Facile, Stereocontrolled Synthetic Route towards Bis-functionalised Pyrrolizidines

Article abstract of DOI:10.1055/s-0037-1609582

A simple and convenient method for the synthesis of bis-functionalised pyrrolizidines starting from readily available N -Cbz- l -prolinal is described. This aldehyde was converted within two concise steps to the corresponding aminoepoxides, which were separately subjected to regioselective cyclisation induced by a reductive cleavage of the Cbz protecting group. The versatile and concise strategy holds great potential for practical application in the straightforward preparation of pyrrolizidine-based drugs and natural products.

Full text of DOI:10.1055/s-0037-1609582

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
special topic
A
en
M. Lindner et al.
Special Topic
Synthesis
Facile, Stereocontrolled Synthetic Route towards Bis-functionalised
Pyrrolizidines
Marcin Lindner
Antoni Krasiński
Janusz Jurczak*
Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Jurczak_group@icho.edu.pl
Published as part of the Special Topic Heterocycles as Catalysts,
Ligands, and Targets
Received: 22.05.2018
Accepted after revision: 19.06.2018
Published online: 23.07.2018
brought to light. These have involved, as key synthetic
steps, the SmI2-mediated intramolecular coupling reac-
tion,16 the Wittig reaction,17 RCM accelerated by 2nd gener-
ation Grubbs catalyst,18 the Mitsunobu reaction,19 exhaus-
tive carbonylation under high pressure,20 RuCl2(PPh3)3-as-
sisted21 and radical cyclisation,22 intramolecular oxime-
olefin cycloaddition,23 the Ireland–Claisen rearrangement,24
Cp2Zr-driven ring contraction,25 diastereoselective Michael
addition,26 and enzymatic aldol reaction.27
DOI: 10.1055/s-0037-1609582; Art ID: ss-2018-c0359-st
Abstract A simple and convenient method for the synthesis of bis-
functionalised pyrrolizidines starting from readily available N-Cbz-L-pro-
linal is described. This aldehyde was converted within two concise steps
to the corresponding aminoepoxides, which were separately subjected
to regioselective cyclisation induced by a reductive cleavage of the Cbz
protecting group. The versatile and concise strategy holds great poten-
tial for practical application in the straightforward preparation of pyr-
rolizidine-based drugs and natural products.
7
7a
1
6
2
Key words alkaloids, heterocycles, diastereoselective synthesis, asym-
metric epoxidation, cyclisation, tandem reaction
N
4
OGlc
5
3
OH
O
O
Pyrrolizidines1 constitute a unique class of omnipresent
alkaloids, comprised of a heterobicyclic [3.3.0] scaffold
bridged with a centrally positioned nitrogen atom (Figure
1). Some of these compounds are recognized as naturally
occurring products isolated from plants, as for instance, Ag-
eratum houstanium,2 Osyris alba,3 Tephesoris kirilowii,4 Se-
necio genus,5 marine fungus6 or their strains,7 Castanosper-
mum austral,8 and Senecio vulgaris (I–VIII, respectively, Fig-
ure 1).9 Such compounds can be also isolated from ants,
butterflies, frogs, and moths.10 Pyrrolizidine derivatives
have been identified as secondary metabolites, whereas
their significant bioactivity has been broadly explored in
terms of sugar mimics, with a great emphasis put on de-
sired glycosidase inhibitory activities.11 Therefore, the po-
tential application of pyrrolizidines as therapeutic agents
against diabetic diseases, viral infections, and cancer12–15
have encouraged several research groups to develop effi-
cient approaches towards diastereoselective synthesis of
polyhydroxylated and other variously functionalized pyr-
rolizidines. A number of stereoselective strategies, relying
on the use of modified proline derivatives, have so far been
O
O
HO
HO
CO2Me
H
H
H
N
N
N
I, retrohoustine
II, janifestine III, thesinine-4'-O-β-D-glucoside
OH
O
HO
OH
H
O
H
H
HO
HO
N
OH
N
OH
N
OH
O
IV, hectorine V, (+)-p-hydroxyphenopyrrozin VI, pochonicine
HO
HO
OH
OMe
H
H
OH
OH
N
N
O
VII, 1-epi-alexine
VIII, pochonicine
Figure 1 Widespread alkaloids with a pyrrolizidine scaffold
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
M. Lindner et al.
Special Topic
Synthesis
one synthetic strategy -
each diastereoisomer available
limited to
one diastereoisomer
OH
OH
∗
Cbz
Cbz
OH
N
N
O
O
N
N
∗
OH
RO
HO
A
Our approach
Izquierdo's approach
Scheme 1 A general access to stereochemically diverse pyrrolizidines
Despite great achievements in the synthesis of various
pyrrolizidines, certain drawbacks are still encountered,
such as multi-step procedures requiring substrate pre-func-
tionalization, harsh reaction conditions, and costly cata-
lysts. Hence the rational development of more convenient,
environment-friendly, and practical methods for assem-
bling pyrrolizidines using readily available oxidants still re-
mains a challenge. Clearly, straightforward and selective ox-
irane ring formation, followed by rapid ring closure, would
be a more practical and economical approach.
The strategies listed above typically aim to synthesize
solely one diastereoisomer of alkaloids, as shown in Scheme
1. Izquierdo and co-workers,28 reported an excellent indi-
um-mediated allylation of L-prolinal29 that allows syn-ori-
ented species to be obtained. Their protocol, however, does
not lead to target other possible diastereoisomers.
Herein we report an efficient and versatile protocol that
gives straightforward access to the desired diastereoisomer
of disubstituted pyrrolizidine scaffolds. In Scheme 1, our
synthetic approach to all existing diastereoisomers of 1,3-
disubstituted pyrrolizidine core A starting from the same
precursors as used by Izquierdo et al. is shown and the pro-
posed synthetic strategy towards the preparation of precur-
sors is illustrated in Scheme 2.
This approach opens the way to the precursor B and fi-
nally to regio- and stereoselective cyclisation, affording di-
astereoisomerically pure species 8–11 (Table 1). Retrosyn-
thetic analysis performed for the assembly of chiral, bis-
substituted pyrrolizidine scaffold A starts by disconnection
of the C3–N4 bond to provide epoxide B, as shown in
Scheme 2. Thus, the key step for the proposed strategy is
envisaged to involve a cascade-type process that starts with
NCbz reductive deprotection and consequent rapid, regio-
selective cyclisation. Epoxide B could be established via oxi-
dation of linear homoallyl alcohol C affording both syn- and
anti-diastereoisomeric forms, ideally with high stereoselec-
tivity for either of them. Allyl group addition to the paren-
tal aldehyde D, in turn, leads to the requisite species C en-
dowed with two well-defined stereogenic centres. The en-
tire path envisaged for the preparation of the target
pyrrolizidines is designed to involve cheap reagents and to
proceed under mild conditions, and so may be considered
appropriate for further synthetic modifications.
Our approach to construct diastereoisomerically pure,
eight-membered bicyclic scaffolds was initiated from readi-
ly available Cbz (compatible with all planned functional
group transformations) protected L-prolinal 1. At the initial
stage, bearing a highly reactive species, we proposed to in-
troduce novel chiral moieties exploiting a stereocontrolled
addition of allyl precursor to the carbonyl group. As was
emphasized, the olefin terminus so formed is prone to un-
dergo further functionalization towards desired regioselec-
tive ring closure with complete chirality transfer. Note,
however, that Li and Zhao30 explored allylstannanes under
acidic conditions. Hall31 reported addition of allylboropina-
colate assisted by combination of Lewis acid (SnCl4) and
chiral diol. Both systems promoted anti-isomer, while an
absence of diol allowed for almost statistical mixture of
products and could be considered in the future as an effi-
cient way to increase the ratio of syn-oriented diastereoiso-
mer. Nevertheless, we employed allylation of N-protected
α-aminoaldehyde 1 with respect to the already reported
strategy (demonstrated by our group for the total synthesis
of preussine32 and bulgecinine33). This practical variant of
OH
R1
R1
3
R1
N
N
N
5
5
3
O
N
2
2
2
3
O
OH
OH
OH
B
C
A
D
R1 = Cbz
1
Scheme 2 Retrosynthetic analysis of 1,3-substituted pyrrolizidine analogues
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
M. Lindner et al.
Special Topic
Synthesis
Barbier-type reaction was successfully adopted in the pres-
ent study (Table 1) and relies on the addition of allyl bro-
mide, zinc dust, and aqueous ammonium chloride to the re-
action mixture to give the desired product in high overall
yield (90%). From the stereochemical viewpoint the pro-
posed approach gives an access to acceptable ratio of the
two products (2/3 = 2:8), which proved to be easily separa-
ble by column chromatography. Both diastereoisomers of
N-protected homoallyl alcohols were in the next step sub-
jected to epoxidation reaction. Drawing upon previously ac-
quired experience we employed three different variants of
catalytic systems based on VO(acac)2 (b), Ti(Oi-Pr)4 (c), and
Al(Ot-Bu)3 (d) combined with tert-butyl hydroperoxide. A
compilation of results obtained is displayed in Table 1.
Synthesizing the specific stereoisomer of preussine,32
we found that under applied conditions (b), the syn-isomer
was mostly promoted. Faced with the above-mentioned
findings we first attempted to employ epoxidation of ole-
fins 2 and 3 assisted by the VO(acac)2/t-BuOOH system
aimed at selective formation of both syn-oriented species
(Table 1). The devised protocol paves the way to the antici-
pated family of epoxides 4, 5 and 6, 7 in the ratios 74:26
and 78:22, respectively. Moreover two pairs of epoxides
were obtained in moderate 46% and 55% yields.
arranged compound 4 was still favoured. However, the ste-
reochemical handicap was compensated for with a very
good 68% yield. We were very pleased to note a striking dif-
ference, over the course of the investigated reaction, strug-
gling against compounds 6 and in particular 7 under speci-
fied conditions (d). We readily induced a direction of olefin
oxidation with desired shift of ratio towards anti-isomer 7
(dr 18:22) with diminished but still acceptable 43% yield
(Table 1). All required diastereoisomeric precursors 4–7 suit
perfectly to carry out the key reaction for a synthesis of tar-
get pyrrolizidines 8–11.
We designed the final cyclisation of γ-aminoepoxides to
be induced by a sequence of two reactions involving the re-
ductive cleavage of Cbz unit, followed by spontaneous nuc-
leophilic attack of the nitrogen lone pair on the tertiary car-
bon atom of the oxirane ring. The assembly of pyrrolizidine
scaffold was performed by applying reductive cleavage of
carbamate masked amine by 10% palladium on charcoal
(Degussa type E 101) under a hydrogen atmosphere. The re-
moval of carboxybenzyl protecting group from amine func-
tion and its spontaneous SN2 reaction was monitored by
TLC.
After 20 hours, readily obtained bicyclic products were
purified by means of column chromatography separation,
providing each of envisaged compounds. The outlined
methodology provided an excess of each of the anticipated,
diastereoisomerically pure pyrrolizidines 8–11, which were
isolated with the same ratio as their oxirane-featured pre-
cursors. We found that no epimerisation occurred during
On the basis of our previous experience, the synthesis of
the remaining anti-oriented epoxides was inspected, taking
into account the methods (c) and (d). The examined strate-
gies necessitated a slight increase in the amount of anti-ar-
ranged isomer (Table 1, 4:5 = 57:43); nevertheless, the syn-
Table 1 D iasteroselective Synthesis of Pyrrolizidines 8–11a
OH
H
Cbz
Cbz
Cbz
N
N
b/c/d
e
a
N
∗
∗
O
∗
N
∗
∗
O
OH
1
OH
OH
Allyl substrate
syn-Epoxide
anti-Epoxide
Overall yield (%) Ratio of epoxidesb syn/anti Separated pyrrolizidinesc
drc
OH
H
OH
Cbz
N
Cbz
Cbz
N
H
N
N
46d
50e
68f
74:26
58:42
57:43
74:26
+
+
N
58:42
57:43
O
O
OH
OH
OH
OH
OH
2
4
5
8, 80%
9, 81%
OH
OH
Cbz
N
Cbz
Cbz
N
H
N
H
N
N
55d
76e
43f
78:22
37:63
12:88
78:22
37:63
12:88
+
+
O
O
OH
OH
OH
OH
OH
3
6
7
10, 84%
11, 85%
a Reaction conditions: (a) allyl bromide, Zn, NH4Cl; (b) VO(acac)2/t-BuOOH; (c) Ti(Oi-Pr)4/t-BuOOH; (d) Al(Ot-Bu)3/t-BuOOH; (e) H2, cat. 10% Pd/C (Degussa).
b Ratio of formed epoxide determined by NMR analysis.
c Pyrrolizidines isolated with diastereomeric ratio corresponding to the ratio of starting epoxides.
d Reagent used: VO(acac)2/t-BuOOH.
e Reagent used: Ti(Oi-Pr)4/t-BuOOH.
f Reagent used: Al(Ot-Bu)3/t-BuOOH.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
M. Lindner et al.
Special Topic
Synthesis
1
the cyclisation, as was corroborated by H NMR spectra of
products. No indolizidine by-products were found either.
The combined yields of individually isolated cyclised prod-
uct pairs 8, 9 and 10, 11 were 80–85%. Successfully isolated
diastereoisomerically pure pyrrolizidines 8–11 were sub-
jected to NMR analyses aimed at stereochemical structure
elucidation. The 1H–13C correlation spectra allowed for pre-
cise assignment of all resonance signals. Subsequently, the
analysis of two-dimensional NOE experiment for each of
the synthesised products allowed us to determine the rela-
tive configurations, taking advantage of strong nuclear
Overhauser effects, which were observed mainly for pro-
tons located at the stereogenic centres. In this context, all
spectra recorded for target compounds 8–11 were analysed
in detail (the accurate assignment and spectra interpreta-
tion are depicted in Supporting Information), shedding
light on diverse correlations detected for (i) the separated
signals of methylene protons (geminal inequality) in the
pyrrolizidine ring and (ii) geminal coupling between hy-
droxyl protons with other spatial protons.
pyrrolizidines with well-defined stereochemistry. The es-
tablished protocol may potentially be transferrable to the
synthesis of amine-terminated pyrrolizidines, utilising an
asymmetric azidiration as a source of the exo-amine group.
All starting materials and reagents were obtained from commercial
suppliers and used without further purification. TLC was performed
on silica gel 60 F254 plates, spots were detected by fluorescence
quenching under UV light at 254 nm. Column chromatography was
performed on silica gel 60 (0.040–0.063 mm). All experimental ma-
nipulations with anhydrous solvents were carried out in flame-dried
glassware under an inert atmosphere of argon. Degassed solvents
were obtained by three freeze-pump-thaw cycles.
All NMR spectra were recorded at 25 °C in DMSO-d6 by Varian VNMRS
500 MHz spectrometer. 1H NMR (500.16 MHz) spectra were refer-
enced to the solvent residual proton signal (DMSO-d6, δH = 2.50). 13C
NMR (128.54 MHz) with total decoupling of protons were referenced
to the solvent (DMSO-d6, δC = 39.52). HRMS spectra were obtained
with an LSI, EI, ESI-TOF mass spectrometer in MeOH or MeCN. Optical
rotations were measured at room temperature using a Jasco J-815 po-
larimeter. IR spectra were recorded on Jasco 6200 FTIPR spectropho-
tometer. Melting points were measured with a Büchi M565 melting
point apparatus and are uncorrected. Elemental analyses were ob-
tained using the elemental analyser Vario (Elementar) EL III analyser.
In order to corroborate spectral analyses, we made an
attempt to get more insight into structural attributes of
pyrrolizidine motif in a solid state. The mono crystals of di-
astereosimerically pure compound 8 suitable for X-ray
crystal structure analysis were obtained by a slow evapora-
tion from methanol. The molecular structure is shown in
Figure 2. Single crystal X-ray diffraction unambiguously
prove the stereochemical identity of compound 8, and con-
firmed the accuracy of stereochemical assignment support-
ed by NMR technique for all of target species 8–11.
Allylation of NCbz-Protected L-Prolinal 1
The aldehyde 1 (1.165 g, 5 mmol) was dissolved in of THF (10 mL) and
cooled down in a crushed ice bath to 0 °C. Subsequently, sat. aq NH4Cl
(2.5 mL) and Zn dust (650 mg, 10 mmol) were added at once. The re-
sulting mixture was vigorously stirred and allyl bromide (0.605 g, 5
mmol) was carefully added dropwise. The reaction mixture was al-
lowed to warm up to r.t. and the mixture was stirred for the next 2 h.
The reaction was terminated by the addition of aq 0.5 M HCl (40 mL)
and Et2O (40 mL). The crude mixture was stirred till the solution be-
came transparent. The aqueous layer was extracted with Et2O (2 × 20
mL). Organic layers were separated, combined, and dried (anhyd Mg-
SO4). The solvent was removed under reduced pressure. The obtained
homoallyl alcohols 2 and 3 (1.4g, 0.35 g) were purified by column
chromatography separation.
(2S,1′S)-2-(1′-Hydroxybut-3′-en-1′-yl)-1-(carbobenzyloxy)pyrroli-
dine (2)34,35
Colorless oil; yield: 1.4 g (80%); [α]D –64.8 (c 0.8, CHCl3).
IR (CHCl3): 3383, 1670, 1421, 1358 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H), 6.03–5.90 (m, 1 H),
5.17–5.08 (m, 4 H), 4.49 (br s, 1 H), 3.97–3.89 (m, 1 H), 3.69–3.56 (m,
2 H), 3.40–3.33 (m, 1 H), 2.40–2.31 (m, 1 H), 2.20–2.11 (m, 1 H), 1.99
(m, 1 H), 1.87 (m, 1 H), 1.79 (m, 1 H), 1.73–1.67 (m, 1 H).
13C NMR (128.5 MHz, CDCl3): δ = 157.96, 136.48, 134.65, 128.51,
128.09, 127.95, 117.18, 74.86, 67.41, 62.85, 47.23, 39.20, 28.36, 24.16.
Figure 2 Molecular structure of pyrrolizidines 8 determined by single
crystal X-ray diffraction33
HRMS LSI (+): m/z ([M + H]+·) calcd for C16H22NO3: 276.1600; found:
In conclusion, we have developed a cheap, readily syn-
thetic protocol towards each of the designed and expected
diastereoisomers of pyrrolizidines 8–11, functionalised
with two different substituents. The conducted epoxidation
does not require additional, sophisticated ligands, while the
key synthetic step based on tandem deprotection–cyclisa-
tion provides a great opportunity to produce the required
276.1602.
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.35;
H, 7.59; N, 5.07.
(2S,1′R)-2-(1′-Hydroxybut-3′-en-1′-yl)-1-(carbobenzyloxy)pyrroli-
dine (3)34,35
Colorless oil; yield: 0.35 mg (20%); [α]D –56.7 (c 1.0, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
M. Lindner et al.
Special Topic
Synthesis
IR (film): 3432, 2975, 1697, 1682, 1420, 1109 cm–1
.
A label ‘x’ given instead of the proton number in the description of 1H
NMR spectrum denotes the molar fraction of one of the diastereoiso-
mers, which occur in the product mixture.
1H NMR (500 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H), 5.95–5.70 (m, 1 H),
5.17–5.05 (m, 4 H), 4.01–3.78 (m, 1 H), 3.61 (m, 1 H), 3.38–3.31 (m, 2
H), 2.22–2.11 (m, 2 H), 2.02–1.72 (m, 4 H).
Mixture of (2S,1′R,3′S)-2-(3′,4′-Epoxy-1′-hydroxbut-1′-yl)-1-(car-
bobenzyloxy)pyrrolidine (4) and (2S,1′R,3′R)-2-(3′,4′-Epoxy-1′-hy-
droxbut-1′-yl)-1-carbobenzyloxy)pyrrolidine (5)
13C NMR (128.5 MHz, CDCl3): δ = 156.23, 136.62, 135.29, 134.90,
128.43, 127.96, 127.83, 117.20, 117.03, 71.84, 71.60, 66.99, 62.94,
61.33, 47.66, 38.31, 37.41, 26.62, 25.57, 24.30, 24.108.
HRMS LSI (+): m/z ([M + H]+·) calcd for C16H22NO3: 276.1600; found:
276.1590.
Colourless oil.
1H NMR (500 MHz, DMSO-d6; 350 K): δ = 7.36–7.26 (m, 5 H), 5.08–
5.06 (m, 2 H), 4.64–4.48 (m, 1 H), 3.95–3.83 (m, 2 H), 3.56–3.44 (m, 1
H), 3.31–3.24 (m, 1 H), 3.03–2.94 (m, 1 H), 2.67 (m, x H), 2.60 [m, (1 –
x) H], 2.41 (m, x H), 2.35 [m, (1 – x) H], 1.92–1.68 (m, 4 H), 1.66–1.56
[m, (1 – x) H], 1.54-1.36 [m, (1 + x) H].
13C NMR (128.5 MHz, DMSO-d6; 350 K): δ (4) = 154.62, 136.74,
127.83, 127.19, 126.98, 69.33, 65.53, 60.86, 49.32, 46.66, 45.42, 34.96,
26.09, 23.08; δ (5) = 154.62, 136.74, 127.83, 127.19, 126.98, 68.94,
65.53, 61.12, 49.19, 46.66, 46.20, 35.33, 25.86, 23.08.
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.77;
H, 7.66; N, 5.03.
Epoxidation of Homoallyl Alcohols 2 and 3 Using the Catalytic Sys-
tem V5+/t-BuOOH; General Procedure
An oven-dried and argon-flushed, three-necked round-bottomed
flask was charged with a solution of the homoallyl alcohol 2 or 3 (3
mmol) in anhyd CH2Cl2 (30 mL), followed by VO(acac)2 (30 mg, 4
mol%) and 4 M tert-butyl hydroperoxide in CH2Cl2 (1.13 mL, 1.5 mol
equiv). The reaction was stirred at r.t. for at least 20 h until no further
progress of the reaction was observed by TLC. The reaction was ter-
minated by the addition of aq 1% Na2S2O5 (until a greenish-blue co-
lour change of the aqueous layer appeared). The aqueous layer was
separated and extracted with CH2Cl2 (2 × 10 mL). The combined or-
ganic layers were dried (anhyd MgSO4) and the solvent was evaporat-
ed under reduced pressure. The residue was purified by column chro-
matography (Table 1).
HRMS LSI (+): m/z calcd ([M + Na]+·) for C16H21NO4Na: 314.1368;
found: 314.1339.
Mixture of (2S,1′R,3′S)-2-(3′,4′-Epoxy-1′-hydroxbut-1′-yl)-1-(car-
bobenzyloxy)pyrrolidine (6) and (2S,1′R,3′R)-2-(3′,4′-Epoxy-1′-hy-
droxbut-1′-yl)-1-(carbobenzyloxy)pyrrolidine (7)
Colourless oil.
1H NMR (500 MHz, DMSO-d6; 350 K): δ = 7.35–7.25 (m, 5 H), 5.11–
5.03 (m, 2 H), 4.59 (d, J = 5.6 Hz, x H), 4.54 [d, J = 5.7 Hz, (1–x) H],
4.04–3.95 (m, 1 H), 3.75–3.71 (m, 1 H), 3.49–3.43 (m, 1 H), 3.31–3.25
(m, 1 H), 2.97–2.91 (m, 1 H), 2.67 (m, x H), 2.63 [m, (1 – x) H], 2.44–
2.38 (m, 1 H), 2.01–1.92 (m, 2 H), 1.81–1.67 [m, (3 – x) H], 1.59 (m, x
H), 1.42–1.32 (m, 1 H).
13C NMR (128.5 MHz, DMSO-d6; 350 K): δ (6) = 153.87, 136.79,
127.84, 127.18, 126.98, 67.72, 65.38, 61.40, 49.12, 46.44, 45.53, 37.01,
24.26, 23.29; δ (7) = 153.87, 136.79, 127.84, 127.18, 126.98, 67.72,
65.38, 61.40, 48.96, 46.44, 45.94, 36.58, 24.26, 23.29.
Epoxidation of Homoallyl Alcohols 2 and 3 Using the Al3+/t-BuOOH
System; General Procedure
An oven-flamed and argon flushed three-necked round bottomed
flask was charged with corresponding homoallyl alcohol (3 mmol),
Al(Ot-Bu)3 (1.11 g, 4.5 mmol), and anhyd benzene (15 mL). The result-
ing mixture was cooled to 5 °C, and a 4 M solution of tert-butyl hy-
droperoxide in CH2Cl2 (1.51 mL, 6 mmol) was added. The reaction
was stirred at 5 °C for the next 5–9 hours, until no further reaction
progress of the reaction was observed by TLC. Afterwards, Et2O (150
mL) and H2O (30 mL) were added and the resulting mixture was vig-
orously stirred at r.t. for 15 min. The aqueous layer was separated and
extracted with Et2O (3 × 50 mL). The combined organic layers were
dried (anhyd MgSO4) and the solvents were evaporated under re-
duced pressure. The residue was purified by column chromatography
(Table 1).
HRMS EI: m/z ([M]+·) calcd for C16H21NO4: 291.1471; found: 291.1474.
Cyclisation of γ-Aminoepoxides; General Procedure
A three-necked round-bottomed flask was charged with a mixture of
epoxy alcohol 4/5 or 6/7 (2.0 mmol) and MeOH (40 mL). The resulting
solution was degassed, subsequently catalyst 10% Pd/C (Degussa, type
E 101, 40 mg) was added at once and the reaction mixture was vigor-
ously stirred at r.t. under H2 for 20 h. Afterwards, the crude product
was filtered through a pad of Celite. The residual solvent was removed
under reduced pressure. The crude material was subjected to column
chromatography to purify and separate the formed diastereoisomers.
Epoxidation of Homoallyl Alcohols 2 and 3 Using the Ti4+/t-BuOOH
System; General Procedure
An oven-dried and argon-flushed, three-necked round-bottomed
flask was charged with the corresponding homoallyl alcohol 2 or 3 (3
mmol), anhyd CH2Cl2 (12 mL), and activated 3Å molecular sieves (150
mg). The resulting solution was cooled down to –15 °C. Consecutively,
a 4 M solution of tert-butyl hydroperoxide in CH2Cl2 (1.51 mL, 6
mmol) and Ti(Oi-Pr)4 (853 mg, 893 μL, 3 mmol) were added dropwise
and the mixture was stirred under an argon atmosphere until no fur-
ther progress of the reaction was observed by TLC. Afterwards, CH2Cl2
(40 mL) and H2O (20 mL) were then added and the mixture was
stirred at 0 °C for 15 min. The aqueous layer was separated and ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic layers were
dried (anhyd MgSO4) and the solvent was evaporated under a reduced
pressure. The residue was purified by column chromatography (Table
1).
(1R,3R,7aS)-1-Hydroxy-3-hydroxymethylpyrrolizidine (8)
Pale-yellow crystals; yield: 129 mg (81%, 0.83 mmol); mp 82–88 °C
(CH2Cl2/pentane); [α]D –3.2 (c 1.0, MeOH).
IR (CHCl3): 3602, 3350, 2966, 1449, 1091, 1021 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 4.82 (br s, 1 H), 4.41 (br s, 1 H), 3.67
(dt, J = 8.9, 6.4, 6.4 Hz, 1 H), 3.34 (d½ABq, J = 5.5 Hz, JAB = 10.5 Hz, 1 H),
3.26 (d½ABq, J = 6.0 Hz, JAB = 10.5 Hz, 1 H), 3.06 (m, 1 H), 2.75 (ddd, J =
10.7, 7.3, 6.1 Hz, 1 H), 2.64 (m, 1 H), 2.58 (m, 1 H), 2.04 (dt, J = 12.0,
6.1, 6.1 Hz, 1 H), 1.77–1.67 (m, 1 H), 1.67–1.60 (m, 1 H), 1.60–1.48 (m,
2 H), 1.42 (ddd, J = 12.0, 9.6, 9.2 Hz, 1 H).
13C NMR (128.5 MHz, DMSO-d6): δ = 75.51, 71.48, 66.36, 65.13, 54.47,
38.50, 29.75, 24.58.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
M. Lindner et al.
Special Topic
Synthesis
HRMS ESI (+): m/z ([M + H]+·) calcd for C8H16NO2: 158.1181; found:
158.1213.
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(1R,3S,7aS)-1-Hydroxy-3-hydroxymethylpyrrolizidine (9)
Yellowish oil; yield: 109 mg (80%, 0.7 mmol); [α]D –5.2 (c 1.0, MeOH).
IR (CHCl3): 3605, 3351, 2970, 1449, 1109, 1065, 1019 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 4.80 (br s, 2 H), 3.82 (m, 1 H), 3.58
(d½ABq, J = 7.2 Hz, JAB = 11.2 Hz, 1 H), 3.50 (d½ABq, J = 5.6 Hz, JAB
.
=
11.2 Hz, 1 H), 3.37 (m, 1 H), 3.22 (dt, J = 7.7, 7.7, 1.9 Hz, 1 H), 2.75–
2.70 (m, 1 H), 2.68–2.62 (m, 1 H), 2.00 (m, 1 H), 1.79–1.69 (m, 2 H),
1.62–1.52 (m, 2 H), 1.34 (m, 1 H).
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2715.
13C NMR (128.5 MHz, DMSO-d6): δ = 74.45, 74.32, 62.24, 59.96, 46.28,
34.86, 28.87, 25.89.
HRMS EI (+): m/z ([M + H]+·) calcd for C8H15NO2: 157.1103; found:
157.1101.
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Chem. 2009, 9, 369.
(1S,3S,7aS)-1-Hydroxy-3-hydroxymethylpyrrolizidine (10)
Yellowish oil; yield: 165 mg (84%, 1.06 mmol); [α]D +15.4 (c 0.15,
MeOH).
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145.
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Yuhara, T. Tetrahedron 1996, 52, 869.
IR (CHCl3): 3603, 3350, 2970, 1447, 1108, 1065, 1018 cm–1
.
1H NMR (500 MHz, DMSO-d6; 363 K): δ = 4.74 (br s, 2 H), 4.00 (m, 1
H), 3.53 (m, 2 H), 3.21 (m, 1 H), 3.03–2.97 (m, 1 H), 2.81 (m, 1 H),
2.66–2.60 (m, 1 H), 2.10 (dt, J = 13.4, 6.8, 6.8 Hz, 1 H), 1.88–1.79 (m, 2
H), 1.73–1.64 (m, 1 H), 1.59–1.52 (m, 2 H).
13C NMR (128.5 MHz, DMSO-d6; 363 K): δ = 69.39, 68.77, 60.82, 60.05,
46.77, 36.50, 25.89, 22.77.
HRMS EI: m/z ([M]+·) calcd for C8H15NO2 157.1103; found: 157.1106.
(17) Majik, M. S.; Jyoti, S.; Tilve, S. G.; Parameswaran, P. S. Synthesis
2007, 663.
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Torisawa, Y. A.; Nakagawa, M. Chem. Pharm. Bull. 2000, 48, 1593.
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Nakamura, N.; Ikeda, M. J. Org. Chem. 1993, 58, 2360.
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1994, 116, 5469.
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2073.
(1S,3R,7aS)-1-Hydroxy-3-hydroxymethylpyrrolizidine (11)
Yellowish oil; yield: 163 mg (85%, 1.09 mmol); [α]D +11.7 (c 1.0,
MeOH).
IR (KBr): 3604, 3352, 2966, 1447, 1096, 1023 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 4.65 (br s, 2 H), 3.97 (m, 1 H), 3.45
(m, 1 H), 3.39 (d½ABq, J = 5.6 Hz, JAB = 10.7 Hz, 1 H), 3.30 (d½ABq, J =
5.7 Hz, JAB = 10.7 Hz, 1 H), 2.92–2.86 (m, 2 H), 2.58 (ddd, J = 9.6, 7.0,
6.8 Hz, 1 H), 1.93–1.86 (m, 2 H), 1.80 (m, 1 H), 1.70–1.55 (m, 2 H), 1.48
(m, 1 H).
13C NMR (128.5 MHz, DMSO-d6): δ = 70.72, 69.34, 66.98, 62.24, 54.25,
38.76, 26.60, 23.66.
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P. Adv. Synth. Catal. 2017, 359, 2090.
HRMS EI: m/z ([M]+·) calcd for C8H15NO2: 157.1103; found: 157.1101.
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2005, 16, 3887.
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(33) CCDC 1844880 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609582.
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The
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F