silica gel, hexane/EtOAc,
5:1) afforded 3a as a colorless oil; yield: 0.156 g (74%); Rf = 0.45
(hexane/EtOAc 2:1); []D20 +7.0 (c 1.14, CH2Cl2).
IR (neat): 2923, 2854, 1461, 1365, 1253, 1052, 728 cm–1
.
HRMS (ESI-TOF): m/z calcd for C20H40N [M+ – C4H10BrOS]: 294.3161;
1H NMR (400 MHz, CDCl3):  = 3.41 (t, J = 6.6 Hz, 2 H), 3.27–3.19 (m, 1
H), 2.98 (d, J = 6.6 Hz, 1 H), 2.03–1.83 (m, 2 H), 1.73–1.48 (m, 4 H),
1.28–1,25 (m, 20 H), 1.21 (s, 9 H), 0.90–0.85 (m, 3 H).
13C NMR (75 MHz, CDCl3):  = 56.1 (CH), 56.0 (C), 36.7 (CH2), 34.2
(CH2), 33.8 (CH2), 32.1 (CH2), 29.9 (CH2), 29.8 (CH2), 29.75 (CH2), 29.7
(CH2), 29.6 (CH2), 29.5 (CH2), 28.9 (CH2), 25.8 (CH2), 22.8 (CH2), 14.2
(CH3).
MS (EI, 70 eV, 70 eV): m/z (%) = 425 (M+ + 2, 0.05), 423 (M+, 0.03), 369
(31), 367 (32), 352 (13), 350 (12), 246 (14), 198 (25), 152 (14), 150
(14), 118 (16), 97 (12), 85 (20), 83 (18), 71 (30), 70 (60), 69 (19), 57
(100), 55 (20), 43 (34), 41 (27).
found: 294.3161.
Pyrrolidines 4 from Bromoalkyl Sulfinamides 3; General Proce-
dure
To a solution of the appropriate bromoalkyl sulfinamide 3 (0.15
mmol) in MeOH (1.50 mL) was added a 2 M solution of HCl in Et2O
(0.75 mL, 1.50 mmol) at 0 °C. The reaction mixture was stirred at the
same temperature for 30 min. Complete formation of the correspond-
ing free amine hydrochloride was followed by TLC. After that, solvents
were evaporated (15 Torr), and the resulting residue was dissolved in
CH2Cl2 (1.00 mL). A 2 M aq solution of NaOH (1.00 mL) was slowly
added at 0 °C, and the reaction mixture was stirred for 2 h at the same
temperature. Then the layers were separated, and the aqueous layer
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1755
A. Sirvent et al.
Feature
Synthesis
was extracted with CH2Cl2 (5 × 5 mL). The combined organic layers
were dried (MgSO4) and concentrated under vacuum (15 Torr). The
residue was the corresponding pure compound 4.
N-Methylation of Pyrrolidines 4; General Procedure
To a solution of the appropriate pyrrolidine 4 (0.15 mmol) in MeOH
(1.00 mL) was added aq HCHO (37%; 0.11 mL, 0.120 g, 1.50 mmol) and
NaBH4 (0.057 g, 1.50 mmol) at 23 °C. The reaction mixture was stirred
at the same temperature for 4 h. After that, solvents were evaporated
(15 Torr), and to the resulting residue was added CH2Cl2 (2.00 mL),
and a 2 M aq solution of NaOH (2.00 mL). The resulting mixture was
stirred for 2 h. Then the layers were separated, and the aqueous layer
was extracted with CH2Cl2 (5 × 5 mL). The combined organic layers
were dried (MgSO4) and concentrated under vacuum (15 Torr). The
residue was the corresponding pure compound 5.
(R)-2-Dodecylpyrrolidine (4a)
Compound 4a was isolated as a yellow wax; yield: 0.036 g (99%); Rf =
0.61 (CH2Cl2/MeOH, 10:1); []D20 –13.3 (c 0.88, MeOH).
IR (neat): 2923, 2854, 1457, 1033, 721 cm–1
.
1H NMR (400 MHz, CD3OD):  = 3.05–2.96 (m, 2 H), 2.88–2.80 (m, 1
H), 2.01–1.92 (m, 1 H), 1.86–1.72 (m, 2 H), 1.61–1.43 (m, 4 H), 1.31–
1.27 (m, 20 H), 0.92–0.87 (m, 3 H).
13C NMR (100 MHz, CD3OD):  = 60.8 (CH), 46.8 (CH2), 36.1 (CH2), 33.1
(CH2), 32.5 (CH2), 30.9 (CH2), 30.8 (CH2), 30.75 (CH2), 30.7 (CH2), 30.65
(CH2), 30.5 (CH2), 28.5 (CH2), 25.7 (CH2), 23.7 (CH2), 14.4 (CH3).
MS (EI, 70 eV): m/z (%) = 239 (M+, 2.20), 238 (7), 98 (2), 96 (4), 83 (4),
71 (12), 70 (100), 57 (4), 56 (6), 55 (7).
(R)-2-Dodecyl-1-methylpyrrolidine (5a)
Compound 5a was isolated as a yellow wax; yield: 0.030 g (80%); Rf =
0.68 (CH2Cl2/MeOH, 10:1); []D20 –33.0 (c 0.67, MeOH).
IR (neat): 2923, 2854, 2776, 1457, 1168, 721 cm–1
1H NMR (300 MHz, CDCl3):  = 3.11–3.02 (m, 1 H), 2.30 (s, 3 H), 2.16–
2.08 (m, 1 H), 1.99–1.87 (m, 1 H), 1.82–1.60 (m, 4 H), 1.52–1.39 (m, 2
H), 1.28–1,24 (m, 20 H), 0.93–0.84 (m, 3 H).
.
HRMS (ESI-TOF): m/z calcd for C16H32N [M+ – H]: 238.2535; found:
238.2529.
13C NMR (75 MHz, CDCl3):  = 66.7 (CH), 57.5 (CH2), 40.6 (CH3), 34.0
(CH2), 32.1 (CH2), 31.0 (CH2), 30.2 (CH2), 29.8 (CH2), 29.5 (CH2), 26.9
(CH2), 22.8 (CH2), 22.0 (CH2), 14.2 (CH3).
MS (EI, 70 eV): m/z (%) = 253 (M+, 2.52), 252 (7), 110 (3), 97 (2), 96 (2),
84 (100), 82 (7), 69 (3), 68 (1), 57 (2), 56 (2), 55 (7).
(R)-2-Tetradecylpyrrolidine (4b)
Compound 4b was isolated as a white solid; mp 58–59 °C (hexane/
CH2Cl2) (Lit.24 mp 56–58 °C); yield: 0.040
g (99%); Rf = 0.62
20
(CH2Cl2/MeOH, 10:1); []D –9.1 (c 0.87, MeOH) [Lit.23 []D20–7.1 (c
1.10, MeOH)].
IR (neat): 2915, 2850, 1461, 910, 725 cm–1
HRMS (ESI-TOF): m/z calcd for C17H34N [M+ – H]: 252.2691; found:
252.2690.
.
1H NMR (300 MHz, CD3OD):  = 3.04–2.89 (m, 2 H), 2.85–2.75 (m, 1
H), 2.00–1.88 (m, 1 H), 1.85–1.72 (m, 2 H), 1.60–1.40 (m, 4 H), 1.31–
1,28 (m, 24 H), 0.92–0.88 (m, 3 H).
13C NMR (75 MHz, CD3OD):  = 60.7 (CH), 46.8 (CH2), 36.5 (CH2), 33.1
(CH2), 32.6 (CH2), 30.85 (CH2), 30.8 (CH2), 30.75 (CH2), 30.7 (CH2),
30.65 (CH2), 30.5 (CH2), 28.5 (CH2), 25.9 (CH2), 23.7 (CH2), 14.4 (CH3).
(–)-Bgugaine [(R)-1-Methyl-2-tetradecylpyrrolidine (5b)]
Compound 5b was isolated as a yellow oil; yield: 0.032 g (79%); Rf =
20
0.68 (CH2Cl2/MeOH, 10:1); []D20 –39.9 (c 0.75, MeOH) [Lit.25 []D
–45.0 (c 1.20, MeOH)].
IR (neat): 2923, 2854, 1461, 1122, 725 cm–1
.
MS (EI, 70 eV): m/z (%) = 267 (M+, 0.43), 266 (1), 110 (1), 96 (3), 83 (7),
71 (5), 70 (100), 55 (3).
1H NMR (400 MHz, CDCl3):  = 3.10–3.04 (m, 1 H), 2.31 (s, 3 H), 2.16–
2.10 (m, 1 H), 2.01–1.87 (m, 1 H), 1.81–1.61 (m, 4 H), 1.47–1,42 (m, 2
H), 1.29–1.25 (m, 24 H), 0.88 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 60.7 (CH), 57.5 (CH2), 40.6 (CH2), 34.0
(CH2), 32.1 (CH2), 31.0 (CH2), 30.2 (CH2), 29.85 (CH2), 29.80 (CH2),
29.75 (CH2), 29.5 (CH2), 26.9 (CH2), 22.8 (CH2), 22.0 (CH2), 14.2 (CH3).
(S)-2-Tetradecylpyrrolidine (ent-4b)
Starting from bromoalkyl sulfinamide ent-3b, compound ent-4b was
isolated as a white solid; yield: 40 mg (99%). Physical and spectro-
scopic data were found to be the same as for 4b; []D +8.3 (c 0.50,
MeOH).
20
MS (EI, 70 eV): m/z (%) = 281 (M+, 0.53), 280 (1), 94 (1), 85 (6), 84
(100), 82 (2), 55 (2).
(R)-2-Hexadecylpyrrolidine (4c)
(+)-Bgugaine [(S)-1-Methyl-2-tetradecylpyrrolidine (ent-5b)]
Compound 4c was isolated as a white solid; mp 40–41 °C (hex-
ane/CH2Cl2); yield: 0.044 g (99%); Rf = 0.63 (CH2Cl2/MeOH, 10:1);
[]D20 –1.15 (c 1.29, MeOH).
IR (neat): 2923, 2854, 1457, 1029, 721 cm–1
1H NMR (500 MHz, CD3OD):  = 3.05–2.97 (m, 2 H), 2.89–2.82 (m, 1
H), 2.01–1.94 (m, 1 H), 1.87–1.74 (m, 2 H), 1.62–1.38 (m, 4 H), 1.32–
1.27 (m, 28 H), 0.90 (t, J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CD3OD):  = 60.9 (CH), 46.8 (CH2), 36.1 (CH2), 33.1
(CH2), 32.4 (CH2), 30.85 (CH2), 30.8 (CH2), 30.75 (CH2), 30.7 (CH2),
30.65 (CH2), 30.6 (CH2), 30.55 (CH2), 30.4 (CH2), 28.4 (CH2), 25.7 (CH2),
23.7 (CH2), 14.4 (CH3).
Starting from bromoalkyl sulfinamide ent-4b, compound ent-5b was
isolated as a yellow oil; yield: 0.040 g (95%). Physical and spectroscop-
20
ic data were found to be the same as for 5b; []D +32.9 (c 0.72,
.
MeOH).
(R)-2-Hexadecyl-1-methylpyrrolidine (5c)
Compound 5c was isolated as a white solid; mp 30–32 °C (hex-
ane/CH2Cl2); yield: 42 mg (89%); Rf = 0.69 (CH2Cl2/MeOH, 10:1); []D
–39.1 (c 0.42, MeOH).
20
IR (neat): 2915, 2850, 1461, 1168, 725 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.11–3.01 (m, 1 H), 2.30 (s, 3 H), 2.18–
2.06 (m, 1 H), 1.98–1.92 (m, 1 H), 1.87–1.55 (m, 4 H), 1.51–1.33 (m, 2
H), 1.29–1.25 (m, 28 H), 0.92–0.84 (m, 3 H).
MS (EI, 70 eV): m/z (%) = 295 (M+, 0.41), 294 (1), 96 (1), 83 (2), 71 (5),
70 (100), 68 (2), 57 (3), 56 (2), 55 (3).
HRMS (ESI-TOF): m/z calcd for C20H40N [M+ – H]: 294.3161; found:
294.3159.
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1756
A. Sirvent et al.
Feature
Synthesis
13C NMR (75 MHz, CDCl3):  = 66.7 (CH), 57.5 (CH2), 40.6 (CH3), 34.0
(CH2), 32.1 (CH2), 31.0 (CH2), 30.2 (CH2), 29.85 (CH2), 29.8 (CH2), 29.75
(CH2), 29.7 (CH2), 29.5 (CH2), 26.9 (CH2), 22.8 (CH2), 22.0 (CH2), 14.2
(CH3).
MS (EI, 70 eV): m/z (%) = 246 (M+ + 2, 21.17), 244 (M+, 21.03), 162 (29),
160 (29), 95 (27), 93 (30), 91 (26), 81 (100), 80 (19), 79 (50), 77 (32),
67 (57), 55 (16).
HRMS (ESI-TOF): m/z calcd for C12H2179Br [M+]: 244.0827; found:
244.0818.
MS (EI, 70 eV): m/z (%) = 309 (M+, 3.35), 308 (12), 110 (3), 97 (2), 96
(2), 85 (15), 84 (100), 82 (6), 70 (3), 69 (4), 56 (3), 55 (7).
HRMS (ESI-TOF): m/z calcd for C21H42N [M+ – H]: 308.3317; found:
(2S,RS)-1-(tert-Butanesulfinyl)-2-[(3E,5E)-dodeca-3,5-dien-1-yl]-
pyrrolidines (11)
308.3316.
A small portion (0.25 mL) of a solution of 9 (0.610 g, 2.50 mmol) in
anhyd THF (2.50 mL) was added dropwise to Mg turnings (0.096 g,
3.75 mmol, 1.5 equiv) and I2 (0.006 g, 0.0025 mmol, 10 mol%) at r.t.
This suspension was then heated with a heat gun until the solvent
started to reflux. The rest of the solution of 9 in THF was added to the
reaction flask, and the mixture was heated at 70 °C for 1 h, and after
that, it was allowed to cool down to r.t. for 1 h. The resulting solution
of 1-dodeca-3,5-dienylmagnesium bromide (10, ~0.5 M in THF, 2.00
mL, 1.00 mmol, 2.5 equiv) was slowly added at –78 °C to a solution of
the sulfinyl imine ent-1a (0.102 g, 0.40 mmol) in anhyd toluene (3.00
mL). The mixture was allowed to reach r.t. over 15 h. After that, it was
cooled down to 0 °C, hydrolyzed with water (10 mL) and extracted
with EtOAc (3 × 15 mL). The organic layers were dried (MgSO4), and
concentrated under vacuum (15 Torr). The residue was purified by
flash column chromatography (silica gel, hexane/EtOAc, 5:1), afford-
ing 11 as a yellow oil; yield: 0.088 g (65%); Rf = 0.50 (hexane/EtOAc
2:1); []D20 +10.9 (c 0.98, CH2Cl2).
(E)-1-Cyclopropylnon-2-en-1-ol (8)
Cyclopropyl bromide (1.452 g, 1.05 mL, 12.00 mmol) was added drop-
wise to a suspension of Mg turnings (0.432 g, 18.00 mmol, 1.5 equiv)
in anhyd THF (7.20 mL). Then a catalytic amount of 1,2-dibro-
moethane (43.0 L, 0.60 mmol, 5 mol%) was added, and the solution
was stirred at r.t. for 4 h. The resulting solution of cyclopropylmagne-
sium bromide (7, ~1.1 M in THF, 5.50 mL, 6.00 mmol) was slowly add-
ed to a solution of (E)-non-2-enal (6, 0.420 g, 0.50 mL, 3.00 mmol) in
anhyd THF (6.50 mL) at –0 °C. The mixture was allowed to reach r.t.
over 15 h. After that, it was cooled down to 0 °C, hydrolyzed with a
sat. aq solution of NH4Cl (5.00 mL), and extracted with Et2O (3 × 10
mL). The organic layers were dried (MgSO4), and concentrated under
vacuum (15 Torr). The residue was pure enough for the next step, af-
fording 8 as a yellow oil; yield: 0.535 g (98%); Rf = 0.32 (hexane/Et2O,
3:1).
IR (neat): 3347, 3077, 2923, 2857, 1457, 1014, 968, 917 cm–1
.
IR (neat): 2923, 2861, 1457, 1361, 1068, 987 cm–1
.
1H NMR (400 MHz, CDCl3):  = 5.70–5.62 (m, 1 H), 5.58–5.50 (m, 1 H),
3.48–3.42 (m, 1 H), 2.07–1.99 (m, 2 H), 1.75 (br s, 1 H), 1.40–1.34 (m,
2 H), 1.33–1.21 (m, 6 H), 1.04–0.93 (m, 1 H), 0.91–0.84 (m, 3 H), 0.57–
0.45 (m, 2 H), 0.36–0.29 (m, 1 H), 0.25–0.18 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 132.3 (CH), 131.4 (CH), 77.2 (CH), 32.4
(CH2), 31.8 (CH2), 29.3 (CH2), 29.0 (CH2), 22.7 (CH2), 17.7 (CH), 14.2
(CH3), 3.1 (CH2), 2.1 (CH).
MS (EI, 70 eV): m/z (%) = 182 (M+, 6.45), 164 (21), 154 (19), 110 (21),
98 (15), 97 (100), 93 (43), 91 (30), 84 (32), 83 (64), 81 (28), 80 (27), 79
(77), 77 (26), 70 (42), 69 (50), 67 (38), 57 (20), 55 (63).
1H NMR (300 MHz, CDCl3):  = 6.08–5.92 (m, 2 H), 5.63–5.49 (m, 2 H),
3.69–3.60 (m, 1 H), 3.51–3.42 (m, 1 H), 3.17–3.10 (m, 1 H), 2.17–1,97
(m, 4 H), 1.88–1.75 (m, 4 H), 1.64–1.46 (m, 2 H), 1.42–1.31 (m, 2 H),
1.32–1.21 (m, 6 H), 1.19 (s, 9 H), 0.91–0.84 (m, 3 H).
13C NMR (75 MHz, CDCl3):  = 133.2 (CH), 131.1 (CH), 130.9 (CH),
130.1 (CH), 58.5 (CH), 57.5 (C), 48.5 (CH2), 34.2 (CH2), 32.7 (CH2), 31.8
(CH2), 30.8 (CH2), 30.0 (CH2), 29.5 (CH2), 29.0 (CH2), 24.4 (CH2), 23.7
(CH3), 22.8 (CH2), 14.2 (CH3).
MS (EI, 70 eV): m/z (%) = 339 (M+, 0.01), 266 (23), 235 (77), 234 (100),
192 (15), 164 (20), 150 (49), 137 (25), 136 (17), 124 (23), 118 (42),
110 (48), 96 (29), 83 (17), 70 (42), 67 (18), 57 (24).
HRMS (ESI-TOF): m/z calcd for
C12H22O
[M+]: 182.1671; found:
182.1678.
HRMS (ESI-TOF): m/z calcd for C16H28N [M+ – C4H9OS]: 234.2222;
found: 234.2227.
(3E,5E)-1-Bromododeca-3,5-diene (9)
A concentrated aq solution of HBr (48%, 0.50 mL, 4.40 mmol, 4.0
equiv) was added to a 10 mL flask containing (E)-1-cyclopropylnon-2-
en-1-ol (8, 0.200 g, 1.10 mmol) at 0 °C. The reaction mixture was
stirred at r.t. for 15 h. After that, hexane (15.0 mL) and H2O (10.0 mL)
were successively added. Then the layers were separated, and the
aqueous layer was extracted with hexane (3 × 15 mL). The combined
organics were dried (MgSO4), and concentrated under vacuum (15
Torr). The residue was purified by flash column chromatography (sili-
(+)-Villatamine B {(S)-2-[(3E,5E)-Dodeca-3,5-dien-1-yl]-N-ethyl-
pyrrolidine (12)}
To a solution of compound 11 (0.066 g, 0.19 mmol) in MeOH (2.00
mL) was added a 2 M solution of HCl in Et2O (0.95 mL, 1.90 mmol) at 0
°C. The reaction mixture was stirred at the same temperature for 30
min. After that, solvents were evaporated (15 Torr), and the resulting
residue was dissolved in MeOH (1.30 mL). Acetaldehyde (0.11 mL,
1.90 mmol, 10.0 equiv) and NaBH4 (0.070 g, 1.90 mmol, 10.0 equiv)
were added to the methanolic solution, and it was stirred for 15 h at
r.t. After that solvents were evaporated (15 Torr), and a 2 M aq solu-
tion of NaOH (2.00 mL) and CH2Cl2 (2.00 mL) were added to the resi-
due. The mixture was stirred for 2 h, and, after that, layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (5 × 5 mL). The
combined organic layers were dried (MgSO4), and concentrated under
vacuum (15 Torr). The residue was not purified, affording 12 as a yel-
ca gel, petroleum ether), affording
9
[90:5:5 mixture of
(E,E)/(E,Z)/(Z,E) isomers] as a colorless oil; yield: 0.256 g (95%); Rf =
0.73 (hexane).
IR (neat): 3012, 2923, 2857, 1454, 987, 732 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.14–5.95 (m, 2 H), 5.65 (dt, J = 14.3,
7.0 Hz, 1 H), 5.52 (dt, J = 14.6, 7.0 Hz, 1 H), 3.38 (t, J = 7.1 Hz, 2 H), 2.62
(q, J = 7.1 Hz, 2 H), 2.06 (q, J = 7.9 Hz, 2 H), 1.42–1.34 (m, 2 H), 1.33–
1.23 (m, 6 H), 0.91–0.87 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 134.8 (CH), 133.4 (CH), 129.8 (CH),
127.6 (CH), 36.1 (CH2), 32.8 (CH2), 32.5 (CH2), 31.9 (CH2), 29.4 (CH2),
29.0 (CH2), 22.7 (CH2), 14.2 (CH3).
20
low oil; yield: 0.049 g (98%); Rf = 0.58 (CH2Cl2/MeOH, 10:1); []D
+45.1 (c 0.45, MeOH) [Lit.14 []D20 +55.2 (c 0.41, MeOH)].
IR (neat): 3016, 2923, 2857, 2788, 1454, 1195, 983, 725 cm–1
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759

1757
A. Sirvent et al.
Feature
Synthesis
1H NMR (300 MHz, CDCl3):  = 6.12–5.84 (m, 2 H), 5.66–5.45 (m, 2 H),
3.21–3.13 (m, 1 H), 2.93–2.82 (m, 1 H), 2.21–1.86 (m, 7 H), 1.81–1,63
(m, 4 H), 1.51–1.41 (m, 2 H), 1.40–1.31 (m, 2 H), 1.30–1.25 (m, 6 H),
1.10 (t, J = 7.1 Hz, 3 H), 0.91–0.85 (m, 3 H).
13C NMR (75 MHz, CDCl3):  = 132.8 (CH), 132.0 (CH), 130.4 (CH),
130.3 (CH), 64.6 (CH), 53.7 (CH2), 48.3 (CH2), 34.0 (CH2), 32.7 (CH2),
31.9 (CH2), 30.6 (CH2), 29.9 (CH2), 29.5 (CH2), 29.3 (CH2), 22.7 (CH2),
22.0 (CH3), 14.2 (CH3), 13.8 (CH3).
(–)-Norhygrine·HCl (15·HCl)
To a solution of compound 14a (0.047 g, 0.15 mmol) in MeOH (2.00
mL) was added a 2 M solution of HCl in Et2O (0.75 mL, 1.50 mmol) at 0
°C. The reaction mixture was stirred at the same temperature for 30
min. After that, solvents were evaporated (15 Torr), and the resulting
residue was dissolved in CH2Cl2 (3.00 mL). Then, a sat. aq NaHCO3
solution was added, and the reaction mixture was stirred at r.t. for 15
h; after that, layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (5 × 5 mL). The combined organic layers contain-
ing (–)-norhygrine [GC-MS: single peak, m/z 127 (M+, 6%)] was treat-
ed with a 2 M HCl solution in Et2O (0.5 mL, 1.0 mmol) for 15 min and
after that the solvents were evaporated (15 Torr) to yield (–)-norhy-
grine hydrochloride (15·HCl) as a white solid; yield: 0.0194 g (79%);
[]D20 –19.1 (c 0.63, EtOH).
MS (EI, 70 eV): m/z (%) = 263 (M+, 2.53), 192 (8), 124 (26), 111 (10), 98
(100), 70 (6).
Reaction of -Keto Acids 13 with Sulfinyl Imine 1a; General Proce-
dure
To a solution of the appropriate -keto acid 13 (0.30 mmol) in THF
(2.00 mL) was added a 1 M solution of LiOEt in THF (0.40 mL, 0.40
mmol) at 0 °C. The reaction mixture was allowed to reach r.t., and
then imine 1a (0.051 g, 0.20 mmol) was added and stirring was con-
tinued for 8 h at the same temperature. The resulting mixture was hy-
drolyzed with H2O (10 mL), and extracted with EtOAc (3 × 15 mL). The
organic phase was dried (MgSO4), and the solvent evaporated (15
Torr). The residue was purified by column chromatography (silica gel,
hexane/EtOAc, 1:2) to yield pure compounds 14.
IR (neat): 3394, 2915, 1708, 1369 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.47 (s, 1 H), 8.24 (s, 1 H), 3.97–3.77
(m, 1 H), 3.41–3.25 (m, 3 H), 2.91 (dd, J = 18.6, 5.9 Hz, 1 H), 2.25–2.18
(m, 1 H), 2.18 (s, 3 H), 2.04–1.87 (m, 2 H), 1.68–1.55 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 205.9 (C), 55.2 (CH), 45.4 (CH2), 45.1
(CH2), 30.5 (CH2), 30.2 (CH3), 23.8 (CH2).
(–)-trans-Dendrochrysanine (16)
To a solution of compound 14a (0.047 g, 0.15 mmol) in MeOH (2.00
mL) was added a 2 M solution of HCl in Et2O (0.75 mL, 1.50 mmol) at 0
°C. The reaction mixture was stirred at the same temperature for 30
min. After that, solvents were evaporated (15 Torr), and the resulting
residue was dissolved in CH2Cl2 (3.00 mL). Then, a sat. aq NaHCO3
solution was added, and the reaction mixture was stirred at r.t. for 15
h; after that, layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (2 × 5 mL). To the combined organic layers con-
taining (–)-norhygrine were successively added a solution of cinnam-
yl chloride (0.046 g, 42.0 L, 0.30 mmol) and DMAP (0.0037 g, 0.03
mmol) in CH2Cl2, and Et3N (0.030 g, 42.0 L, 0.30 mmol) at 0 °C. The
resulting mixture was stirred at r.t. for 16 h. After that, it was hydro-
lyzed with water (10 mL) and extracted with CH2Cl2 (3 × 5 mL). The
organic layers were dried (MgSO4), and concentrated under vacuum
(15 Torr). The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc, 2:1), affording 16 as a yellow wax; 91.5:8.5
er [GC (CP-Chirasil-Dex CB column, Tinjector = 275 °C, Tdetector = 250 °C,
Tcolumn = 100 °C (10 min) and 100–200 °C (2.5 °C/min), P = 101 kPa):
tmajor = 38.45 min, tminor = 38.76 min]; yield: 0.0296 g (77%); Rf = 0.28
(hexane/EtOAc, 1:1); []D20 –17.2 (c 1.00, CH2Cl2) [Lit.26 []D20 –11.8 (c
= 0.15, CHCl3)].
(4S,SS)-N-(tert-Butanesulfinyl)-4-amino-7-bromoheptan-2-one
(14a)
Purification by flash column chromatography (silica gel, hexane/EtOAc,
1:2) afforded 14a as a colorless oil; yield: 0.053 g (85%); Rf = 0.18
(hexane/EtOAc, 1:3); []D20 +39.0 (c 1.23, CH2Cl2).
IR (neat): 3217, 2958, 1709, 1415, 1365, 1254, 1049, 895, 733 cm–1
1H NMR (400 MHz, CDCl3):  = 4.06 (d, J = 9.4 Hz, 1 H), 3.57–3.47 (m, 1
H), 3.41 (t, J = 6.6 Hz, 2 H), 2.99–2.78 (m, 2 H), 2.16 (s, 3 H), 2.07–1.95
(m, 1 H), 1.95–1.84 (m, 1 H), 1.84–1.59 (m, 2 H), 1.21 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 208.0 (C), 56.0 (C), 53.3 (CH), 49.1
(CH2), 34.2 (CH2), 33.3 (CH2), 31.1 (CH3), 29.6 (CH2), 22.7 (CH3).
MS (EI, 70 eV): m/z (%) = 257 (M+ – C4H8, 17), 255 (17), 199 (100), 197
(98), 158 (18), 70 (23), 57 (64), 43 (46), 41 (18).
.
HRMS (ESI-TOF): m/z calcd for C7H13NO2S [M+ – C4H8Br]: 175.0667;
found: 175.0672.
(3S,SS)-N-(tert-Butanesulfinyl)-3-amino-6-bromo-1-(3,4-dimeth-
oxyphenyl)hexan-1-one (14b)
Purification by flash column chromatography (silica gel, hexane/EtOAc,
1:2) afforded 14b as a yellow oil; yield: 0.071 g (82%); Rf = 0.17
(hexane/EtOAc, 1:3); []D20 +36.6 (c 0.93, CH2Cl2).
IR (neat): 2962, 2875, 1708, 1647, 1597, 1415, 1369, 1153, 1061, 976,
764, 702 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.68 (d, J = 15.5 Hz, 1 H), 7.51 (d, J = 1.8
Hz, 2 H), 7.40–7.33 (m, 3 H), 6.71 (d, J = 15.5 Hz, 1 H), 4.64–4.58 (m,
0.2 H, minor atropoisomer), 4.56–4.46 (m, 0.8 H, major atroisomer),
3.74–3.55 (m, 2 H), 3.27 (dd, J = 16.4, 3.5 Hz, 0.8 H, major atropoiso-
mer), 2.77–2.74 (m, 0.4 H, minor atropoisomer), 2.46 (dd, J = 16.4, 9.3
Hz, 0.8 H, major atropoisomer), 2.19 (s, 3 H), 2.18 (s, 1 H), 2.02 – 1.93
(m, 2 H), 1.82 – 1.69 (m, 1 H).
IR (neat): 3270, 2950, 1666, 1589, 1516, 1458, 1415, 1358, 1261,
1157, 1022, 872, 810, 760 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.58 (dd, J = 8.4, 2.1 Hz, 1 H), 7.50 (d, J =
2.0 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 4.23 (d, J = 9.1 Hz, 1 H), 3.95 (s, 3
H), 3.93 (s, 3 H), 3.80–3.64 (m, 1 H), 3.49–3.26 (m, 4 H), 2.16–1.99 (m,
1 H), 2.02–1.84 (m, 1 H), 1.83–1.72 (m, 2 H), 1.23 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 197.8 (C), 153.8 (C), 149.2 (C), 130.25
(C), 123.1 (CH), 110.2 (CH), 56.2 (CH3), 56.2 (CH3), 56.1 (CH), 54.1
(CH), 44.0 (CH2), 34.4 (CH2), 33.4 (CH2), 29.8 (CH2), 22.9 (CH3).
MS (EI, 70 eV): m/z (%) = 379 (M+ – C4H8, 5), 377 (5), 297 (12), 181
(32), 180 (31), 166 (11), 165 (100), 117 (63), 70 (21), 57 (24).
13C NMR (100 MHz, CDCl3):  = 207.3 (C), 164.9 (C), 142.2 (CH), 135.3
(C), 129.6 (CH), 128.8 (CH), 127.9 (CH), 118.9 (CH), 54.0 (CH3), 53.1
(CH), 47.2 (CH2), 47.1 (CH2), 30.4 (CH2), 24.1 (CH2).
MS (EI, 70 eV): m/z (%) = 200 (M+ – CH2COCH3, 2), 132 (12), 131 (100),
126 (16), 103 (34), 102 (6), 84 (21), 77 (17), 70 (6).
HRMS (ESI-TOF): m/z calcd for C14H2079BrNO4S [M+ – C4H8]: 377.0296;
found: 377.0305.
HRMS (ESI-TOF): m/z calcd for C16H19NO2 [M+]: 257.1416; found:
257.1419.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759

1758
A. Sirvent et al.
Feature
Synthesis
(–)-Ruspolinone (17)
(4R,RS)-N-(tert-Butanesulfinyl)-4-amino-7-chloroheptan-2-one
(ent-18)
To a solution of compound 14b (0.15 mmol) in MeOH (1.50 mL) was
added a 2 M solution of HCl in Et2O (0.75 mL, 1.50 mmol) at 0 °C. The
reaction mixture was stirred at the same temperature for 30 min. Af-
ter that, solvents were evaporated (15 Torr) and the resulting residue
was dissolved in CH2Cl2 (4.00 mL). A 2 M aq solution of NaOH (2.00
mL) was slowly added at 0 °C, and the reaction mixture was stirred for
2 h at the same temperature. Then the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 8 mL). The combined or-
ganic layers were dried (MgSO4), and concentrated under vacuum (15
Torr). The residue was not purified, affording 17 as a colorless wax;
Starting from chloro imine ent-1b, and after purification by flash col-
umn chromatography (silica gel, hexane/EtOAc, 1:2) ent-18 was af-
forded as a yellow oil; yield: 0.0434 g (81%). Physical and spectroscop-
20
ic data were found to be the same as for 18; []D –41.6 (c 1.47,
CH2Cl2).
Reaction of -Keto Amine Derivatives 18 with Aldehydes; General
Procedure
To a solution of the appropriate -keto amine derivative 18 (0.039 g,
0.15 mmol) in MeOH (1.50 mL) was added a 2 M solution of HCl in
Et2O (0.75 mL, 1.50 mmol) at 0 °C. The reaction mixture was stirred at
the same temperature for 30 min. After that, solvents were evaporat-
ed (15 Torr), and to the resulting residue were successively added L-
proline (0.0035 g, 0.03 mmol), MgSO4 (0.018 g, 0.15 mmol), EtOH
(1.50 mL), Et3N (0.016 g, 28.0 L, 0.15 mmol), and the corresponding
aldehyde (0.15 mmol, 0.011 g, 13.75 L, for n-butanal; 0.017 g, 21.0
L, for heptanal). The resulting mixture was stirred for 6 h at r.t. Then,
it was hydrolyzed with a sat. aq solution of NaHCO3 (8.00 mL), and ex-
tracted with EtOAc (3 × 15 mL). The organic phase was extracted with
0.15 M HCl (3 × 15 mL), and the resulting acidic aqueous phase was
basified with a 1 M aq NaOH solution (pH 9–10), and extracted with
EtOAc (3 × 15 mL). The new organic phase was dried (MgSO4), and the
solvent was evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, CH2Cl2/MeOH, 95:1) to yield pure com-
pounds 19.
98.5:1.5 er [GC (CP-Chirasil-Dex CB column, Tinjector = 275 °C, Tdetector
=
250 °C, Tcolumn = 100 °C (10 min) and 100–200 °C (2.5 °C/min), P = 101
kPa): tminor = 33.24 min, tmajor = 33.59 min]; yield: 0.0343 g (92%); Rf =
20
0.25 (CH2Cl2/MeOH, 10:1); []D –20.2 (c 0.79, CH2Cl2) [Lit.19 for (–)-
ruspolinone []D20 –29.7 (c = 0.74, CH2Cl2)].
IR (neat): 2950, 2873, 1666, 1589, 1512, 1458, 1415, 1260, 1150,
1018, 876, 810, 760 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.59 (dd, J = 8.4, 2.0 Hz, 1 H), 7.52 (d, J =
2.0 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.66–
3.51 (m, 1 H), 3.15 (dd, J = 6.4, 4.9 Hz, 2 H), 3.11–2.88 (m, 2 H), 2.76 (s,
1 H), 2.09–1.93 (m, 1 H), 1.96–1.70 (m, 2 H), 1.53–1.37 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 198.2 (C), 153.4 (C), 149.1 (C), 130.5
(C), 122.9 (CH), 110.2 (CH), 110.1 (CH), 56.15 (CH3), 56.1 (CH3), 55.0
(CH), 46.25 (CH2), 44.5 (CH2), 31.4 (CH2), 24.8 (CH2).
MS (EI, 70 eV): m/z (%) = 180 (M+ – C4H7N, 55), 166 (11), 165 (100),
137 (11), 122 (7), 79 (10), 77 (10), 51 (5).
HRMS (ESI-TOF): m/z calcd for C14H19NO3 [M+]: 249.1365; found:
(5R,8aS)-5-Propylhexahydroindolizin-7(1H)-one (19a)
249.1360.
Purification by flash column chromatography (silica gel, CH2Cl2/
MeOH, 95:1) afforded 19a as a yellow oil; 98:2 er [GC (CP-Chirasil-
Dex CB column, Tinjector = 275 °C, Tdetector = 250 °C, Tcolumn = 100 °C (10
min) and 100–200 °C (2.5 °C/min), P = 101 kPa): tminor = 30.77 min,
tmajor = 31.25 min]; yield: 0.0155 g (57%); Rf = 0.17 (CH2Cl2/MeOH,
99:1); []D20 –22.7 (c 0.90, CH2Cl2).
(4S,SS)-N-(tert-Butanesulfinyl)-4-amino-7-chloroheptan-2-one
(18)
To a solution of -keto acid 13a (0.031 g, 0.30 mmol) in THF (2.00 mL)
was added a 1 M solution of LiOEt in THF (0.40 mL, 0.40 mmol) at 0
°C. The reaction mixture was allowed to reach r.t., and then imine 1b
(0.042 g, 0.20 mmol) was added and stirring was continued for 8 h at
the same temperature. The resulting mixture was hydrolyzed with
H2O (10 mL), and extracted with EtOAc (3 × 15 mL). The organic phase
was dried (MgSO4), and the solvent was evaporated (15 Torr). The res-
idue was purified by flash column chromatography (silica gel, hex-
ane/EtOAc, 1:2), affording 18 as a yellow oil; yield: 0.0434 g (81%); Rf =
0.18 (hexane/EtOAc, 1:3); []D20 +43.0 (c 1.21, CH2Cl2)
IR (neat): 2958, 2873, 2792, 1712, 1458, 1373, 1053, 806, 733 cm–1
.
1H NMR (400 MHz, CDCl3):  = 3.28 (td, J = 8.8, 2.5 Hz, 1 H), 2.50 (dd,
J = 11.0, 2.1 Hz, 1 H), 2.43–2.20 (m, 5 H), 2.13 (q, J = 8.9 Hz, 1 H), 2.01–
1.87 (m, 2 H), 1.85–1.76 (m, 1 H), 1.73–1.62 (m, 1 H), 1.60–1.50 (m, 1
H), 1.49–1.34 (m, 2 H), 1.31–1.16 (m, 1 H), 0.93 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 209.6 (C), 64.1 (CH), 61.2 (CH), 50.4
(CH2), 47.3 (CH2), 45.8 (CH2), 37.2 (CH2), 30.9 (CH2), 21.6 (CH2), 18.3
(CH2), 14.4 (CH3).
MS (EI, 70 eV): m/z (%) = 138 (M+ – C3H7, 100), 124 (20), 110 (9), 97
(10), 96 (100), 70 (10), 68 (7), 55 (7), 54 (6).
HRMS (ESI-TOF): m/z calcd for C8H12NO [M+ – C3H7]: 138.0919; found:
138.0924.
IR (neat): 3218, 2958, 1709, 1411, 1363, 1266, 1049, 894, 729 cm–1
.
1H NMR (400 MHz, CDCl3):  = 4.02 (d, J = 9.2 Hz, 1 H), 3.47 (t, J = 6.2
Hz, 3 H), 2.92–2.70 (m, 2 H), 2.09 (s, 3 H), 1.91–1.74 (m, 1 H), 1.70 (m,
3 H), 1.14 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 208.2 (C), 56.1 (C), 53.45 (CH), 49.2
(CH2), 44.7 (CH2), 33.0 (CH2), 31.1 (CH3), 29.5 (CH2), 22.8 (CH3).
MS (EI, 70 eV): m/z (%) = 211 (M+ – C4H8, 15), 155 (37), 153 (100), 147
(5S,8aR)-5-Propylhexahydroindolizin-7(1H)-one (ent-19a)
Starting from -keto amine derivative ent-18, and after purification
by flash column chromatography (silica gel, CH2Cl2/MeOH, 95:1) ent-
19a was afforded as a yellow oil; 98.5:1.5 er [GC (CP-Chirasil-Dex CB
column, Tinjector = 275 °C, Tdetector = 250 °C, Tcolumn = 100 °C (10 min) and
100–200 °C (2.5 °C/min), P = 101 kPa): tmajor = 30.74 min, tminor = 31.40
min]; yield: 0.0149 g (55%). Physical and spectroscopic data were
found to be the same as for 19a; []D20 +21.1 (c 0.44, CH2Cl2).
(12), 57 (49), 43 (33), 41 (17).
HRMS (ESI-TOF): m/z calcd for C7H1335ClNO [M+ – C4H9SO]: 162.0686;
found: 162.0691.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759

1759
A. Sirvent et al.
Feature
Synthesis
(5R,8aS)-5-Hexylhexahydroindolizin-7(1H)-one (19b)
Carballo, R. M.; Ramírez, M. A.; Fernández, I.; Martín, V. S.;
Padrón, J. I. Chem. Eur. J. 2016, 22, 15529. (e) Gao, P.; Sipos, G.;
Foster, D.; Dorta, R. ACS Catal. 2017, 7, 6060.
Purification by flash column chromatography (silica gel, CH2Cl2/
MeOH, 95:1) afforded 19b as a yellow oil; 95.5:4.5 er [GC (CP-Chirasil-
Dex CB column, Tinjector = 275 °C, Tdetector = 250 °C, Tcolumn = 100 °C
(10 min) and 100–200 °C (2.5 °C/min), P = 101 kPa): tmajor = 38.49 min,
tminor = 38.88 min]; yield: 0.0178 g (53%); Rf = 0.17 (CH2Cl2/MeOH,
99:1); []D20 –17.8 (c 0.40, CH2Cl2).
(3) For reviews, see: (a) Morton, D.; Stockman, R. A. Tetrahedron
2006, 62, 8869. (b) Ferreira, F.; Botuha, C.; Chemla, F.; Pérez-
Luna, A. Chem. Soc. Rev. 2009, 38, 1162. (c) Robak, M. T.;
Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
(4) See, for instance: (a) Sirvent, J. A.; Foubelo, F.; Yus, M. Chem.
Commun. 2012, 48, 2543. (b) Barros, O. S. R.; Sirvent, J. A.;
Foubelo, F.; Yus, M. Chem. Commun. 2014, 50, 6898. (c) Sirvent,
J. A.; Foubelo, F.; Yus, M. J. Org. Chem. 2014, 79, 1356. (d) García-
Muñoz, M. J.; Dema, H. K.; Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 2015, 26, 362. (e) García-Muñoz, M. J.; Foubelo, F.;
Yus, M. J. Org. Chem. 2016, 81, 10214. (f) Maciá, E.; Foubelo, F.;
Yus, M. Tetrahedron: Asymmetry 2017, 28, 1407. (g) Maciá, E.;
Foubelo, F.; Yus, M. Heterocycles 2019, 99, 248. (h) Sirvent, A.;
García-Muñoz, M. J.; Yus, M.; Foubelo, F. Eur. J. Org. Chem. 2020,
113. (i) Hernández-Ibáñez, S.; Barros, O. S. R.; Lahosa, A.; García-
Muñoz, M. J.; Benlahrech, M.; Behloul, C.; Foubelo, F.; Yus, M.
Tetrahedron 2020, 76, 130842.
IR (neat): 2927, 2862, 2781, 1720, 1458, 1373, 1053, 968, 798 cm–1
.
1H NMR (400 MHz, CDCl3):  = 3.29 (td, J = 8.8, 2.5 Hz, 1 H), 2.55–2.45
(m, 1 H), 2.42–2.21 (m, 3 H), 2.14 (q, J = 9.0 Hz, 1 H), 2.03–1.86 (m, 2
H), 1.88–1.76 (m, 1 H), 1.75–1.64 (m, 1 H), 1.63–1.51 (m, 1 H), 1.51–
1.40 (m, 1 H), 1.35–1.18 (m, 10 H), 0.89 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 209.7 (C), 64.1 (CH), 61.3 (CH), 50.4
(CH2), 47.3 (CH2), 45.8 (CH2), 34.9 (CH2), 31.9 (CH2), 30.9 (CH2), 29.6
(CH2), 25.0 (CH2), 22.7 (CH2), 21.6 (CH2), 14.2 (CH3).
MS (EI, 70 eV): m/z (%) = 138 (M+ – C3H7, 100), 139 (17), 138 (100), 97
(6), 96 (77), 68 (5), 55 (5).
HRMS (ESI-TOF): m/z calcd for C8H12NO [M+ – C6H13]: 138.0919;
found: 138.0920.
(5) Reddy, L. R.; Prashad, M. Chem. Commun. 2010, 46, 222.
(6) (a) Leemans, E.; Mangelinckx, S.; De Kimpe, N. Chem. Commun.
2010, 48, 3122. (b) Reddy, L. R.; Das, S. G.; Liu, Y.; Prashad, M.
J. Org. Chem. 2010, 75, 2236. (c) Pablo, O.; Guijarro, D.; Yus, M.
J. Org. Chem. 2013, 78, 9181.
Funding Information
For continuous financial support we thank the Spanish Ministerio de
Economía y Competitividad (MINECO; projects CTQ2014-53695-P,
CTQ2014-51912-REDC, CTQ2016-81797-REDC, CTQ2017-85093-P),
Ministerio de Ciencia, Innovación y Universidades (RED2018-102387-
T, PID2019-107268GB-100), FEDER, the Generalitat Valenciana
(PROMETEOII/2014/017), and the University of Alicante (VIGROB-068).
(7) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913. (b) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55,
8883.
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(b) Sirvent, A.; Foubelo, F. Lett. Org. Chem. 2018, 15, 345.
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metry 1995, 6, 1877.
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(10) Majik, M. S. Lett. Org. Chem. 2017, 14, 147.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610763.
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1749–1759