Total synthesis of 275A lehmizidine frog skin alkaloid (or of its enantiomer)

Article abstract of DOI:10.1016/j.tetasy.2010.08.014

A concise asymmetric total synthesis of the potentially bioactive 275A lehmizidine frog skin alkaloid (or of its enantiomer) is described. Key features of the protocol include an acyliminium butenyl Grignard addition and a seven-membered intramolecular reductive amination step. Both reactions ensure a high degree of diastereocontrol, with installation of the same relative configuration at the C3, C5 and C10 stereocentres as in the natural product 275A. Despite this total synthesis, the absolute configuration of the natural product remains unknown, due to the lack of specific rotation data for alkaloid 275A.

Full text of DOI:10.1016/j.tetasy.2010.08.014

Tetrahedron: Asymmetry 21 (2010) 2329–2333
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of 275A lehmizidine frog skin alkaloid (or of its enantiomer)
Giordano Lesma a, , Alessandro Sacchetti b, Alessandra Silvani a
⇑
a Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy
b Politecnico di Milano, Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘Giulio Natta’, via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2010
Accepted 20 August 2010
A concise asymmetric total synthesis of the potentially bioactive 275A lehmizidine frog skin alkaloid (or
of its enantiomer) is described. Key features of the protocol include an acyliminium butenyl Grignard
addition and a seven-membered intramolecular reductive amination step. Both reactions ensure a high
degree of diastereocontrol, with installation of the same relative configuration at the C3, C5 and C10 ste-
reocentres as in the natural product 275A. Despite this total synthesis, the absolute configuration of the
natural product remains unknown, due to the lack of specific rotation data for alkaloid 275A.
Ó 2010 Elsevier Ltd. All rights reserved.
H
1. Introduction
3
10
R
N
Dendrobatid frogs of Central and South America have been a
large source of synthetically interesting and biologically active
compounds with over 800 alkaloids that encompass over 20 struc-
tural classes being detected in their skin extracts, probably deriv-
ing from dietary ants.1
Some of them are known to target nAChRs: epibatidine is a
quite remarkable as a nicotinic agonist, while histrionicotoxins,
pumiliotoxin and some indolizidines are potent blockers of nico-
tinic channels.2 Recent studies show that frog alkaloids alter the
function of nicotinic receptors in a subtype-selective manner, sug-
gesting that an analysis of these compounds and analogues may
aid in the development of selective drugs useful in degenerative
CNS pathologies.3
The structural diversity and pharmacological activity associated
with these alkaloids have stimulated research in numerous syn-
thetic groups.4 Alkaloid 275A 1 (Fig. 1), one of the major com-
pounds isolated from skin extracts of the Colombian poison frog
Dendrobates lehmanni, possesses an unusual 1-azabicy-
clo[5.3.0]decane ring system. At present, the same ring system,
coupled with different substitutions at C3, was postulated for nine
other alkaloids, assigned to the lehmizidine class, named after the
frog species from which they were discovered. After that a gross
structure was presented for alkaloid 275A in 1999,5 the relative
stereochemistry of which has been definitively established in
2001 from Garraffo et al.,6 by comparison of tetrahydro-1 with
the four synthetic diastereoisomers. To the best of our knowledge,
neither the asymmetric synthesis of the naturally occurring alka-
loid, nor biological studies have been reported, presumably due
to a lack of material.
5
Me
Alkaloid 275A 1
CH)
(R = (CH2)7C
Figure 1. Lehmizidine alkaloids.
As a continuation of our focus on the development of new
methodologies for the stereoselective synthesis of pharmacologi-
cally significant scaffolds, such as indolizidine, quinolizidine alka-
loids and analogues,7 we became intrigued by the chemical
architecture of this compound and pursued its total synthesis.
2. Results and discussion
Figure 2 illustrates our retrosynthetic strategy. Keeping as the
last step the introduction of the two carbon acetylene group, it
was envisioned that the seven-membered ring of the natural prod-
uct 1 could be accessed by an intramolecular reductive amination.
Through a cross metathesis reaction, the required intermediate
was thought to be formed from a suitable 2,5-trans-disubstituted
pyrrolidine and methyl vinyl ketone. The properly functionalised
pyrrolidine could be accessed by acyliminium chemistry in order
to introduce the but-1-enyl side chain and by alkyl cuprate nucle-
ophilic substitution to achieve the seven carbon side chain.
Starting from the known methyl lactamol 2,8 readily available
from commercial L-pyroglutamic acid, butenylation was realised
using butenylmagnesium bromide and the CuBrꢀSMe2 complex,
⇑
Corresponding author. Tel.: +39 0250314079; fax: +39 0250314078.
E-mail address: giordano.lesma@unimi.it (G. Lesma).
following the protocol by Pedregal.9 After Boc deprotection and
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.014

2330
G. Lesma et al. / Tetrahedron: Asymmetry 21 (2010) 2329–2333
resulting in a concomitant intramolecular reductive amination and
H
H
6OX
cyclisation (Scheme 2). This type of reaction is well documented
starting from the appropriate ketopyrrolidines to afford indolizi-
dine12 and pyrrolizidine13 ring systems. Since to the best of our
knowledge, there are only a few examples, of seven-membered
intramolecular reductive amination steps, the stereochemical out-
come was difficult to predict.
6
N
N
Me
Me
275A 1
6 OX
OX
N
N
H
6
H
H
PG
X
(a)
(d)
6
6
N
N
10
Me
Me
O
1
11 (X = OTBS)
12 (X = OH)
13 (X = Br)
(b)
(c)
CO2Bn
MeO
CO2Bn
N
PG
N
Boc
Ref. 8
Scheme 2. Reagents and conditions: (a) (i) H2, Pd/C 10%, MeOH, rt, (ii) chromato-
graphic separation, 76% (overall); (b) TBAF, THF, 0 °C to rt, 62%; (c) CBr4, PPh3,
CH2Cl2, 0 °C to rt, 93%; (d) lithium acetylide ethylenediamine complex, DMSO, rt,
45%.
PG = Protecting Group
Figure 2. Basic strategy for the construction of the lehmizidine skeleton of alkaloid
275A 1.
We were pleased to observe that the indicated 5S diastereoiso-
mer 11 was mainly obtained (5:1 dr, after chromatographic sepa-
ration), as the result of a stereoselective palladium-catalysed
reduction from the less hindered face of the rigid cyclic iminium
intermediate. Steric hindrance of the nine carbon side chain at
C3 proved to play a key role in this transformation. The combina-
tion of 2D NMR NOESY experiments with computational14 evalua-
tion of interatomic distances on the minimum conformer for both
diastereoisomers at C5 (Fig. 3) allowed us to establish the configu-
ration of the newly formed stereocentre of 11. Installation of the
chromatographic separation, the major trans-diastereoisomer 3
(9:1 dr) was isolated in satisfactory yields (Scheme 1).
After protection of 3 as the Cbz derivative 4, we pursued the
exploitation of the ester group in order to set up the required seven
carbon side chain. Reduction of 4 with LiBH4 to give 5, followed by
treatment with tosyl chloride afforded tosylate 6 in high yield.
With compound 6 in hand, we turned our attention to the Cu-cat-
alysed alkylation chemistry. Reaction with CuI and the appropriate
Grignard reagent, prepared from the 6-(t-butyldimethylsilyl-
oxy)hexyl bromide 7,10 provided an unsatisfactory yield of 9 after
24 h, with the majority of the remaining material consisting of
starting tosylate 6. By using the cuprate reagent, prepared from
the iodo derivative 8,11 t-BuLi and CuI, trans-pyrrolidine 9 could
be obtained in satisfactory yield. Accurate temperature control
proved to be necessary in order to preserve the stability of the cup-
rate reagent and to ensure a clean reaction. At this point, cross
metathesis reaction was carried out with a stoichiometric amount
of methyl vinyl ketone in a 0.05 M toluene solution, using the
Grubbs–Hoveyda catalyst. The reaction proceeded smoothly at
40 °C in 6 h to afford 10 in 90% yield.
R
10
R
H
N
3
3H
N
H
H
Me
H
10
Me
5
5
H
CH
11a (3R,5R,10R)
R = (CH2)7C
11 (3R,5S,10R)
major diastereoisomer
minor diastereoisomer
Pyrrolidine 10 was subjected to the removal of the Cbz group by
treatment with catalytic Pd/C (10%) under a hydrogen atmosphere,
Figure 3. Diagnostic NOE contacts for 11 and 11a.
(a)
(c)
MeO
CO2Bn
CO2Bn
CH2OX
N
N
N
R
Boc
Cbz
2
3
4
(R = H)
(R = Cbz)
5 (X = H)
6 (X = OTs)
(b)
(d)
O
(e)
(f)
6 OTBS
6 OTBS
N
N
Cbz
Cbz
9
10
X
OTBS
X = Br 7
X = I
8
Scheme 1. Reagents and conditions: (a) (i) but-3-enylmagnesium bromide, CuBrꢀMe2S, BF3ꢀEt2O, THF dry, ꢁ78 °C to rt, 84%, (ii) 30% TFA in CH2Cl2, (iii) chromatographic
separation, 74% (overall); (b) Cbz-Cl, TEA, CH2Cl2, 96%; (c) LiBH4 2 M in THF, 0 °C, 84%; (d) p-TsCl, TEA, DMAP, CH2Cl2, 0 °C to rt, 97%; (e) 8, t-BuLi 1.7 M in pentane, CuI, Et2O/
hexane, ꢁ78 to ꢁ5 °C, 81%; (f) methyl vinyl ketone, Ru-cat. Hoveyda–Grubbs, toluene, 40 °C, 90%.

G. Lesma et al. / Tetrahedron: Asymmetry 21 (2010) 2329–2333
2331
same relative configuration at the C3, C5 and C10 stereocentres, as
in the natural product 275A, was thus completed.
(400 MHz, CDCl3, major trans diastereoisomer description, two con-
formers) d = 7.41–7.31 (m, 5H), 5.91–5.77 (m, 1H), 5.29–4.94 (m,
4H), 4.40 (d, J = 8.4 Hz, 0.4H, minor conformer), 4.30 (d, J. = 8.4 Hz,
0.6H, major conformer), 4.05 (dt, J = 8.8, 3.2 Hz, 0.6H, major con-
former), 3.94 (dt, J = 8.9, 2.8 Hz, 0.4H, minor conformer), 2.32–
2.16 (m, 1H), 2.14–1.88 (m, 4H), 1.87–1.76 (m, 1H), 1.73–1.61 (m,
1H), 1.48 (s, 3.6H, minor conformer), 1.45–1.37 (m, 1H), 1.36 (s,
5.4H, major conformer). 13C NMR (100 MHz, CDCl3, major trans dia-
stereoisomer description, two conformers) d = 173.0 (major) and
172.7 (minor), 153.7, 138.2 (major) and 138.0 (minor), 135.9 (min-
or) and 135.7 (major), 128.6–128.1 (5C), 114.8 (minor) and 114.6
(major), 79.9 (minor) and 79.8 (major), 66.6, 59.8 (major) and
59.6 (minor), 57.9 (major) and 57.5 (minor), 33.8 (minor) and
33.1 (major), 30.9, 28.5 (minor) and 28.3 (major) (3C), 27.6, 27.4.
To a stirred solution of (2S)-2-benzyl 1-tert-butyl 5-(but-3-
enyl)pyrrolidine-1,2-dicarboxylate (5.12 g, 14.2 mmol) in dry
CH2Cl2 (100 mL) under a nitrogen atmosphere, trifluoroacetic acid
(50 mL) was added and the reaction mixture was stirred at rt for
2 h. To this mixture a NaHCO3-saturated aqueous solution was
slowly added until pH 10. The phases were separated and the
aqueous layer was repeatedly extracted with CH2Cl2. The com-
bined organic phases were then washed with a NaHCO3-saturated
aqueous solution, dried over Na2SO4, filtered and evaporated to
dryness. The residue was finally purified by flash chromatography
on silica gel (n-hexane/EtOAc 55:45) to afford 1.13 g (74% overall)
Conversion of 11 into the final target compound 1 was performed
in a few steps. The exposure of 11 to TBAF led to the desilylated prod-
uct 12, which was converted into the corresponding bromide 13, by
the reaction with CBr4 and PPh3. The alkyl bromide underwent dis-
placement with lithium acetylide–ethylendiamine complex in
DMSO15 and produced the desired alkyne 1 in satisfactory yield.16
The specific rotation of our synthetic 1 had a negative value
{½a 2D5
ꢂ
¼ ꢁ19:2 (c 0.5, CHCl3)}. Since the [
a] value or an authentic
sample of the alkaloid 275A is not at present available, the absolute
configuration of the natural product remains unknown.
D
3. Conclusions
In conclusion, we have accomplished a concise, asymmetric
synthesis of the 275A lehmizidine frog skin alkaloid (or of its enan-
tiomer). Starting from L-pyroglutamic acid as the source of chiral-
ity, key features of this protocol are an acyliminium butenyl
Grignard addition and a seven-membered intramolecular reduc-
tive amination step, both ensuring a high degree of diastereocon-
trol. It should be noted that the described sequence is adaptable
to the generation of a variety of natural analogues, above all other
natural lehmizidines, bearing different substituents at C3.
of
3 (major trans diastereoisomer) as a light yellow oil.
4. Experimental
½
a 2D5
ꢂ
¼ ꢁ39:2 (c 1.0, CHCl3). 1H NMR (400 MHZ, CDCl3) d = 7.42–
7.32 (m, 5H), 5.90–5.78 (m, 1H), 5.18 (s, 2H), 5.05 (dd, J = 17.0,
1.6 Hz, 1H), 4.97 (dd, J = 10.0, 0.8 Hz, 1H), 3.93 (dd, J. = 6.0, 5.6 Hz,
1H), 3.30–3.22 (m, 1H), 2.45–2.30 (s, br, 1H), 2.32–2.20 (m, 1H),
2.19–2.04 (m, 2H), 1.99–1.84 (m, 2H), 1.65–1.35 (m, 3H). 13C
NMR (100 MHz, CDCl3) d = 175.5, 138.5, 135.8, 128.6–128.2 (5C),
114.6, 66.7, 59.4, 58.1, 35.8, 31.5, 31.4, 29.6. HRMS (ESI) calcd for
4.1. General information
All solvents were distilled and properly dried, when necessary,
prior to use. All chemicals were purchased from commercial
sources and used directly, unless otherwise indicated. All reactions
were run under N2, unless otherwise indicated. All reactions were
monitored by thin layer chromatography (TLC) on precoated Silica
Gel 60 F254; spots were visualised with UV light or by treatment
with 1% aqueous KMnO4 solution. Products were purified by flash
chromatography on Silica Gel 60 (230–400 mesh). 1H and 13C NMR
spectra were recorded using 300 and 400 MHz spectrometers.
Chemical shifts (d) are expressed in ppm relative to TMS at
d = 0 ppm for 1H NMR and to CDCl3 at d = 77.16 ppm for 13C
NMR. High-resolution MS spectra were recorded using a FT-ICR
(Fourier Transform Ion Ciclotron Resonance) instrument, equipped
with ESI source, or a standard MS instrument, equipped with EI
source. IR spectra were recorded using a FTIR instrument.
C16H21NO2 259,1572, found 259,1564.
4.3. (2S,5R)-Benzyl-1-benzyloxycarbonyl-5-(but-3-enyl)pyrroli-
dine-1,2-dicarboxylate (4)
To a stirred solution of 3 (2.84 g, 10.9 mmol) in dry THF (20 mL)
under a nitrogen atmosphere, triethylamine (1.52 mL, 10.9 mmol,
1 equiv) and benzyloxycarbonylchloride (3.12 mL, 21.8 mmol,
2 equiv) were added. The mixture was left to stir at rt for 4 h, then
diluted with EtOAc and washed with a saturated aqueous NH4Cl
solution until the aqueous phase had a neutral pH. The organic
layer was then dried over Na2SO4, filtered and concentrated in va-
cuo. Purification of the residue by flash chromatography on silica
gel (n-hexane/EtOAc 8:2) provided 4.12 g (96%) of 4 as a colourless
4.2. (2S,5R)-Benzyl 5-(but-3-enyl)pyrrolidine-2-carboxylate (3)
oil. ½a 2D5
ꢂ
¼ ꢁ64:8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3, two con-
formers) d = 7.40–7.22 (m, 10H), 5.90–5.80 (m, 0.6H, major con-
former), 5.78–5.68 (m, 0.4H, minor conformer), 5.26–4.91 (m,
6H), 4.47 (d, J = 8.4 Hz, 0.4H, minor conformer), 4.42 (d,
J = 8.4 Hz, 0.6H, major conformer), 4.12 (dt, J = 8.4, 3.2 Hz, 0.6H,
major conformer), 4.06 (dt, J = 8.4, 3.2 Hz, 0.4H, minor conformer),
2.34–2.19 (m, 1H), 2.14–1.92 (m, 5H), 1.87–1.68 (m, 1H), 1.49–1.37
(m, 1H). 13C NMR (100 MHz, CDCl3, two conformers) d = 173.2,
154.9, 138.6 (major) and 138.4 (minor), 137.3, 136.3, 129.4–
128.5 (10 C), 115.4 (minor) and 115.3 (major), 67.8, 67.4 (major)
and 67.3 (minor), 60.6 (minor) and 60.3 (major), 59.2 (major)
and 58.3 (minor), 34.3 (minor) and 33.6 (major), 31.3, 29.3 (major)
and 28.9 (minor), 28.2 (minor) and 28.1 (major). HRMS (ESI) calcd
for C24H27NO4 393,1940, found 393,1949.
To
a
stirred suspension of CuBrꢀMe2S (4.90 g, 23.8 mmol,
4 equiv) in dry THF (30 mL) at ꢁ50 °C under a nitrogen atmosphere,
but-3-enylmagnesium bromide (29.8 mL, 1.0 M in THF, 29.8 mmol,
5 equiv) was added dropwise and stirring was continued at ꢁ50 °C
for 30 min. The mixture was cooled to ꢁ78 °C and BF3ꢀEt2O
(3.02 mL, 23.8 mmol, 4 equiv) was added dropwise. After 30 min,
a solution of 2 (2.00 g, 5.9 mmol) in dry THF (6 mL) was added
slowly and the reaction mixture was further stirred at ꢁ78 °C for
30 min, then allowed to warm to rt over 1 h. After completion of
the reaction, a 2:1:1 mixture of H2O/concd NH3/NH4Cl-saturated
aqueous solution was added. The resulting mixture was vigorously
stirred and then repeatedly extracted with EtOAc. The combined or-
ganic fractions were washed with H2O and brine, and dried over
Na2SO4. Filtration and evaporation of the solvent under reduced
pressure, followed by purification by flash chromatography on sil-
ica gel (n-hexane/EtOAc 9:1), afforded 1.80 g of (2S)-2-benzyl 1-
tert-butyl-5-(but-3-enyl)pyrrolidine-1,2-dicarboxylate, as a light
yellow oil (9:1 mixture of C5 diastereoisomers). 1H NMR
4.4. (2R,5S)-Benzyl 2-(but-3-enyl)-5-(hydroxymethyl)
pyrrolidine-1-carboxylate (5)
Lithium borohydride (5.5 mL, 2.0 M in THF, 11.0 mmol,
1.5 equiv) was added portionwise to a vigorously stirred solution

2332
G. Lesma et al. / Tetrahedron: Asymmetry 21 (2010) 2329–2333
of 4 (2.90 g, 7.4 mmol) in dry THF (24 mL) at 0 °C under a nitrogen
atmosphere. The reaction mixture was allowed to stir overnight at
0 °C and at this temperature was diluted with H2O and acidified by
the dropwise addition of an HCl 2 M aqueous solution. The result-
ing mixture was extracted with EtOAc and the combined organic
phase was washed with H2O. The aqueous fractions were back-ex-
tracted with EtOAc and the combined organic phases were washed
with brine, dried over Na2SO4, filtered and evaporated in vacuo.
The residue was purified by flash chromatography on silica gel
(n-hexane/EtOAc from 8:2 to 6:4) yielding 1.80 g (84%) of 5 as a
of 9 as a light yellow oil. ½a D25
ꢂ
¼ ꢁ41:8 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3, two conformers) d = 7.41–7.31 (m, 5H), 5.92–
5.79 (m, 0.5H, conformer A), 5.78–5.65 (m, 0.5H, conformer B),
5.21 (d, J = 12.4 Hz, 1H), 5.09 (d, J = 12.4 Hz, 1H), 5.05–4.90 (m,
2H), 3.88–3.74 (m, 2H), 3.61 (t, J = 6.4 Hz, 2H), 2.11–1.12 (m,
20H), 0.92 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz, CDCl3, two con-
formers) d = 154.3, 138.2 and 138.0, 137.1, 128.4–127.8 (5C), 114.6,
66.4, 63.3, 58.3 and 57.7, 57.7 and 57.2, 34.0–26.6 (9C), 26.0 (3C),
25.8, 18.4, ꢁ5.2 (2C). HRMS (ESI) calcd for C29H49NO3Si 487,3482,
found 487,3468.
colourless oil. ½a D25
ꢂ
¼ ꢁ45:4 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3, two conformers) d = 7.37–7.32 (m, 5H), 5.90–5.76 (m,
0.3H, minor conformer), 5.75–5.60 (m, 0.7H, major conformer),
5.18 (d, J = 12.3 Hz, 1H), 5.10 (d, J = 12.3 Hz, 1H), 5.01–4.86 (m,
2H), 4.09–3.99 (m, 1H), 3.92–3.82 (m, 1H), 3.77–3.58 (m, 2H),
2.45–2.20 (s, br, 1H), 2.14–1.22 (m, 8H). 13C NMR (75 MHz, CDCl3,
two conformers) d = 156.5, 138.0 (minor) and 137.7 (major), 136.4,
128.5–128.0 (5C), 114.9, 67.2 (major) and 67.0 (minor), 64.0, 60.4,
58.7 (minor) and 58.4 (major), 32.7, 30.7, 28.1, 26.6. HRMS (ESI)
calcd for C17H23NO3 289,1678, found 289,1660.
4.7. (2R,5R)-Benzyl 2-(7-(tert-butyldimethylsilyloxy)heptyl)-5-
((E)-5-oxohex-3-enyl)pyrrolidine-1-carboxylate (10)
To a stirred solution of 9 (965 mg, 2.0 mmol) and methyl vinyl
ketone (165 lL, 2.0 mmol, 1 equiv) in dry toluene (40 mL) under
a nitrogen atmosphere, Ru-catalyst (Hoveyda–Grubbs second gen-
eration) (62 mg, 5 mol %) was added. The solution was stirred at
40 °C for 6 h. The solvent was then evaporated and the residue
was purified by flash chromatography on silica gel (n-hexane to
n-hexane/EtOAc 8:2) yielding 952 mg (90%) of 10 as a light yellow
4.5. (2R,5S)-Benzyl 2-(but-3-enyl)-5-(tosyloxymethyl)
pyrrolidine-1-carboxylate (6)
oil. ½a 2D5
ꢂ
¼ ꢁ38:2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3, two con-
formers) d = 7.39–7.31 (m, 5H), 6.82 (dt, J = 16.0, 7.0 Hz, 0.6H, ma-
jor conformer), 6.64 (dt, J = 16.0, 7.0 Hz, 0.4H, minor conformer),
6.12 (d, J = 16.0 Hz, 0.6H, major conformer), 6.01 (d, J = 16.0 Hz,
0.4H, minor conformer), 5.26–5.05 (m, 2H), 3.90–3.74 (m, 2H),
3.61 (t, J. = 6.4 Hz, 2H), 2.25 (s, 1.8H, major conformer), 2.16 (s,
1.2H, minor conformer), 2.27–1.18 (m, 20H), 0.92 (s, 9H), 0.07 (s,
6H). 13C NMR (100 MHz, CDCl3, two conformers) d = 198.4, 154.4,
147.6 (major) and 147.1 (minor), 136.9, 131.6, 128.4–127.9 (5C),
66.6, 63.3, 58.4 (minor) and 57.9 (major), 57.5 (major) and 56.8
(minor), 33.9–26.6 (9C), 26.6, 26.0 (3C), 25.8, 18.4, -5.2 (2C). HRMS
(ESI) calcd for C31H51NO4Si 529,3587, found 529,3562.
To an ice-cooled solution of 5 (1.45 g, 5.0 mmol) in dry CH2Cl2
(30 mL) under a nitrogen atmosphere, triethylamine (1.40 mL,
10.1 mmol, 2 equiv), then p-toluenesulfonyl chloride (1.39 g,
7.3 mmol, 1.5 equiv) portionwise and dimethylaminopyridine
(61 mg, 0.5 mmol, 0.1 equiv) were added. The reaction mixture
was stirred at rt for 5 h, then diluted with CH2Cl2 and washed with
1 M HCl aq solution, NaHCO3-saturated aqueous solution and
brine. The organic phase was dried over Na2SO4, filtered and con-
centrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (n-hexane/EtOAc 8:2) afforded
2.15 g (97%) of 6 as a colourless oil. ½a D25
ꢂ
¼ ꢁ43:4 (c 1.0, CHCl3).
4.8. (3R,5S,10R)-3-(7-(tert-Butyldimethylsilyloxy)heptyl)-5-
methyloctahydro-1H-pyrrolo[1,2-a]azepine (11)
1H NMR (300 MHz, CDCl3, two conformers) d = 7.75 (d, J = 8.1 Hz,
1H), 7.67 (d, J = 8.1 Hz, 1H), 7.39–7.23 (m, 7H), 5.84–5.71 (m,
0.5H, conformer A), 5.70–5.58 (m, 0.5H, conformer B), 5.15–4.86
(m, 4H), 4.24–3.73 (m, 4H), 2.42 (s, 1.5H, conformer A), 2.41 (s,
1.5H, conformer B), 2.10–1.22 (m, 8H). 13C NMR (75 MHz, CDCl3,
two conformers) d = 154.2, 144.8, 137.8 and 137.6, 136.4, 132.9,
129.9–127.8 (9C), 114.8, 69.3 and 69.0, 66.8, 58.3 and 57.7, 56.1
and 55.5, 32.9–25.5 (4C), 21.6. HRMS (EI) calcd for C24H29SNO5
443,1766, found 443,1735.
To a solution of 10 (500 mg, 0.94 mmol) in dry MeOH (25 mL)
Pd/C 10% (100 mg) was added. The resultant mixture was stirred
under a hydrogen atmosphere for 72 h at rt. The mixture was fil-
tered over a Celite pad and rinsed with MeOH. The solvent was
evaporated in vacuo and the residue was purified by flash chroma-
tography on silica gel (EtOAc/MeOH/NH3 aqueous 97:2.5:0.5) yield-
ing 273 mg (76%) of 11 [major (5S)-diastereoisomer] as a light
brown oil. ½a 2D5
ꢂ
¼ ꢁ27:9 (c 1.0, CHCl3). 1H NMR (400 MHz, CD3CN)
4.6. (2R,5R)-Benzyl 2-(but-3-enyl)-5-(7-(tert-butyldimethylsilyl-
oxy)heptyl)pyrrolidine-1-carboxylate (9)
d = 3.63 (t, J = 6.4 Hz, 2H), 3.29–3.20 (m, 1H), 3.12–3.00 (m, 2H),
2.12–1.26 (m, 24H), 1.06 (d, J = 6.4 Hz, 3H), 0.91 (s, 9H), 0.07 (s,
6H). 13C NMR (100 MHz, CD3CN) d = 64.3, 62.6, 60.2, 52.5, 39.2–
27.0 (12C), 26.8 (3C), 24.1, 22.2, ꢁ4.6 (2C). HRMS (EI) calcd for
Under a nitrogen atmosphere, a 1.7 M solution of tert-butyllith-
ium in pentane (9.2 mL, 15.6 mmol, 8 equiv) was added dropwise
to a solution of 8 (2.68 g, 7.8 mmol, 4 equiv) in a 1:1 mixture of
dry hexane and dry Et2O (20 mL) at ꢁ78 °C. Stirring was continued
at ꢁ78 °C for 15 min before warming to rt over 1 h. The solution
was re-cooled to ꢁ78 °C and added to a slurry of copper(I) iodide
(746 mg, 3.9 mmol, 2 equiv) in dry Et2O (20 mL) via cannula. The
mixture was then warmed to ꢁ10 °C over 1 h and stirred for a fur-
ther 20 min between ꢁ10 °C and ꢁ5 °C. The resultant cuprate re-
agent was re-cooled to ꢁ60 °C before a solution of 6 (868 mg,
1.9 mmol) in dry Et2O (10 mL) was added dropwise. The mixture
was further stirred and allowed to warm to ꢁ5 °C for 1 h. The reac-
tion was quenched by addition of NH4Cl-saturated aqueous solu-
tion and the pH was adjusted to 7 with concentrated NH3. The
resultant mixture was repeatedly extracted with EtOAc and the
combined organic extracts were dried over Na2SO4. Filtration, fol-
lowed by solvent removal and purification by flash chromatogra-
phy on silica gel (n-hexane/EtOAc 95:5), afforded 751 mg (81%)
C
23H46NOSi (M+ꢁ1) 380.3349, found 380.3338.
4.9. 7-((3R,5S,10R)-5-Methyloctahydro-1H-pyrrolo[1,2-
a]azepin-3-yl)heptan-1-ol (12)
Tetrabutylammonium fluoride (1.17 mL, 1.0 M in THF,
1.17 mmol, 1.9 equiv) was added at 0 °C under a nitrogen atmo-
sphere to a solution of 11 (235 mg, 0.62 mmol) in dry THF
(14 mL) and the reaction mixture was stirred at 0 °C for 2 h. The
temperature was then raised to rt for 2 h. The reaction mixture
was diluted with EtOAc and washed with NaHCO3-saturated aque-
ous solution. The organic layer was dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash chroma-
tography on silica gel (EtOAc/MeOH/NH3 aqueous 97:2.5:0.5) to af-
ford 103 mg (62%) of 12 as a yellow oil. ½a D25
¼ ꢁ38:9 (c 1.0,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3 + CF3CO2D) d = 4.26–4.10 (m,
1H), 3.83–3.70 (m, 1H), 3.76 (t, J. = 6.4 Hz, 2H), 3.54–3.36 (m,

G. Lesma et al. / Tetrahedron: Asymmetry 21 (2010) 2329–2333
2333
1H), 2.42–1.24 (m, 25H), 1.44 (d, J = 6.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d = 67.2, 66.2, 63.7, 58.3, 33.6–25.1 (12C), 19.7.
HRMS (EI) calcd for C17H33NO 267.2562, found 267.2568.
(12C), 25.0, 23.1. HRMS (ESI) calcd for C19H33N 275,2613, found
275,2595.
References
4.10. (3R,5S,10R)-3-(7-Bromoheptyl)-5-methyloctahydro-1H-
pyrrolo[1,2-a]azepine (13)
1. Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575. and
references cited therein.
2. Daly, J. W. J. Med. Chem. 2003, 46, 445–452. and references cited therein.
3. Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.; Sasaoka, T.;
Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharm. 2004, 66, 1061–1069.
4. Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165. and references cited therein.
5. Daly, J. W.; Garraffo, H. M.; Spande, T. F.. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon Press: New York, 1999; Vol. 13, pp
1–161. Chapter 1.
To a stirred solution of 12 (110 mg, 0.4 mmol) in dry CH2Cl2
(4 mL) under
a
nitrogen atmosphere, tetrabromomethane
(172 mg, 0.5 mmol) was added. The solution was cooled to 0 °C
and triphenylphosphine (157 mg, 0.6 mmol) was added. The reac-
tion mixture was stirred for 2 h at 0 °C and for 12 h at rt. Removal
of the solvent under reduced pressure gave the crude product,
which was purified by flash chromatography on silica gel (EtOAc
to EtOAc/MeOH/NH3 aq 98:1:1) to afford 123 mg (93%) of 13 as a
6. Garraffo, H. M.; Jain, P.; Spande, T. F.; Daly, J. W.; Jones, T. H.; Smith, L. J.; Zottig,
V. E. J. Nat. Prod. 2001, 64, 421–427.
7. (a) Lesma, G.; Colombo, A.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 590–
596; (b) Lesma, G.; Colombo, A.; Landoni, N.; Sacchetti, A.; Silvani, A.
Tetrahedron: Asymmetry 2007, 18, 1948–1954; (c) Danieli, B.; Lesma, G.;
Passarella, D.; Sacchetti, A.; Silvani, A. Tetrahedron Lett. 2005, 46, 7121–7123;
(d) Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti, A.; Silvani, A.; Virdis, A. Org.
Lett. 2004, 6, 493–496; (e) Crippa, S.; Danieli, B.; Lesma, G.; Passarella, D.;
Sacchetti, A.; Silvani, A.; Virdis, A. Tetrahedron 2004, 60, 6437–6442; (f) Danieli,
B.; Lesma, G.; Passarella, D.; Piacenti, P.; Sacchetti, A.; Silvani, A. Tetrahedron
Lett. 2002, 43, 7155–7158; (g) Consonni, A.; Danieli, B.; Lesma, G.; Passarella,
D.; Piacenti, P.; Silvani, A. Eur. J. Org. Chem. 2001, 1377–1383.
8. Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett. 2004, 6, 1469–1471.
9. Collado, I.; Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995, 60, 5011–5015.
10. (a) Suhara, Y.; Oka, S.; Kittaka, A.; Takayama, H.; Waku, K.; Sugiura, T. Bioorg.
Med. Chem. 2007, 15, 854–867; (b) Nannei, R.; Dallavalle, S.; Merlini, L.; Bava,
A.; Nasini, G. J. Org. Chem. 2006, 71, 6277–6280.
yellow oil.
½
a 2D5
ꢂ
¼ ꢁ33:6 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3 + CF3CO2D) d = 4.22–4.16 (m, 1H), 3.94–3.85 (m, 1H), 3.54–
3.40 (m, 1H), 3.43 (t, J = 6.4 Hz, 2H), 2.42–1.29 (m, 24H), 1.44 (d,
J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) d = 66.6, 65.6, 57.5,
33.8, 33.0–25.6 (12C), 19.1. HRMS (ESI) calcd for C17H32BrN
329,1718, found 329,1726.
4.11. (3R,5S,10R)-5-Methyl-3-(non-8-ynyl)octahydro-1H-
pyrrolo[1,2-a]azepine (1)
11. Evans, P. et al Org. Biomol. Chem. 2008, 6, 4649–4661.
Under a nitrogen atmosphere, lithium acetylide–ethylenedia-
mine complex (90%) (82 mg, 0.8 mmol) was suspended in dry
DMSO (2 mL) and cooled to 15 °C with stirring. Compound 13
(88 mg, 0.3 mmol) was dissolved in dry DMSO (2 mL) and added
dropwise to the acetylide suspension. The reaction mixture was al-
lowed to warm to rt and was stirred for 2 h. The mixture was then
poured over an ice/brine solution and the product was extracted
with CH2Cl2. The combined extracts were washed with brine, dried
over Na2SO4, filtered and concentrated. Purification of the residue
by flash chromatography on silica gel (EtOAc/MeOH/NH3 aqueous
12. (a) Conchon, E.; Gelas-Mialhe, Y.; Remuson, R. Tetrahedron: Asymmetry 2006,
17, 1253–1257; (b) Riesinger, S. W.; Löfstedt, J.; Pettersson-Fasth, H.; Bäckvall,
J.-E. Eur. J. Org. Chem. 1999, 3277–3280; (c) Célimène, C.; Dhimane, H.;
Saboureau, A.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 1585–1588.
13. Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry 2002, 13, 1581–
1585.
14. SPARTAN’08, Wavefunction, Irvine, CA.
15. Corona, C.; Bryant, B. K.; Arterburn, J. B. Org. Lett. 2006, 8, 1883–1886.
16. Some trace of a dimeric compound, tentatively ascribed to the competitive
double substitution of ethylenediamine on bromide 13, was also detected.
Me
7
H
N
7
H
97:2.5:0.5) yielded 37 mg (45%) of 1 as a yellow oil. ½a D25
¼ ꢁ19:2
ꢂ
N
N
(c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) d = 3.92–3.85 (m, 1H),
3.34–3.25 (m, 1H), 3.20–3.12 (m, 1H), 2.22–2.14 (m, 2H), 1.97 (t,
J = 2.6 Hz, 1H), 1.80–1.29 (m, 24H), 1.25 (d, J = 6.4 Hz, 3H). 13C
NMR (100 MHz, CDCl3) d = 85.6, 68.2, 66.4, 65.2, 57.4, 33.0–25.6
N
H
H
Me
HRMS (ESI) calcd for C36H70N4
558, 5600, found 558, 5632.