5,6-Dihydroindolizines as convenient precursors of indolizidine 167B and analogues

Article abstract of DOI:10.1055/s-2005-918407

Starting from 5-carboxyethyl-5,6-dihydroindolizine, the title alkaloid was obtained in 25% overall yield via differently C5-substituted 5,6-dihydroindolizines and final exhaustive hydrogenation. An alternative strategy for the synthesis of optically activ

Full text of DOI:10.1055/s-2005-918407

PAPER
3119
5,6-Dihydroindolizines as Convenient Precursors of Indolizidine 167B and
Analogues
5
, 6-Dihydroindoliz
i
ines as
u
Convenient
d
Precursors
o
i
f
Indol
t
izidine
t
167B a Guazzelli,a Raffaello Lazzaroni,a Roberta Settambolo*b
a
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
ICCOM-CNR, Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
Fax +33(050)2219260; E-mail: settambolo@dcci.unipi.it
b
Received 4 April 2005; revised 25 May 2005
idine 167B begin with the pyrrolidine ring and then
construction of the piperidine ring, the most frequent dis-
connection being at the N4–C5 bond,6 although cyclisa-
tion via the C8–C9 bond is also known.7
Abstract: Starting from 5-carboxyethyl-5,6-dihydroindolizine, the
title alkaloid was obtained in 25% overall yield via differently C5-
substituted 5,6-dihydroindolizines and final exhaustive hydrogena-
tion. An alternative strategy for the synthesis of optically active in-
dolizidine 167B and analogues still based on 5,6-dihydroindolizine
intermediates is given.
We recently described an approach to 5,6-dihydroindoliz-
ine core, based on the C8–C9 bond formation via an in-
tramolecular cyclodehydration of 4-(pyrrol-1-yl)butanals,
coming from rhodium-catalysed hydroformylation of N-
allylpyrroles.8 5,6-Dihydroindolizines are rare and we
employed them in a formal synthesis of Myrmicarin 217.9
We now show that these compounds can be used as pre-
cursors of indolizidine 167B and analogues.
Keywords, (–)-indolizidine 167B, 5,6-dihydroindolizines, synthe-
sis, 4-(pyrrol-1-yl)butanal, enantioselective hydrogenation
Indolizidine alkaloids are a class of compounds widely
diffused in nature and characterized by interesting wide
ranging biological properties. Many indolizidines with
alkyl chains of various length in different positions of the
bicyclic core have been identified as venomous constitu-
ents of ant species or neotropical frogs,1 some of these be-
ing non-competitive blockers of nicotinic acetylcholine
receptor channels.2 Indolizidine 167B (Figure 1) was orig-
inally identified as a trace component in the skin secre-
tions of a frog belonging to the genus Dendrobates on the
Isla de Còlon, Panama, and later identified in a single pop-
ulation of D. speciosus.3
As depicted in Scheme 1 we envisaged that the saturated
5-alkylindolizidine [alkyl = n-Pr in (–)-indolizidine 167B
(1)] could be directly obtained from 5,6-dihydroindolizine
2, where the alkyl group present in position 5 of the ring
skeleton is the same or a direct precursor of that in the tar-
get molecule.
Compound 2 could be obtained through a functional
group transformation starting from indolizine ester 3. This
compound has been synthesized from glutamic acid, the
crucial step being the cyclodehydration of the pyrrolylbu-
tanal 4.9 5-Carboxyethyl-5,6-dihydroindolizine (3) repre-
sents a key intermediate; in fact, while the manipulation of
the ester group allows access to various 5-substituted-5,6-
dihydroindolizines, the independent use of both the dou-
ble bond and/or the pyrrole positions could allow synthe-
sis of more complex indolizidine derivatives.
2
1
H
9
3
8
7
N
N
5
6
indolizidine
(–)-indolizidine 167B
The strategy was successful, as demonstrated by the syn-
thesis of optically active indolizidine 167B and analogues.
The synthetic pathway we adopted is described in
Scheme 2 and utilises 5,6-dihydroindolizine ester 3 as the
starting material and introduces some new 5,6-dihydroin-
dolizines as convenient intermediates.
Figure 1
Although the structure has recently been questioned,4 this
alkaloid remains a target for many research groups,5 both
in its racemic and optically active form. Most of the syn-
thetic strategies proposed for the total synthesis of indoliz-
H
O
N
N
N
N
O
O
R
R
R = n-Pr
(–)-indolizidine 167B (1)
O
O
2
3
4
Scheme 1
SYNTHESIS 2005, No. 18, pp 3119–3123
x
x.
x
x
.
2
0
0
5
Advanced online publication: 06.10.2005
DOI: 10.1055/s-2005-918407; Art ID: P04805SS
© Georg Thieme Verlag Stuttgart · New York

3120
G. Guazzelli et al.
PAPER
H
i
ii
iii
N
3
N
N
5
O
6
1
ix
x
N
N
iv
vii R = Et
viii
6'
8
v
vi
N
N
N
HO
TsO
R
7
9
10 a R = H
b R = Et
Scheme 2 A: i) DIBAL-H–hexane (1.9 equiv), THF, –78 °C, 1.5 h, –78 °C, workup from –78 °C → r.t., 61% yield; ii) CH3CH2PPh3Br–
NaNH2, THF, from –30 °C → r.t., 22.5 h, 52% yield; iii) H2, Rh/C (5%), 10 atm, 90 min, 80% yield B: iv) LiAlH4, THF, 0 °C → r.t., 1 h, 99%
yield; v) Et3N, TsCl, CH2Cl2, r.t., 5 h, 69% yield; vi) LiAlH4, Et2O, 0 °C → r.t., 22 h, 55% yield for 10a; Li2CuCl4, EtMgBr, THF, –78 °C →
r.t., 63 h, 52% yield for 10b; vii) H2, Rh/C (5%), 10 atm, 60 min, 65% yield; viii) NaBH4, MeOH, r.t.; ix) CH3PPh3Br–NaNH2, THF, –30 °C
→ r.t.; x) H2, Rh/C (5%), r.t.
The pathway is diastereoselective and only the diastereo- graphic column, which is convenient with other similar
mer corresponding to indolizidine 167B (–)-(1) was structures, were unsuccessful.12,13 On the other hand no
formed, as evidenced by the comparison of the obtained racemisation has been previously observed11 by us for the
1H and 13C NMR data with those reported for the same transformation of a formyl group into a terminal double
isomer.10
bond under the same methylenation conditions. In order to
clarify if the formation of an internal instead of a terminal
double bond could play a crucial role in racemisation, the
synthesis of (–)-5-vinyl-5,6-dihydroindolizine (6¢) was
Pathway A
The reduction of (–)-3 to aldehyde (–)-5 was carried out at accomplished via methylenation of 5 with commercial
–78 °C. From our previous work on an analogous transfor- methyltriphenylphosphonium bromide/NaNH2 instant
mation in the synthesis of optically active 1-allylpyrroles ylide (Scheme 2).
from the corresponding a-aminoacids,11 we knew that the
The olefin 6¢ having the same optical purity as the starting
ester reduction might cause racemisation but only in a low
aldehyde 5 was obtained,13,14 thus the aldehyde 5 proved
extent if the addition of tartrate solution occurs at –78 °C.
configurationally stable in the adopted conditions. Taking
In this case we obtained (–)-(S)-5-formyl-5,6-dihydroin-
into account that the reaction to 6 is slower than that form-
dolizine (5) with an optical purity of 80%. In particular
ing 6¢, enolisation of the aldehyde group could probably
this datum was valued by transforming the aldehyde (–)-5
occur in the former transformation, with the consequent
racemisation observed.
into the corresponding alcohol (+)-7, its amax value9 being
known (Scheme 2). The olefination of (–)-5 into (+)-6 was
carried out with the Schlosser–Schaub instant ylide re-
Pathway B
agent (ethyltriphenyl phosphonium bromide and sodium
amide) by addition of the aldehyde to the preformed ylide
cooled at low temperature (–30 °C) to avoid racemisation.
This has proven to be the lowest temperature at which we
can observe any reaction between the reagents, but the re-
action mixture must be heated to room temperature to ob-
tain a complete conversion of the starting material. When
the isolate 6 was submitted to hydrogenation with Rh/C
catalytic system, (–)-indolizidine167B was obtained, with
an optical purity of 42%, as determined from the compar-
ison of its specific rotation with the amax value reported in
the literature.10 The olefination or hydrogenation step or
both could be in principle responsible for racemisation.
Preliminary attempts of elution of 6 on chiral chromato-
To avoid the drawback of the C5 configurational lability
in (–)-5 during the olefination step to (+)-6, we looked to
an alternative enantioselective synthesis having (+)-(S)-5-
hydroxymethyl-5,6-dihydroindolizine (7) as key interme-
diate. As reported above, this species can be obtained in
high optical purity (80%) via reduction of the aldehyde
(–)-5 (Scheme 2) with NaBH4 in MeOH. However, we
have previously obtained it in enantiomerically pure
form9 (98%) directly from (–)-(S)-5-carboxyethyl-5,6-di-
hydroindolizine (3) by treatment with LiAlH4 in THF. In
the current work, we have studied yet another synthetic
pathway in a preliminary way to (–)-indolizidine 167B
Synthesis 2005, No. 18, 3119–3123 © Thieme Stuttgart · New York

PAPER
5,6-Dihydroindolizines as Convenient Precursors of Indolizidine 167B
3121
were used without further purification. 5-Carboxyethyl-5,6-dihy-
droindolizine (3) was prepared as reported in the literature.9 TLC
analyses were performed on aluminium oxide 60 F254 neutral plates
from Merck. For preparative chromatography Merck aluminium
oxide 90 active (neutral, 70–230 mesh) was used. Optical rotations
were measured with a JASCO DIP-370 digital polarimeter at the
given temperature. Melting points were taken using a Reichart
Thermovar apparatus and are uncorrected. Microanalyses were per-
formed at Laboratorio di Microanalisi, Istituto di Chimica Organi-
ca, Facoltà di Farmacia, Università di Pisa. 1H NMR and 13C NMR
spectra were recorded at 200 MHz and 50 MHz, respectively, on a
Varian Gemini 200 spectrometer. Chemical shifts are given in d
(ppm) relative to CDCl3.
starting from (–)-(S)-5-carboxyethyl-5,6-dihydroindoliz-
ine (3) (steps iv, v, vi, vii, Scheme 2).
With respect to the previous procedure (steps i, ii, iii
Scheme 2), an additional step was present in this reaction
sequence. The reduction of 3 was carried out as previously
reported.9 After one hour, the conversion was complete
and the reaction was quenched with MeOH and saturated
aqueous solution of mixed sodium potassium tartrate. The
reaction was relatively fast and furnished (+)-(S)-hy-
droxymethyl-5,6-dihydroindolizine (7) in almost quanti-
tative yield. The tosylation step also occurred very easily;
the reactants were mixed together and stirred at room tem-
perature, providing (+)-(S)-5-(p-toluenesulfonyloxymeth-
yl)-5,6-dihydroindolizine (9) in good yield (69%).
(–)-(S)-5-Formyl-5,6-dihydroindolizine (5)
To a solution of (–)-(S)-5-carboxyethyl-5,6-dihydroindolizine (3;
4.9 g, 25.6 mmol) in THF–hexane (1:4) cooled at –78 °C a 1 M hex-
ane solution of DIBAL-H (50 mL, 50 mmol) was added and stirring
was continued at that temperature for 1.5 h. The reaction mixture
was then quenched with MeOH (9 mL) at –78 °C and a sat. aq so-
lution of mixed sodium potassium tartrate (100 mL) was added.
When the temperature was raised to the r.t., the two phases separat-
ed, the aqueous phase was extracted with Et2O (3 × 150 mL) and the
combined organic layers washed with water (4 × 150 mL). The or-
ganic layers were dried (Na2SO4), concentrated in vacuo and puri-
fied by vacuum distillation (70 °C, 0.05 mm Hg) to afford (–)-(S)-5
as a yellow oil (2.3 g, 15.6 mmol, 61%); [a]D25 –161.2 (c = 1.4, ben-
zene).
Some attempts of substitution reactions at C5 on 9 were
carried out. For the first time the introduction of a hydride
has been accomplished by treatment of 9 with LiAlH4, at
room temperature. The simplest 5-alkyl-5,6-dihydroin-
dolizine, i.e. (–)-(R)-5-methyl-5,6-dihydroindolizine
(10a) was obtained with the same ee value as the starting
3.15,16 Tamura and Kochi’s Cu(II) system17 seemed to be
the proper reagent for the introduction of an ethyl group
instead of the tosyl one in forming the n-propyl substitu-
ent at C5. Preliminary tests showed that by using catalytic
quantities (5%) of Li2CuCl4 (added as a THF solution) 1H NMR: d = 9.54 (br s, 1 H, CHO), 6.71 (t, J = 1.4 Hz, 1 H, HPyr),
6.47 (dt, J = 2.0, 9.8 Hz, 1 H, PyrCH=), 6.27 (t, J = 3 Hz, 1 H, HPyr),
with high excess of EtMgBr (9-fold) (–)-(R)-n-propyl-
6.18 (dd, J = 1.2, 3.4 Hz, 1 H, HPyr), 5.59 (m, 1 H, CH2CH=), 4.52
5,6-dihydroindolizine (10b) was formed but only partial
(t, J = 5.6 Hz, 1 H, NCH), 2.87 (m, 2 H, CH2).
conversion (20%) of the starting material was observed.
Increasing the quantity of racemic reagent (50%), the con-
version of the starting material rose to 70%, but also side-
products started to appear. In both cases (–)-(R)-n-propyl-
13C NMR: d = 25.6, 62.6, 107.9, 109.9, 116.6, 120.9, 121.2, 129.0,
200.5.
MS: m/z = 147 (31) [M+], 118 (100), 91 (20), 63 (11).
5,6-dihydroindolizine with an ee of 98% was ob-
Anal. Calcd for C12H9NO: C, 73.50; H, 6.12; N, 9.52. Found: C,
tained,15,16 giving pure (–)-indolizidine 167B via final 72.90; H, 6.30; N, 9.58.
enantioselective rhodium-catalyzed hydrogenation.
(+)-(S)-5-(Propen-1-yl)-5,6-dihydroindolizine (6)
In conclusion we have disclosed a new three-step synthe-
sis of indolizidine 167B from 5-carboxyethyl-5,6-dihy-
droindolizine (3) in a 25% overall yield. By means of
some transformations of the carboxyethyl group into dif-
ferent functionality at the 5-position many new 5,6-dihy-
droindolizines were prepared. Other 5-alkyl-substituted
indolizidines can be obtained in a similar manner via the
same synthetic iteration; the availability of the Wittig re-
agent to introduce the proper alkenyl group at C5 in 5-
A mixture of ethyltriphenylphosphonium bromide and NaNH2 (10
g, 24 mmol) in anhyd THF (280 mL) was stirred at r.t. for 1 h and
then cooled to –30 °C. A solution of (–)-(S)-5 (1.89 g, 12.9 mmol)
in anhyd THF (80 mL) was added and the mixture was stirred at
–30 °C for 1.5 h and allowed to warm to 0 °C. After stirring for 17 h
at 0 °C and for further 4 h at r.t., the crude mixture was hydrolysed
(200 mL of water). The aqueous phase was extracted with hexane
(3 × 150 mL) and the combined organic layers were washed until
neutral, dried (Na2SO4), concentrated in vacuo and submitted to
vacuum distillation to afford (+)-(S)-5-(propen-1-yl)-5,6-dihy-
formyl-5,6-dihydroindolizine 5 being the sole crucial key. droindolizine (6; 80 °C, 0.01 mm Hg) as an orange viscous liquid
(1.1 g, 6.70 mmol, 52%); [a]D20 +10.31 (c = 1.8, CH2Cl2).
The enantiopure (–)-167B was also obtained via an enan-
1H NMR: d = 6.67 (t, J = 2.0 Hz, 1 H, HPyr), 6.49 (dd, J = 2.2, 9.6
Hz, 1 H, PyrCH=), 6.16 (t, J = 3.1 Hz, 1 H, HPyr), 6.11 (dd, J = 1.6,
3.2 Hz, 1 H, HPyr), 5.92–5.55 (m, 3 H, CH3CH=, CH2CH=,
CHCH=), 4.79 (m, 1 H, NCH), 2.40 (m, 2 H, CH2), 1.77 (dd, J = 1.8,
7.0 Hz, 3 H, CH3).
13C NMR: d = 13.2, 27.9, 31.2, 50.7, 106.5, 107.8, 118.1, 119.3,
120.3, 128.4, 129.4.
tioselective four-step synthesis, still based on 5,6-dihy-
droindolizine derivatives. The above findings indicate
that the 5,6-dihydroindolizine core, owing to the stability
shown in different experimental conditions as well as to
the possibility to an independent use of the C7–C8 double
bond, seem to be a very useful scaffold for fine chemicals.
MS: m/z = 159 (100) [M+], 144 (43), 130 (20), 118 (48), 117 (50),
104 (10), 91 (20), 80 (16), 63 (12).
Reactions requiring an inert atmosphere were conducted under an-
hyd N2, and the glassware were oven-dried (120 °C). Anhydrous
solvents were purified prior to use as follows. CH2Cl2 was distilled
from CaCl2, THF and Et2O were distilled from sodium under N2.
All reagents were purchased in the highest quality available and
Anal. Calcd for C11H13N: C, 83.02; H, 8.80; N, 7.55. Found: C,
82.88; H, 8.63; N, 7.62.
Synthesis 2005, No. 18, 3119–3123 © Thieme Stuttgart · New York

3122
G. Guazzelli et al.
PAPER
(–)-(S)-5-Ethenyl-5,6-dihydroindolizine (6¢)
solution (30 mL) and the aqueous layers were extracted with
CH2Cl2 (3 × 50 mL). The combined organic phases were washed
(4 × 250 mL), dried and evaporated in vacuo. Column chromatog-
raphy (CH2Cl2–hexane 1:1 as eluent) gave (+)-(S)-5-(p-toluene-
sulfonyloxymethyl)-5,6-dihydroindolizine (9; 0.99 g, 3.27 mmol,
A mixture of methyltriphenylphosphonium bromide and NaNH2
(10 g, 24 mmol) in anhyd THF (160 mL) was stirred at r.t. for 1 h.
To the yellow suspension cooled at –30 °C a solution of (–)-5 (1.32
g, 8.9 mmol) in anhyd THF (70 mL) was added. After 1.25 h the
temperature was increased to r.t. and the mixture was stirred for 19
h. The reaction mixture was then hydrolysed with water (150 mL).
The aqueous phase was extracted with hexane (3 × 150 mL) and the
combined organic layers were washed until neutral. After drying
(Na2SO4), the hexane solution was concentrated in vacuo affording,
after vacuum distillation (40 °C, 0.01 mm Hg), (–)-(S)-5-ethenyl-
5,6-dihydroindolizine (6¢) as an orange liquid (0.55 g, 3.80 mmol,
42%); [a]D25 –60.9 (c = 1.2, CH2Cl2).
24
69%) as an orange solid (mp 50–52 °C); [a]D = +4.60 (c = 1.0,
CH2Cl2).
1H NMR: d = 7.72 (d, J = 8.2 Hz, 2 H, HPh), 7.34 (d, J = 8.2 Hz, 2
H, HPh), 6.63 (br s, 1 H, HPyr), 6.36 (dd, J = 2.8, 9.6 Hz, 1 H,
PyrCH=), 6.12 (t, J = 3.2 Hz, 1 H, HPyr), 6.02 (br s, 1 H, HPyr), 5.49
(m, 1 H, CH2CH=), 4.38 (m, 1 H, NCH), 4.01 (m, 2 H, CH2O), 2.70
(m, 1 H, CH2), 2.48–2.33 (m, 4 H, CH2, CH3).
13C NMR: d = 22.0, 25.8, 52.9, 69.6, 107.2, 108.9, 116.1, 120.4,
121.1, 128.1 (3 × C), 130.2 (2 × C), 132.7, 145.5.
MS: m/z = 303 (52) [M+], 131 (29), 118 (100), 91 (32), 65 (41).
1H NMR: d = 6.67 (br s, 1 H, HPyr), 6.47 (d, J = 9.4 Hz, 1 H,
PyrCH=), 6.17 (t, J = 3.1 Hz, 1 H, HPyr), 6.10 (br s, 1 H, HPyr), 5.95
(m, 1 H, CHCH=), 5.68 (m, 1 H, CH2CH=), 5.25 (d, J = 10.0 Hz, 1
H, trans-CH=CH2), 5.03 (d, J = 16.8 Hz, 1 H, cis-CH=CH2), 4.53
(q, J = 7.2 Hz, 1 H, NCH), 2.63 (m, 1 H, CH2), 2.44 (m, 1 H, CH2).
13C NMR: d = 31.0, 57.5, 106.7, 108.2, 117.6, 117.7, 120.1, 120.4,
129.5, 137.8.
Anal. Calcd for C16H17NO3S: C, 63.37; H, 5.61; N, 4.62; S, 10.56.
Found: C, 63.45; H, 5.65; N, 4.58; S, 10.60.
(–)-(R)-5-Methyl-5,6-dihydroindolizine (10a)
To a suspension of LiAlH4 (1.450 g, 11.8 mmol) in anhyd Et2O,
(+)-(S)-5-(p-toluenesulfonyloxymethyl)-5,6-dihydroindolizine (9;
0.725 g, 2.39 mmol) was added at 0 °C. The reaction mixture was
warmed to r.t. and stirred for 22 h. The reaction mixture was hydrol-
ysed with humid Et2O (60 mL) and a sat. aq solution of NH4Cl (70
mL), and the aqueous layer was extracted with Et2O (3 × 100 mL).
The combined organic phases were washed (3 × 200 mL), dried
(Na2SO4) and evaporated carefully in vacuo. After purification by
column chromatography (hexane as eluant), (–)-(S)-5-methyl-5,6-
dihydroindolizine (10a)15,16 was obtained as a yellow oil (0.173 g,
1.30 mmol, 55%); ee 98%; [a]D21 = – 107.5 (c = 1.18, CH2Cl2).
MS: m/z = 145 (100) [M+], 144 (97), 130 (24), 118 (81), 117 (78),
115 (11), 104 (27), 91 (22), 90 (18), 89 (19), 80 (10), 78 (10), 77
(14), 65 (13), 63 (13).
Anal. Calcd for C12H11N: C, 82.76; H, 7.59; N, 9.66. Found: C,
82.85; H, 7.63; N, 9.71.
(–)-(5R,9R)-Octahydroindolizine (1)
Step iii: A solution of (+)-(S)-6 (80 mg, 0.50 mmol) in Et2O (5 mL)
containing 5% Rh-C (85 mg) was hydrogenated under vigorous stir-
ring in a steel vessel at r.t. and at 10 atm for 1.5 h. The catalyst was
removed by filtration and the solution was concentrated in vacuo to
afford (–)-1 (69 mg, 0.41 mmol, 80%) as a colourless oil (42% op-
tical purity). The spectroscopic data of this product are in complete
agreement with the reported data.10
(–)-(R)-5-Propyl-5,6-dihydroindolizine (10b)
To a solution of (+)-(S)-5-(p-toluenesulfonyloxymethyl)-5,6-dihy-
droindolizine (9; 0.194 g, 0.64 mmol) in anhyd THF were added at
–78 °C a 3 M ethereal solution of EtMgBr (12 mmol, 19 equiv, 4
mL) and a THF solution of Li2CuCl4 (0.28 M, 0.756 mmol, 1.18
equiv, 2.7 mL). After allowing the reaction mixture to warm to r.t.
very slowly (63 h), a sat. aq solution of NH4Cl (40 mL) was added,
and the aqueous layers were extracted with Et2O (3 × 60 mL). The
combined organic phases were washed (3 × 100 mL), dried
(Na2SO4) and concentrated at atmospheric pressure. Purification by
column chromatography (hexane as eluent) afforded (–)-(R)-5-pro-
pyl-5,6-dihydroindolizine (10b) as an orange oil (0.054 g, 0.33
mmol, 52%); ee 98%; [a]26D –46.3 (c = 0.86, CH2Cl2)}.
Step vii: Compound (–)-(1) was obtained from (–)-(R)-10b under
the above reported reduction conditions in 65% yield and 98% op-
tical purity.10
(+)-(S)-5-Hydroxymethyl-5,6-dihydroindolizine (7)
To a suspension of LiAlH4 (0.960 g, 25.3 mmol) in anhyd THF (60
mL) cooled at 0 °C a solution of (–)-3 (1.99 g, 10.4 mmol) in anhyd
THF was added. The reaction mixture was heated to r.t. and, after 1
h stirring, MeOH (8 mL) and a sat. aq solution of mixed sodium po-
tassium tartrate (50 mL) were added. The aqueous phase was ex-
tracted with Et2O (3 × 70 mL) and the combined organic phases
were washed with water (3 × 150 mL), dried (Na2SO4) and concen-
trated in vacuo to afford (+)-(S)-5-hydroxymethyl-5,6-dihydroin-
dolizine (7)9 (1.54 g, 10.3 mmol, 99%) as an orange oil, in 98%
optical purity; [a]D20 +69.6 (c = 1, CH2Cl2).
Acknowledgment
This work was supported by the Ministero dell’ Università e della
Ricerca Scientifica e Tecnologica (60% funds).
To a solution of (–)-(S)-5-formyl-5,6-dihydroindolizine (5; 56.5
mg, 0.38 mmol) in MeOH (1.5 mL) NaBH4 (80 mg, 2.1 mmol) was
added. After stirring at r.t. for 45 min, the reaction was quenched
with a sat. aq solution of NH4Cl (3 mL). Addition of Et2O (5 mL)
was followed by separation and extraction of the aqueous phase
with Et2O (3 × 3 mL). The combined organic layers were washed
with water (3 × 10 mL), dried (Na2SO4) and concentrated in vacuo
to afford (+)-(S)-5-hydroxymethyl-5,6-dihydroindolizine (7)9 (47.7
mg, 0.32 mmol, 84%) in 80% optical purity; [a]D20 = +55.7 (c = 1,
CH2Cl2).
References
(1) (a) Daly, J. W.; Garaffo, H. M.; Spande, T. F. Alkaloids
(N.Y.) 1993, 43, 185. (b) Edwards, M. W.; Daly, J. W.;
Myers, C. W. J. Nat. Prod. 1988, 51, 1188.
(2) Aronstam, R. S.; Daly, J. W.; Spande, T. F.; Narayanan, T.
K.; Albuquerque, E. X. Neurochem. Res. 1986, 11, 1227.
(3) Daly, J. W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25,
1023.
(4) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives, Vol. 13; Pelletier, S.
W., Ed.; Pergamon Press: Amsterdam, 1999, 1–161.
(5) (a) Ganapati Reddy, P.; Baskaran, S. J. Org. Chem. 2004, 69,
3093. (b) Michael, J. P. Nat. Prod. Rep. 2003, 20, 458; and
references reported therein.
(+)-(S)-5-(p-Toluenesulfonyloxymethyl)-5,6-dihydroindolizine
(9)
The alcohol (+)-7 (0.71 g, 4.76 mmol), tosyl chloride (1.65 g, 8.7
mmol) and Et3N (1.78 g, 17.6 mmol) were stirred in anhyd CH2Cl2
at r.t. for 5 h. The brown solution was poured into sat. aq NaHCO3
Synthesis 2005, No. 18, 3119–3123 © Thieme Stuttgart · New York

PAPER
5,6-Dihydroindolizines as Convenient Precursors of Indolizidine 167B
3123
(6) (a) Peroche, S.; Remuson, R.; Gelas-Mialhe, Y.; Gramain,
trifluoroacetyl, 50 m × 0.25 mm) capillary column]. The
chromatographic conditions were set up for analysing a
racemic sample of 814 prepared in the same manner. The
compound 8 showed the same ee value as the starting
aldehyde 5. This result gives evidence that the vinyl group
hydrogenation as well as the endocyclic double bond
hydrogenation do not influence the configuration of the
asymmetric centre, accounting for the internal bond
formation in the alkyl chain of 6, and not for its
hydrogenation, as the sole step responsible for racemisation
observed in the synthesis of (–)-indolizidine 167B.
(14) Selected data for 8: 1H NMR: d = 6.67 (br s, 1 H), 6.15 (t,
J = 3.1 Hz, 1 H), 5.81 (br s, 1 H), 3.94 (m, 1 H), 2.75 (m, 2
H), 2.07 (m, 2 H), 1.91 (m, 2 H), 1.68 (m, 2 H), 0.98 (t, J =
7.3 Hz, 3 H).
J.-C. Tetrahedron Lett. 2001, 42, 4617. (b) Back, T. G.;
Nakajima, K. J. Org. Chem. 2000, 65, 4543. (c) Zaminer,
J.; Stapper, C.; Blechert, S. Tetrahedron Lett. 2002, 43,
6739.
(7) (a) Corvo, M. C.; Pereira, M. M. A. Tetrahedron Lett. 2002,
43, 455. (b) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.;
Gramain, J.-C.; Canet, I. Tetrahedron Lett. 1999, 40, 1661.
(8) (a) Settambolo, R.; Caiazzo, A.; Lazzaroni, R. Tetrahedron
Lett. 2001, 42, 4045. (b) Settambolo, R.; Miniati, S.;
Lazzaroni, R. Synth. Commun. 2003, 17, 2953.
(9) Settambolo, R.; Guazzelli, G.; Lazzaroni, R. Tetrahedron:
Asymmetry 2003, 14, 1447.
(10) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55,
4688.
(11) Settambolo, R.; Guazzelli, G.; Mengali, L.; Mandoli, A.;
Lazzaroni, R. Tetrahedron: Asymmetry 2003, 14, 2491.
(12) Chiral gas chromatography was performed on chiral
capillary column CHIRALDEX G-TA (g-cyclodextrin
trifluoroacetyl, 50 m × 0.25 mm).
(13) The evaluation of ee of the olefin (–)-6¢ was accomplished
by transforming it into the new partially hydrogenated 5-
ethyl-5,6,7,8-tetrahydroindolizine (8; Scheme 2) which,
unlike 6¢, was separated into its enantiomers by chiral gas
chromatography [CHIRALDEX G-TA (g-cyclodextrin
MS: m/z = 149 (78) [M+], 121 (43), 120 (100), 106 (15), 93
(14), 80 (14), 65 (7).
(15) The ee evaluation was accomplished via GC chiral gas
chromatography under the same analytical conditions
previously adopted for the same substrate prepared in an
alternative way.16
(16) Settambolo, R.; Guazzelli, G.; Mandoli, A.; Lazzaroni, R.
Tetrahedron: Asymmetry 2004, 15, 1821.
(17) (a) Tamura, M.; Kochi, J. Synthesis 1971, 303. (b) Fouquet,
G.; Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 82.
Synthesis 2005, No. 18, 3119–3123 © Thieme Stuttgart · New York