A robust route towards functionalized pyrrolizidines as precursors for daphniphyllum alkaloids

Article abstract of DOI:10.1055/s-0033-1340677

A diastereoselective Fráter-Seebach-type alkylation provides access to a highly functionalized pyrrolizidine, which could serve as a key building block for the total synthesis of ?Daphniphyllum alkaloids, such as oldhamine A. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340677

LETTER
▌741
lAetteRr obust Route towards Functionalized Pyrrolizidines as Precursors for
Daphniphyllum Alkaloids
A Pyrrolizidine Precursor for Daphniphyllum Alkaloids
Michael Pangerl, Ignaz Höhlein, Dirk Trauner*
Ludwig-Maximilians-Universität München, Department of Chemistry and Pharmacy, Butenandtstraße 5–13, 81377 München, Germany
Fax +49(89)218077800; E-mail: Dirk.Trauner@lmu.de
Received: 05.11.2013; Accepted after revision: 03.01.2014
CO2Me
Abstract: A diastereoselective Fráter–Seebach-type alkylation
–
H
CO2
provides access to a highly functionalized pyrrolizidine, which
could serve as a key building block for the total synthesis of
Daphniphyllum alkaloids, such as oldhamine A.
N
O
Key words: Daphniphyllum alkaloids, pyrrolizidines, hetero-
cycles, asymmetric synthesis, oldhamine A
HN
+
O
OH
(–)-daphnezomine A (1)
OH
(–)-daphlongeramine A (2)
Daphniphyllum alkaloids are attractive synthetic targets
due to their architectural beauty and structural diversity.
To date, more than a dozen different skeletal types have
been identified, three of which are shown in Figure 1.
(–)-Daphnezomine A (1) is the eponymous representative
of the daphnezomine alkaloids and incorporates an aza-
adamantane core in its polycyclic ring system. (–)-Daph-
longeramine A (2), which is a paxdaphnine A-type alka-
loid, features a furan moiety, which is connected to a
highly fused core structure.1 Another striking molecule is
(+)-oldhamine A (3), a member of the daphnicyclidin-type
alkaloids. The natural product was isolated in 2008 by Tan
and coworkers from Daphniphyllum oldhamii, a dioecious
evergreen tree native to the southeast of China. Its struc-
ture was elucidated by NMR spectroscopy as well as X-ray
crystallography.2 Oldhamine A features six fused rings,
five stereogenic centers, one of which is quaternary, and a
cyclopentadienide anion that forms an internal salt with an
ammonium moiety present in a pyrrolizidine substructure
in 3. Herein we present an efficient and scalable synthesis
of a highly functionalized pyrrolizidine that could serve as
a synthetic precursor of 3.
O
O
O
H
Me
H
Me
O
HN
+
H
(+)-oldhamine A (3)
Figure 1 A selection of norterpenoid alkaloids from the species
Daphniphyllum
O
cuprate
O
conjugate addition
O
condensation
Me
O
H
N
H
Me
(–)-ent-3
O
O
enolate
addition
McMurry
reaction
For economic reasons, we decided to aim for (–)-ent-
oldhamine A (ent-3), the enantiomer of the natural prod-
uct. Our retrosynthetic analysis of ent-3 is shown in
Scheme 1. Our plan was to install the quaternary stereo-
center in ent-3 with a stereoselective addition of a methyl
cuprate to the fulvene system in precursor 4, followed by
intramolecular acylation of the resulting cyclopentadi-
enide. Fulvene 4 can be further simplified retrosyntheti-
cally to pyrrolizidine 5. Thus, we needed to develop a
reliable strategy to access 5 and ultimately settled on L-pyro-
glutamic acid (6) or L-glutamic acid (7) as starting mate-
rial.
OH
H
N
conjugate
addition
MeOOC
H
Me
O
4
5
4
N
H
OH
H
BnO
O
O
L-pyroglutamic acid (6)
N
Me
O
NH2
4
HO
OH
5
EtO
5
O
O
L-glutamic acid (7)
SYNLETT 2014, 25, 0741–0745
Advanced online publication: 13.02.2014
Scheme 1 Retrosynthetic analysis of ent-3
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340677; Art ID: ST-2013-B1030-L
© Georg Thieme Verlag Stuttgart · New York

742
M. Pangerl et al.
LETTER
In the forward direction, we initially attempted to synthe- Next, lactam 9 was reduced using Super-Hydride® and the
size 5 from L-pyroglutamic acid (6). To this end, N-Boc resulting hemiaminal was converted into the methylated
pyrrolidinone 8, which is readily available from 6,3 was N,O-acetal using toluenesulfonic acid in methanol
treated with LiHMDS and benzyloxymethyl chloride (Scheme 4).4 A subsequent cuprate addition to the imini-
(Scheme 2). However, the desired product was only ob- um ion generated in situ by treatment with boron trifluo-
tained in a moderate yield of 27% and as a mixture with ride diethyl etherate followed by exposure of the resulting
the undesired diastereomer and other side products, such product to TFA in the presence of thioanisole furnished
as products of double alkylation.4
amine 14 in good overall yield. A small sample of 14 was
hydrolyzed to give the corresponding amino acid 15 as a
crystalline material, which could be characterized by
X-ray crystallography, confirming the relative stereo-
chemistry (Figure 2).
O
BnO
LiHMDS,
BOMCl
O
4
5
N
Boc
OEt
O
O
9
N
Boc
OEt
(45%, dr 3:2)
O
+
1) LiEt3BH
2) TsOH, MeOH
O
8
BnO
O
BnO
9
N
Boc
OEt
N
H
OEt
Me
3) MeMgBr, CuBr⋅SMe2, BF3⋅OEt2,
then TFA, thioanisole
10
14
Scheme 2 Synthesis of benzyl ether 9 starting from L-pyroglutamic
acid derivative 84
(40% over 3 steps)
[20 g scale]
Since such a poor yield and diastereoselectivity at the be-
ginning of a synthetic route was unacceptable, we next in-
vestigated the alkylation of an acyclic precursor,5
following a precedent provided by Hanessian (Scheme
3).6 Treatment of glutamate 11 with two equivalents of
LiHMDS and subsequent addition of BOMCl resulted in
a clean and high-yielding transformation into benzyl ether
12. No formation of the diastereomer was observed in this
Fráter–Seebach-type alkylation. In order to convert di-
ester 12 into the corresponding lactam, it was successively
treated with TFA for N-deprotection, heated for two days
in toluene and finally protected again as the N-Boc lactam.
Compound 13 was then converted into ethyl ester 9 by sa-
ponification of the methyl ester with LiOH followed by
esterification of the resulting material with ethanol in the
presence of DCC and DMAP. This transesterification was
necessary since the Fráter–Seebach alkylation did only
proceed in good selectivity with the methyl ester present
in 11, but subsequent reactions failed if the methyl ester
was retained.
O
BnO
1) ethylpropiolate
KHMDS
N
OEt
Me
5
2) NaBH3CN, AcOH
(81%)
[2 g scale]
(72% over two steps)
[2 g scale]
16% overall yield
from cheap commercial
starting materials
OEt
O
16
Scheme 4 Synthesis of the pyrrolizidine portion 5 present in ent-3
Figure 2 Chemical structure and crystal structure of amino acid 15
Attempts to further functionalize 14 via a conjugate addi-
tion to various acrylates were unsuccessful, presumably
due to the high sterical hindrance of the secondary amine.
However, when ethyl propiolate was used, the reaction
took place instantaneously, forming a vinylogous carba-
mate in an almost quantitative yield. Without further puri-
fication, this compound was reduced with sodium
cyanoborohydride in the presence of acetic acid to give
the tertiary amine 16 in good overall yield. Finally,
KHMDS was found to be the best base to initiate a
Claisen–Dieckmann condensation, which afforded the de-
sired pyrrolizidine 5 as a single diastereomer. The con-
figuration of the newly generated stereogenic center was
established by NOE experiments (see Supporting Infor-
mation).
BnO
MeO
LiHMDS (2 equiv);
then BOMCl
NHBoc
OMe
NHBoc
OMe
4
MeO
5
(89%, dr 99:1)
[20 g scale]
O
O
O
O
11
12
TFA;
then toluene, Δ;
then Boc2O, DMAP
1) LiOH
2) DCC, DMAP, EtOH
O
BnO
9
N
Boc
OMe
O
(51%, 96% brsm)
[20 g scale]
(91%)
[20 g scale]
13
Scheme 3 Synthesis of benzyl ether 9, starting from L-glutamic acid
derivative 11
In summary, we have developed a scalable route for a key
building block in the synthesis of pyrrolizidine-containing
Synlett 2014, 25, 741–745
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Pyrrolizidine Precursor for Daphniphyllum Alkaloids
743
30 min at this temperature. The resulting LiHMDS solution was
cooled to –78 °C and to this solution was added dropwise a solution
of 11 (20.4 g, 74.1 mmol, 1.00 equiv) in THF (200 mL) over the
course of 20 min. After being stirred for 30 min at this temperature,
a solution of BOMCl (20.5 mL, 148 mmol, 2.00 equiv) in THF (200
mL) was added dropwise over the course of 20 min to be stirred for
additional 3 h at –78 °C. The reaction mixture was quenched with
an aq 1.00 M HCl solution (100 mL), and the bulk of solvent was
removed in vacuo. The residue was redissolved in Et2O (500 mL)
and washed with a sat. aq NaHCO3 solution (500 mL) and brine
(300 mL), dried over MgSO4, filtered, and concentrated. The crude
product was purified by column chromatography (silica, EtOAc–
hexanes = 1:10 → 1:2) to give 12 as a colorless oil (26.1 g, 89%).
Rf = 0.38 (EtOAc–hexanes = 1:3). 1H NMR (300 MHz, CDCl3, mix-
ture of rotamers): δ = 7.39–7.23 (m, 5 H), 5.13 (br s, 0.5 H) 4.70 (s,
2 H), 4.55–4.50 (m, 1 H), 4.35 (br s, 0.5 H), 3.76–3.63 (m, 6.5 H),
2.88–2.75 (m, 0.5 H), 2.52–2.29 (m, 1 H), 2.24–1.92 (m, 3 H), 1.46
(s, 4.5 H), 1.45 (s, 4.5 H). 13C NMR (75 MHz, CDCl3, mixture of
rotamers): δ = 174.1, 173.2, 172.7, 172.6, 155.4, 155.4, 141.0,
137.9, 128.5 (2 C), 128.2 (2 C), 127.9, 127.8, 127.7 (2 C), 127.6 (2
C), 127.5, 127.0, 80.1, 80.0, 73.1, 70.1, 65.3, 52.4, 52.3, 52.1, 52.0,
51.8, 42.6, 31.1, 30.1, 28.3, 28.2 (3 C), 27.8 (3 C). IR: 3370, 2978,
Daphniphyllum alkaloids. Our route yields multigram
quantities of 5, proceeds over 13 steps, and requires only
six chromatographic purifications. The usefulness of
Fráter–Seebach alkylations for the synthesis of 2,4-anti-
substituted glutamate derivatives has been confirmed. Our
building block could not only prove useful for a total syn-
thesis of oldhamine A but also for other Daphniphyllum
alkaloids, such as the enantiomer of (–)-daphnipaxinin.
(S)-1-tert-Butyl ethyl 5-oxopyrrolidine-1,2-dicarboxylate (8) and
(S)-dimethyl 2-(tert-butoxycarbonylamino)pentanedioate (11) were
prepared according to literature procedures.5,3
(2S,4R)-1-tert-Butyl 2-Ethyl 4-(Benzyloxymethyl)-5-oxopyrro-
lidine-1,2-dicarboxylate (9) from 84
To a solution of HMDS (56.3 mL, 256 mmol, 1.30 equiv) in THF
(88.0 mL) was added a solution of n-BuLi (2.50 M in hexanes, 95.6
mL, 241 mmol, 1.20 equiv) dropwise at 0 °C. After complete addi-
tion, the mixture was allowed to warm to r.t. and stirred for another
30 min at this temperature. The resulting LiHMDS solution was
cooled to –78 °C and to this solution was added dropwise a solution
of 8 (51.7 g, 201 mmol, 1.00 equiv) in THF (200 mL) over the
course of 20 min. Then, HMPA (45.4 mL, 261 mmol, 1.30 equiv)
was added over the course of 5 min, and the mixture was stirred for
1 h at –78 °C. The resulting mixture was cannulated to a cooled so-
lution of benzyloxymethyl chloride (55.7 mL, 402 mmol, 2.00
equiv) in THF (100 mL) at –78 °C over the course of 25 min and
stirred for 1 h at this temperature. The reaction was quenched with
a 1:1 mixture of H2O and a sat. aq NH4Cl solution (35.0 mL) and
after warming to r.t., the bulk of the solvent was removed in vacuo.
The residue was diluted with Et2O (1000 mL) and successively
washed with a sat. aq NaHCO3 solution (800 mL) and brine (800
mL). The organic layer was separated, dried over MgSO4, filtered,
and concentrated in vacuo. The resulting residue was purified by
column chromatography (silica, EtOAc–hexanes = 1:10 → 1:2) to
give 9 as a colorless oil (20.8 g, 27%) and 10 as a colorless oil (13.6
g, 18%).
19
1731, 1712, 1512, 1366, 1160 cm–1. [α]D –39.6 (c 1.0, MeOH).
ESI-HRMS: m/z calcd for C20H29NNaO7: 418.1842 [M + Na]+;
found: 418.1835.
(2R,4R)-1-tert-Butyl 2-Methyl 4-(Benzyloxymethyl)-5-oxopyr-
rolidine-1,2-dicarboxylate (13)
A mixture of 12 (17.9 g, 45.4 mmol, 1.00 equiv), CH2Cl2 (50.0 mL)
and TFA (46.0 mL) was stirred for 1 h at r.t. After removal of the
solvent in vacuo, the residue was diluted with a sat. aq Na2CO3 so-
lution (30.0 mL) and a sat. aq NaHCO3 solution (270 mL) and sub-
sequently extracted with Et2O (5 × 350 mL). The combined extracts
were washed with brine (500 mL), dried over MgSO4, and concen-
trated. The resulting residue was dissolved in toluene (150 mL) and
heated to reflux for 48 h. The mixture was allowed to cool to r.t. and
concentrated to give a brown oil. To a solution of this residual oil in
CH2Cl2 (60.0 mL) was added DMAP (6.65 g, 54.4 mmol, 1.20
equiv), Boc2O (10.9 g, 49.9 mmol, 1.10 equiv), and Et3N (6.94 mL,
49.9 mmol, 1.10 equiv) to be stirred for 16 h at r.t. The reaction mix-
ture was diluted with Et2O (350 mL), washed with an aq 1.00 M
HCl solution (350 mL), a sat. aq NaHCO3 solution (350 mL) and
brine (250 mL), dried over MgSO4, and concentrated. The crude
product was purified by column chromatography (EtOAc–hexanes
= 1:5 → 1:2) to give 13 as a colorless oil (8.46 g, 51%) along with
recovered starting material (12, 7.71 g, 45%). Rf = 0.25 (EtOAc–
Compound 9
1
Rf = 0.34 (EtOAc–hexanes, 1:2). H NMR (300 MHz, CHCl3):
δ = 7.40–7.26 (m, 5 H), 4.65–4.42 (m, 3 H), 4.23–4.10 (m, 2 H),
3.76 (dd, J = 9.4, 4.2 Hz, 1 H), 3.66 (dd, J = 9.4, 7.3 Hz, 1 H), 2.99–
2.79 (m, 1 H), 2.67–2.43 (m, 1 H), 2.16–1.96 (m, 1 H), 1.49 (s, 9 H),
1.24 (t, J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CHCl3): δ = 173.0,
171.3, 149.3, 137.8, 128.6, 128.4 (2 C), 127.7 (2 C), 83.6, 73.3,
69.1, 61.5, 57.6, 43.6, 27.9 (3 C), 25.0, 14.1. IR: 2981, 1791, 1748,
1
hexanes = 1:3). H NMR (400 MHz, CDCl3): δ = 7.44–7.09 (m, 5
H), 4.52 (td, J = 9.1, 6.2 Hz, 1 H), 4.45 (d, J = 3.4 Hz, 2 H), 3.79–
3.56 (m, 5 H), 2.90–2.77 (m, 1 H), 2.49 (dt, J = 13.6, 9.5 Hz, 1 H),
2.05 (dt, J = 13.4, 6.7 Hz, 1 H), 1.46 (s, 9 H). 13C NMR (75 MHz,
CDCl3): δ = 173.0 171.7, 149.2, 137.8, 128.4 (2 C), 127.7 (2 C),
127.6, 83.6, 73.3, 69.0, 57.5, 52.3, 43.6, 27.8 (3 C), 25.0. IR: 1727,
1181 cm–1. [α]D18 –42.2 (c 1.0, MeOH). ESI-HRMS: m/z calcd for
C19H25NNaO6: 386.1580 [M + Na]+; found: 386.1575.
18
1719, 1369, 1318, 1153 cm–1. [α]D –47.6 (c 1.0, MeOH). ESI-
HRMS: m/z calcd for C20H27NNaO6: 400.1736 [M + Na]+; found:
400.1731.
Compound 10
1
Rf = 0.38 (EtOAc–hexanes, 1:2). H NMR (300 MHz, CHCl3):
δ = 7.36–7.25 (m, 5 H), 4.58–4.44 (m, 3 H), 4.25–4.15 (m, 2 H),
3.71 (ddd, J = 13.1, 9.5, 4.6 Hz, 2 H), 2.87 (dddd, J = 10.5, 9.1, 5.5,
3.7 Hz, 1 H), 2.35 (ddd, J = 13.3, 10.5, 9.9 Hz, 1 H), 2.20–2.12 (m,
1 H), 1.48 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H). 13C NMR (150 MHz,
CHCl3): δ = 173.0, 171.4, 149.3, 137.8, 128.4, 127.7 (2 C), 127.6 (2
C), 83.5, 73.4, 68.4, 61.6, 57.4, 42.8, 27.9 (3 C), 25.6, 14.2. IR:
(2S,4R)-1-tert-Butyl 2-Ethyl 4-(Benzyloxymethyl)-5-oxopyrro-
lidine-1,2-dicarboxylate (9) from 13
To a solution of 13 (1.50 g, 4.13 mmol, 1.00 equiv) in EtOH (25.0
mL) was added a 1.50 M aq LiOH solution (5.50 mL, 8.26 mmol,
2.00 equiv). The mixture was stirred for 4 h at r.t. and was then con-
centrated in vacuo. The residue was diluted with an aq 1.00 M HCl
solution (250 mL) and extracted with CH2Cl2 (3 × 250 mL). The
combined extracts were dried over MgSO4, filtered, and concen-
trated. The resulting residue was redissolved in CH2Cl2 (25.0 mL),
and to the solution was added DCC (937 mg, 4.54 mmol, 1.10
equiv), DMAP (555 mg, 4.54 mmol, 1.10 equiv), and EtOH (2.00
mL, 33.9 mmol, 8.20 equiv) to be stirred for 16 h at r.t. Then, the
mixture was filtered, and the filter cake was washed with Et2O
(3 × 50.0 mL). The combined filtrates were washed with brine (150
mL), dried over MgSO4, filtered, and concentrated. Purification by
18
2980, 1791, 1748, 1719, 1369, 1154 cm–1. [α]D –34.9 (c 1.0,
MeOH). ESI-HRMS: m/z calcd for C20H27NNaO6: 400.1736 [M +
Na]+; found: 400.1729.
(2R,4S)-Dimethyl 2-(Benzyloxymethyl)-4-(tert-butoxycarbonyl-
amino)pentanedioate (12)
To a solution of HMDS (36.4 mL, 171 mmol, 2.31 equiv) in THF
(30.4 mL) was added a solution of n-BuLi (2.50 M in hexanes, 62.2
mL, 156 mmol, 2.10 equiv) dropwise at 0 °C. After complete addi-
tion, the mixture was allowed to warm to r.t. and stirred for another
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 741–745

744
M. Pangerl et al.
LETTER
column chromatography (silica, EtOAc–hexanes = 1:5 → 1:1) gave
9 as a colorless oil (1.41 g, 91%). The analytical data of the sample
were identical with the material prepared from 8.
lidine-2-carboxylate as a colorless oil. Rf = 0.21 (EtOAc–hexanes,
1:5). H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 13.4 Hz, 1 H),
1
7.37–7.27 (m, 5 H), 4.54–4.39 (m, 3 H), 4.20–4.05 (m, 5 H), 3.69–
3.56 (m, 1 H), 3.50 (dd, J = 9.5, 6.7 Hz, 1 H), 3.40 (dd, J = 9.5, 6.6
Hz, 1 H), 2.60–2.43 (m, 1 H), 2.13–2.02 (m, 1 H), 1.95–1.78 (m, 1
H), 1.31 (d, J = 6.3 Hz, 3 H), 1.26–1.19 (m, 6 H). 13C NMR (150
MHz, CDCl3): δ = 172.1, 169.2, 145.7, 138.0, 128.4 (2 C), 127.7,
127.5 (2 C), 87.3, 77.2, 73.2, 70.8, 61.4, 60.1, 59.0, 45.7, 31.5, 18.8,
14.6, 14.1. IR: 1728, 1680 cm–1. [α]D19 –66.4 (c 1.0, MeOH). ESI-
HRMS: m/z calcd for C21H30NO5: 376.2124 [M]+; found: 376.2118.
(2S,4S,5R)-Ethyl 4-(Benzyloxymethyl)-5-methylpyrrolidine-2-
carboxylate (14)
To a solution of 9 (18.3 g, 48.4 mmol, 1.00 equiv) in THF (250 mL)
was added dropwise a solution of LiEt3BH (1.00 M in THF, 58.0
mL, 58.0 mmol, 1.00 equiv) at –78 °C over the course of 10 min.
After being stirred for 30 min, the reaction was quenched with a sat.
aq NaHCO3 solution (20.0 mL) and allowed to warm to 0 °C. To the
mixture was added H2O2 (25.0 mL) in one portion and stirred at
0 °C for 30 min. The solvent was removed in vacuo, and the residue
was redissolved in a 2:1 mixture of EtOAc and H2O (810 mL). The
organic layer was separated, dried over MgSO4, filtered, and con-
centrated to a colorless oil. To a solution of this residual oil (ca. 18.0
g) in MeOH (255 mL) was added PTSA·H2O (1.84 g, 9.67 mmol,
0.200 equiv) to be stirred for 18 h at r.t. The reaction was quenched
with a sat. aq NaHCO3 solution (22.0 mL), the solvent was removed
in vacuo, and the residue was redissolved in a mixture of Et2O (540
mL) and H2O (270 mL). The organic layer was separated, washed
with brine (180 mL), dried over MgSO4, filtered, and concentrated
to give a colorless oil.
The crude material obtained as described above was redissolved in
glacial acid (5.00 mL, 87.3 mmol, 11.0 equiv). To this solution was
added NaBH3CN (1.00 g, 15.9 mmol, 2.00 equiv), and the resulting
mixture was stirred for 30 min at r.t. The reaction was quenched by
dropwise addition of a 10% aq HCl solution (15.0 mL). After being
stirred for 15 min, a sat. aq Na2CO3 solution (30.0 mL) was added
dropwise, and the resulting mixture was poured into a sat. aq
NaHCO3 solution (270 mL). The mixture was extracted with
CH2Cl2 (3 × 150 mL), the combined extracts were washed with
brine (300 mL), dried over MgSO4, filtered, and concentrated to a
colorless crude product, which was purified by column chromato-
graphy (EtOAc–hexanes, 1:11 → 1:9) to give 16 as a colorless oil
1
(2.16 g, 72%). Rf = 0.28 (EtOAc–hexanes, 1:5). H NMR (400
To a suspension of CuBr·SMe2 complex (46.3 g, 225 mmol, 4.65
equiv) in Et2O (400 mL) was added dropwise a solution of MeMgBr
(3.00 M in Et2O, 75.0 mL, 225 mmol, 4.65 equiv) over the course
of 15 min at –40 °C and stirred for 1 h at this temperature. Then, the
resulting yellow suspension was cooled to –78 °C and BF3·OEt2
(27.8 mL, 225 mmol, 4.65 equiv) was added dropwise over the
course of 15 min. After being stirred for 30 min at –78 °C, a solution
of the residual colorless oil from the previous reaction (ca. 19.0 g)
in Et2O (60.0 mL) was added over the course of 10 min. The flask
was rinsed with additional Et2O (15.0 mL), and the reaction mixture
was stirred for 15 min at –78 °C. Then, the mixture was allowed to
warm to r.t. and stirred for 1 h at this temperature. The reaction was
quenched by a dropwise addition of a 1:1 mixture of a sat. aq NH4Cl
solution and a 28% aq NH3 solution (260 mL). The resulting mix-
ture was stirred for 30 min at r.t. and was then diluted with Et2O
(250 mL). The organic layer was separated, washed with H2O (300
mL) and brine (250 mL), dried over MgSO4, and concentrated in
vacuo to give a residue that was redissolved in a mixture of CH2Cl2
(50.0 mL) and TFA (50.0 mL). To the mixture was added thio-
anisole (5.69 mL, 48.4 mmol, 1.00 equiv) to be stirred for 2 h at r.t.
The reaction mixture was quenched by dropwise addition of a sat.
aq Na2CO3 solution (100 mL) and was then poured into a sat. aq
NaHCO3 solution (800 mL). The mixture was extracted with
CH2Cl2 (5 × 250 mL), the combined extracts were concentrated and
after purification with column chromatography (silica gel, CHCl3–
MeOH–Et3N, 100:1:1), 14 was obtained as a colorless oil (5.43 g,
MHz, CDCl3): δ = 7.35–7.19 (m, 5 H), 4.53–4.45 (m, 2 H), 4.13–
4.04 (m, 4 H), 3.83–3.69 (m, 1 H), 3.50 (dd, J = 9.0, 6.7 Hz, 1 H),
3.40 (dd, J = 8.9, 7.7 Hz, 1 H), 3.08–2.91 (m, 2 H), 2.78–2.67 (m, 1
H), 2.54–2.42 (m, 2 H), 2.36–2.24 (m, 1 H), 2.08–1.97 (m, 1 H),
1.67–1.57 (m, 1 H), 1.24–1.19 (m, 6 H), 1.08 (d, J = 5.9 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 174.3, 172.3, 138.5, 128.3 (2 C),
127.5 (2 C), 127.4, 73.3, 73.1, 62.2, 60.3, 60.1, 59.9, 45.3, 43.4,
34.2, 31.1, 18.1, 14.3, 14.2. IR: 2977, 2854, 1729, 1369, 1179 cm–1.
[α]D19 –63.8 (c 1.0, MeOH). ESI-HRMS: m/z calcd for C21H32NO5:
378.2280 [M + H]+; found: 378.2273.
(2S,5R,6S,7aS)-Ethyl 6-(Benzyloxymethyl)-5-methyl-1-oxo-
hexahydro-1H-pyrrolizine-2-carboxylate (5)
To a mixture of 16 (1.67 g, 4.40 mmol, 1.00 equiv) and toluene
(18.0 mL) was added a solution of KHMDS (0.500 M in toluene,
2.00 mL, 8.80 mmol, 2.00 equiv) at 0 °C. The mixture was stirred
for 0.5 h at 0 °C and was then allowed to warm to r.t. to be stirred
for 0.5 h at this temperature. The reaction was quenched with a sat.
aq NH4Cl solution (20.0 mL), diluted with a sat. aq NH4Cl solution
(500 mL), and extracted with CH2Cl2 (5 × 150 mL). The aqueous
phase was diluted with a sat. aq Na2CO3 solution (100 mL) and ex-
tracted with CH2Cl2 (3 × 150 mL). A second time, the aqueous
phase was diluted with a sat. aq Na2CO3 solution (100 mL) and ex-
tracted with CH2Cl2 (2 × 150 mL). The combined extracts were
concentrated and purified by reversed phase column chromato-
graphy (H2O–MeOH, 5:1 → 2:1) to give 5 as a colorless solid (1.13
1
1
40%). Rf = 0.28 (CHCl3–MeOH, 100:5). H NMR (600 MHz,
g, 81%). Rf = 0.33 (CHCl3–MeOH, 100:10). H NMR (400 MHz,
CDCl3): δ = 7.36–7.27 (m, 5 H), 4.51–4.47 (m, 2 H), 4.15 (q, J = 7.2
Hz, 2 H), 3.89–3.81 (m, 1 H), 3.46 (dd, J = 9.2, 5.9 Hz, 1 H), 3.36
(dd, J = 9.2, 6.8 Hz, 1 H), 3.15–3.03 (m, 1 H), 2.46–2.40 (m, 1 H),
2.20 (br s, 1 H), 1.98–1.94 (m, 1 H), 1.76–1.69 (m, 1 H), 1.25 (t,
J = 6.8 Hz, 3 H), 1.17 (d, J = 6.2 Hz, 3 H). 13C NMR (150 MHz,
CDCl3): δ = 175.5, 138.4, 128.3 (2 C), 127.5, 127.4 (2 C), 73.1,
72.1, 60.9, 58.4, 56.7, 46.6, 34.1. 20.8, 14.2. IR: 2960, 2859, 1728,
acetone-d6): δ = 7.35–7.24 (m, 5 H), 4.51–4.47 (m, 2 H), 4.16–4.09
(m, 2 H), 3.67–3.29 (m, 5 H), 2.71–2.47 (m, 1 H), 2.33–2.20 (m, 1
H), 2.10–2.07 (m, 1 H), 2.04–1.94 (m, 1 H), 1.72–1.58 (m, 1 H),
1.22 (t, J = 7.1 Hz, 3 H), 1.16 (d, J = 5.9 Hz, 3 H). 13C NMR (100
MHz, acetone-d6): δ = 214.9, 168.4, 138.9, 128.2 (2 C), 127.3 (2 C),
127.3, 72.6, 71.5, 71.1, 61.2, 60.7, 48.7, 47.1, 30.1, 29.2, 18.2, 13.6.
IR: 2978, 1677, 1580, 1452, 1260, 1171, 1071 cm–1. [α]D19 –36.2 (c
1.0, MeOH). ESI-HRMS: m/z calcd for C19H25NO4: 332.1862 [M]+;
found: 332.1856.
19
1367, 1204 cm–1. [α]D –12.1 (c 1.0, MeOH). ESI-HRMS: m/z
calcd for C16H23NO3: 277.1678 [M]+; found: 277.1685.
(2S,4S,5R)-Ethyl 4-(Benzyloxymethyl)-1-(3-ethoxy-3-oxopro-
pyl)-5-methylpyrrolidine-2-carboxylate (16)
Acknowledgment
To a solution of 14 (2.20 g, 7.93 mmol, 1.00 equiv) in CH2Cl2 (8.50
mL) was added ethyl propiolate (0.890 mL, 8.73 mmol, 1.10 equiv)
over the course of 1 min. After being stirred for 1 h at r.t., all volatile
substances were removed in vacuo. An analytical sample of the
crude material was purified by column chromatography (silica gel,
EtOAc–hexanes, 1:10 → 1:5) to afford (2S,4S,5R)-ethyl 4-(benzyl-
oxymethyl)-1-[(E)-3-ethoxy-3-oxoprop-1-enyl]-5-methylpyrro-
We thank Dr. Peter Mayer at the Ludwig-Maximilians-Universität
München for elucidating the X-ray structure of 15.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Synlett 2014, 25, 741–745
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Pyrrolizidine Precursor for Daphniphyllum Alkaloids
745
(3) (a) Silverman, R. B.; Levy, M. A. J. Org. Chem. 1980, 45,
815. (b) Jain, R. Org. Prep. Proced. Int. 2001, 33, 405.
(4) Kondo, T.; Nekado, T.; Sugimoto, I.; Ochi, K.; Takai, S.;
Kinoshita, A.; Hatayama, A.; Yamamoto, S.; Kawabata, K.;
Nakai, H.; Toda, M. Bioorg. Med. Chem. 2008, 16, 190.
(5) Kokotos, G.; Padrón, J. M.; Martín, T.; Gibbons, W. A.;
Martín, V. S. J. Org. Chem. 1998, 63, 3741.
References
(1) (a) Morita, H.; Yoshida, N.; Kobayashi, J. J. Org. Chem.
1999, 64, 7208. (b) Kobayashi, J.; Kubota, T. Nat. Prod.
Rep. 2009, 26, 936.
(2) Tan, C.; Di , Y.; Wang, Y.; Wang, Y.; Mu, S.; Gao, S.;
Zhang, Y.; Kong, N.; He, H.; Zhang, J.; Fang, X.; Li, C.; Lu,
Y.; Hao, X. Tetrahedron Lett. 2008, 49, 3376.
(6) Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39,
5887.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 741–745

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