Enzyme assisted enantioselective synthesis of the alkaloid (+)-aloperine

Article abstract of DOI:10.1016/j.tetasy.2004.06.056

The enantioselective synthesis of the lupinine alkaloid (+)-aloperine is described. The synthetic scheme presents three steps that are mediated by enzymes: kinetic resolution, oxidation of a primary alcohol to an aldehyde and oxidation of a secondary alco

Full text of DOI:10.1016/j.tetasy.2004.06.056

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2921–2925
Enzyme assisted enantioselective synthesis of the alkaloid
(+)-aloperine
Alessio Barilli,a Francesca Belinghieri,a Daniele Passarella,a,* Giordano Lesma,a
Sergio Riva,b,* Alessandra Silvania and Bruno Danielia
a
`
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
bIstituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco 9, 20131 Milano, Italy
Received 1 June 2004; accepted 29 June 2004
Available online 11 September 2004
Abstract—The enantioselective synthesis of the lupinine alkaloid (+)-aloperine is described. The synthetic scheme presents three
steps that are mediated by enzymes: kinetic resolution, oxidation of a primary alcohol to an aldehyde and oxidation of a secondary
alcohol to a ketone.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
extensive use of enzymatic systems for the preparation
of advanced intermediates.
Aloperine 1, a member of a small family of C15 lupinine
alkaloids,1 was first isolated in 1935 from the seeds and
leaves of Sophora alopecuroides2 a shrub that grows in
China and Russia, and later from Leptorhabdos parviflor
Benth. The use of the plant in traditional Chinese
medicine3 and the results of the recent investigation con-
cerning the pharmacological activity (cardiovascular,
anti-inflammatory, antiallergic) of the isolated alkaloid
moved the OvermanÕs group towards an intense syn-
thetic interest in this molecule, culminating in its first
enantioselective total synthesis.4 We recently reported
the synthesis of ( )-aloperine using as a crucial step an
efficient intermolecular Diels–Alder reaction. The re-
quired diene was prepared following an aza-annulation
reaction of an activated alkyne, easily accessible from
racemic piperidine-2-ethanol rac-2.5 We then turned
our attention towards the enantioselective synthesis of
the natural (+)-aloperine and to this end we recently de-
scribed a convenient preparation of the enantiopure
amino alcohol 2 by enzymatic resolution of piperidine-
2-ethanol.6 In continuing our efforts towards the devel-
opment of general strategy for the enantioselective
synthesis of piperidine-containing alkaloids we describe
here the elaboration of 2 to 1, which takes advantage of
2. Results and discussion
According to the retrosynthetic approach shown in
Scheme 1, the enantiopure N-Boc derivative (R)-2 was
chosen as a starting material. This compound was made
available on a gram-scale by sequential transesterifica-
tions mediated by two enzymes, Lipase PS and porcine
pancreatic lipase (Scheme 2) showing opposite enantio-
selectivity.6 The preparation of aldehyde 3 was carried
out by Swern oxidation, but this process proved to be
17
H
6
16
7
H
11
N
H
N
N
H
H
N-C10
9
H
10
N
Bn
H
X
H
1 (+)-aloperine
A
D.-A.
reaction
Aza-
-annulation
H
6
H
N
R
OH
R
N
Boc
2
N
Bn
O
B
*
Corresponding authors. Tel.: +34 02 50314080; fax: +34 02 50314078
(D.P.); e-mail addresses: daniele.passarella@unimi.it; sergio.riva@
icrm.cnr.it
Scheme 1. Retrosynthetic scheme of aloperine synthesis.
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.056

2922
A. Barilli et al. / Tetrahedron: Asymmetry 15 (2004) 2921–2925
pounds 5 and 7 were evaluated by chiral HPLC (Chiral-
OH
Ref. 6
cel OD) as 90% in agreement with the one of the starting
compound 2. Reduction of 7 with NaBH4 gave a mix-
ture of diastereoisomeric alcohols 8 that were dissolved
in toluene and refluxed in the presence of pTSA and
methyl acrylate to give, after 10days, compounds 9
(56%) and 10 (28%) that differ for the configuration at
C(9), C(11) and C(7) (Scheme 3).
H
N
Boc
OH
N
Boc
2
a
OH
b
H
H
CHO
N
N
Boc
TMS
Boc
4
3
O
a
H
O
a
H
N
Boc
N
Boc
O
H
6
7
N
Bn
O
N
Boc
5 X = TMS
6 X = H
c
X
b
Scheme 2. Reagents and conditions: (a) Laccase–TEMPO, O2; (b)
EtMgBr, HC„C–SiMe3, ꢀ78ꢁC; (c) TBAF.
H
6
c
OH
H
N
H
N
Boc
8
Boc
N
Bn
O
H
H
hard to reproduce on a large scale and the recovery of
the reaction product was not free from troubles. Our
desire to simplify the purification process and to im-
prove the ecocompatibility of the process moved us to
investigate the use of polymer supported reagents, such
as TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)-poly-
styrene in the presence of N-chlorosuccinimmide, but
unfortunately this resulted in poor yields and long reac-
tion times.7 Recently it has been described that the
oxidation of alcohols (especially primary) to carbonyl
compounds can be performed using molecular oxygen
and the oxidative enzymes laccase in the presence of
TEMPO as a mediator. The mediator is capable of
utilizing oxidation mechanisms not directly available
through laccases, thereby expanding the synthetic
usefulness of these enzymes.8 Although the literature
examples are confined to simple substrates,9 we found
this methodology very attractive and, exploiting the
availability of the laccases from Trametes pubescens or
from Myceliophtora termophyla in the laboratory of
one of us,10 we decided to study the enzymatic oxida-
tion of 2. The use of either one of the two laccases in
biphasic systems made of water buffered solution and
EtOAc was successful and after 4h the reactions were
complete.
N
Bn
O
MeOOC
H
9
N
H
7
11
N
Bn
Boc
9
O
MeOOC
H
H
10
Scheme 3. Reagents and conditions: (a) BnNH2, CH2CHCOCl; (b)
NaBH4; (c) pTSA, CH2CHCOOMe, 110ꢁC.
Compound 9 was then elaborated to give the target
(+)-aloperine by N-Boc hydrolysis, LiAlH4 reduction,
reaction with CBr4–PPh3 to form the N–C(10) bond
and, finally, removal of the protecting benzyl group by
ethylendiamine and lithium. The final compound
25
D
the expected 90% ee (Scheme 4).
presented an ½aŠ ¼ þ68 (c 1, EtOH), consistent with
H
H
H
H
6
a
N
H
N
H
H
Boc
With a good method to get the aldehyde 3 in hand, eth-
ynylation with a Grignard reagent, prepared from
trimethylsilylacetylene gave, in a clean reaction, the
diastereomeric alcohols 4 (1:1) in 86% yield. The oxida-
tion of the sensitive activated secondary alcohols 4 to 5
was successful in Swern oxidation or using the system
laccase (from Trametes pubescens or from Myceliophtora
termophyla)––TEMPO, while the use of TEMPO–poly-
styrene was not productive.
N
Bn
O
N
Bn
O
H
H
MeOOC
MeOOC
11
9
b
H
H
6
c,d
N
N12
R
N
H
H
H
N
Compound 6, obtained by the cleavage of the C–Si bond
with TBAF, was reacted with benzylamine in THF at
25ꢁC, and the intermediate enamine was directly cyc-
lized with acryloyl chloride in THF at 65ꢁC to give
the dihydropyridinone 7 in 56% yield. The ees of com-
H
13 R = Bn
R = H
H
e
1
Bn
12
10
HO
Scheme 4. Reagents and conditions: (a) TFA; (b) LiAlH4; (c) CBr4–
PPh3; (d) Et3N; (e) Li, NH2–(CH2)2–NH2.

A. Barilli et al. / Tetrahedron: Asymmetry 15 (2004) 2921–2925
2923
3. Conclusion
4.1.2. 2-(2-Oxo-ethyl)-piperidine-1-carboxylic acid tert-
butyl ester 3. solution of DMSO (0.16mL,
A
The reported enantioselective synthesis of (+)-aloper-
ine is a further demonstration of the importance of
integrating biocatalysis into organic synthesis. Specifi-
cally, in the course of the synthetic scheme the target
molecule has been obtained by combining a usual enzy-
matic kinetic resolution mediated by lipases with
two oxidation steps accomplished by laccases. Needless
to say, this work further exemplifies the synthetic use-
fulness of the chiral synthon N-Boc-piperidine-2-
ethanol.
2.25mmol) in CH2Cl2 (1mL) was added dropwise at
ꢀ78ꢁC and under nitrogen atmosphere to a 2M solu-
tion of (COCl)2 (0.47mL, 0.94mmol) in CH2Cl2
(4mL). After 10min of stirring at ꢀ78ꢁC, a solution
of 2 (180mg, 0.785mmol) in CH2Cl2 (2mL) was added
to the mixture at ꢀ78ꢁC. After 20min, freshly distilled
Et3N (0.52mL, 3.73mmol) was added to the reaction
mixture at ꢀ78ꢁC. The mixture was allowed to warm
up to room temperature and was left stirring for 4h.
Water (10mL) and HCl 1N (10mL) were added and
the solution was extracted with CH2Cl2 (3 · 10mL).
The organic layer was dried over Na2SO4 and concen-
trated under reduced pressure to afford a pale yellow
oil (140mg). Column chromatography on silica gel (hex-
ane–AcOEt, 4:1) afforded 130mg of 3 (0.62mmol, 80%
yield). 1H NMR (300MHz, CDCl3) d 1.45 (9H, s),
1.50–1.71 (6H, m), 2.45–2.61 (1H, m), 2.72–2,81 (2H,
m), 3.94(1H, br d, J = 13Hz), 4.75–4.90 (1H, m), 9.72
(1H, t, J = 4Hz); 13C NMR (75.4MHz, CDCl3) d 17.0,
4. Experimental
4.1. Materials
The laccase from Myceliophtora thermophyla was from
Novozymes while the laccase from Trametes pubescens
was provided by Prof. Haltrich (Universitat fur Boden-
kultur, Wien, Austria). Ee values were determined by
chiral HPLC.
23.4, 27.1 (3C), 27.8, 37.4. 42.8, 44.1, 78.1, 152.9,
25
D
199.0. ½aŠ ¼ þ48:0 (c 1, CHCl3).
4.1.1. Enzymatic kinetic resolution of N-Boc-piperidine-2-
ethanol6. Vinyl acetate (30mL, 325mmol) and lipase
PS (1g) were added to a solution of N-Boc-piperidine-
2-ethanol (10g, 43.7mmol) in hexane (250mL). The
mixture was stirred at room temperature (19ꢁC) for
190min, following the course of the reaction by HPLC
(Chiracel OD column). The enzyme was removed by fil-
tration and the solvent and the residual vinyl acetate
were evaporated. The resulting oil was then dissolved
in methyl tert-butyl ether (120mL), and vinyl butyrate
(15mL) and the porcine pancreatic lipase (4g) were
added to this solution. The new reaction mixture was
stirred for 12h at rt (19ꢁC), following the course of
the reaction by HPLC (two consecutive Chiracel OD
columns). The enzyme was removed by filtration and
the solvent was evaporated to give a yellow oil, which
was purified by flash chromatography (AcOEt–hexane,
1:9) to afford 2 (OAc) (5.4g, 45%, 63% ee), ent-2
(OCOPr-S) (3.846g, 30%, 85% ee) (HPLC) and rac-2
(2.4g, 24%, 4% ee). To a solution of 2 (OAc) (2.17g,
8mmol) dissolved in MeOH (85mL), Na2CO3 (4.39g)
was added. The solution was stirred at room tempera-
ture for 4h, then Na2CO3 was filtered and the solvent
was evaporated. The resulting oil was dissolved in
CH2Cl2 (50mL) and washed with water and brine. The
organic layer was evaporated to give 2 (1.78g, 98%,
63% ee) as a pale yellow oil, which required no further
purification. Lipase PS (130mg) and vinyl acetate
(11.7mL) were added to a solution of 2 (63% ee) (4g,
17.46mmol) dissolved in hexane (75mL). The reaction
mixture was stirred at room temperature for 3h
30min, following the course of the reaction by HPLC
(Chiracel OD column). The enzyme was removed by fil-
tration and the solvent was evaporated. The resulting oil
was purified by flash chromatography (AcOEt–hexane,
1:4) to give 2 (OAc) (2.263g, 48%, ee 90%) and rac-2
(1.887g, 47%). The hydrolysis of 2 (OAc) in MeOH
4.1.3. Enzyme laccase oxidation mediated by TEMPO.
Preparation of 3 and 5. To a solution of 2 or 4
(0.2mmol) in EtOAc (10mL) and water (10mL) buff-
ered at pH4–5 (sodium acetate), TEMPO (9mg,
0.06mmol) and laccase (80units) were added. The reac-
tion time was 2–4h. For compound 2, the resulting mix-
ture was extracted with EtOAc, dried over Na2SO4,
filtrated and evaporated under reduce pressure, provid-
ing the crude product (41mg, yield 90%), that was
directly used for the next step. The same procedure
was applied to product 4, which gave the crude product
with 95% yield (61mg).
4.1.4. 2-(2-Oxo-but-3-ynyl)-piperidine-1-carboxylic acid
tert-butyl ester 6. Trimethylsilylacetylene (373mg,
3.80mmol) was added to a cold (0ꢁC) solution of ethyl-
magnesiumbromide (506mg, 3.80mmol) dissolved in
THF (10mL). This solution was stirred for 1h at 5–
15ꢁC and for 15min at room temperature. A solution
of the aldehyde 3 (724mg, 3.18mmol) in THF (6mL)
was then added dropwise over a 30min period. The reac-
tion solution was allowed to stir for an additional 30min
before being quenched with NH4Cl(satd) and concen-
trated. The resulting mixture was extracted with AcOEt,
the organic phase was washed with NH4Cl(satd) and
brine. The evaporation of the solvent gave a mixture of
diastereoisomers 4 (890mg, 86%) that were directly used
for the next step. A DMSO solution (280lL, 3.91mmol)
in CH2Cl2 (2mL) was added to a solution of oxalyl chlo-
ride (170lL, 1.96mmol) in CH2Cl2 (13mL) at ꢀ78ꢁC
over a period of 5min. After the mixture was stirred
for 30min, a solution of 4 (198mg, 0.61mmol) was added
to the CH2Cl2 solution and the reaction mixture was stir-
red at the same temperature for 90min. Et3N (115lL,
8.15mmol) was then added to the reaction mixture,
which was gradually warmed to room temperature and
diluted with CH2Cl2. The CH2Cl2 solution was washed
with water and brine, dried and concentrated to dryness
to give 5 as a brown oil (172mg, 87%, ee 90%).
and Na2CO3 gave
2
(90% ee). Compound 2:
25
D
½aŠ ¼ þ19:3 (c 1, CHCl3).6

2924
25
A. Barilli et al. / Tetrahedron: Asymmetry 15 (2004) 2921–2925
½aŠ ¼ ꢀ32:5 (c 1, CHCl3). To a solution of compound 5
i-PrOH–Et3N, 27:1:2) gave a yellow oil of 11 (214mg).
Compound 11: Rf (CH2Cl2–EtOH–NH4OH concd 5%
4:1) 0.5; H NMR (300MHz, CDCl3) d 7.40–7.05 (5H,
D
(112mg, 0.34mmol) in THF–MeOH (5mL–138 lL),
TBAF (1M in THF, 130lL) was added at ꢀ20ꢁC. After
30min, NH4Cl solution was added and the solution was
extracted with CH2Cl2. Evaporation of the organic sol-
vent, gave compound 6 as an oil (71mg, 84%). Rf
1
m), 5.50 (1H, br s), 5.20 (1H, A portion of AB system),
4.31 (1H, B portion of AB system), 3.92–3.83 (1H, m),
3.56 (3H, s), 3.12–2.95 (2H, m), 2.70–0.85 (16H, m).
13C NMR (75.4MHz, CDCl3) d 172.7, 172.2, 137.2,
133.6, 128.6 (2C), 127.8 (2C), 127.3, 123.1, 59.8, 56.7,
51.5, 47.2, 46.6, 39.3, 38.1, 32.7, 30.4, 29.3, 26.3, 26.1,
25.4. Anal. Calcd for C23H30N2O3: C, 72.22; H, 7.91;
1
(EtOAc–hexane, 1:4) 0.2; H NMR (300MHz, CDCl3)
d 4.88–4.77 (1H, m), 4.08–3.93 (1H, br d, J = 13Hz),
2.90–2.65 (3H, m), 1.80–1.30 (7H, m), 1.45 (9H, s). 13C
NMR (50.3MHz, CDCl3) d 184.9, 154.5, 81.6, 79.8,
78.8, 47.3, 45.8, 39.2, 28.7, 28.3 (3C), 25.1, 18.8. Anal.
N, 7.32. Found: C, 72.27. H, 7.95. N, 7.32. EIMS 382
25
D
Calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found:
(23%), 322 (48%), 299 (100%). ½aŠ ¼ þ162 (c 1,
25
D
C, 66.85. H, 8.48. N, 5.50. ½aŠ ¼ ꢀ30 (c 1, CHCl3). Chi-
CHCl3).
ral HPLC Analysis (Analytical) of 5. Column: Chiracel
OD; UV detector: k 210nm; solvent: petroleum ether–i-
PrOH, 19:1; flow rate: 0.7mL/min; retention time: 5,
7.15min; ent-5, 6.05min.
4.1.7.
1-Benzyl-8-hydroxymethyl-6-piperidin-2-yl-
1,2,3,4,6,7,8,8a-octahydro-1H-quinoline 12. To a sus-
pension of LiAlH4 (115mg, 3.03mmol) in THF
(15mL), a solution of 11 (430mg, 1.12mmol) was added
dropwise at 0ꢁC. The reaction mixture was maintained
at 0ꢁC for 6h. LiAlH4 (402mg, 10.58mmol) was added
in several portions and after 4days at room temperature
the reaction was concluded. AcOEt was added and after
2h the reaction mixture was poured into water. The
organic layer was concentrated to give a yellow oil
(361mg, 94%) that was directly used in the next step.
A small amount was purified by chromatography
(AcOEt–MeOH–Et3N 15:1:1). Compound 12: Rf
(AcOEt–MeOH–Et3N, 15:1:1) 0.13; 1H NMR
(300MHz, CDCl3) d 7.55–7.10 (5H, m), 5.51 (1H, br
s), 4.00 (1H, A portion of AB system), 3.91 (1H, dd,
J = 12.5, 10Hz), 3.65 (1H, dd, J = 12.5, 10Hz), 3.31
(1H, B portion of AB system), 3.22 (1H, br d,
J = 7.5Hz), 3.13 (1H, br d, J = 12.5Hz), 2.88–2.75
(1H, m), 2.70–1.22 (19H, m). 13C NMR (100.6MHz,
CDCl3) d 139.2,135.9, 128.8 (2C), 128.7 (2C), 127.3,
124.4, 63.3, 61.6, 60.9, 51.6, 47.2, 39.9, 36.4, 34.4 (2C),
31.0, 30.1, 26.3, 24.9, 23.4. Anal. Calcd for
4.1.5. 2-[2-Benzyl-6-oxo-1,4,5,6-tetrahydro-pyridin-3-yl)-
2-oxo-ethyl]-piperidine-1-carboxylic acid tert-butyl ester
7. Benzylamine (354lL, 3.25mmol) was added to a
solution of 6 (743mg, 2.96mmol) at 0ꢁC. After the solu-
tion was warmed to room temperature, stirring was
maintained for 18h. Acryloyl chloride (263lL,
3.25mmol) was added at room temperature. After being
heated for 18h at reflux, the solution was washed with a
saturated aqueous NaHCO3 and the organic layer ex-
tracted with EtOAc. Evaporation of the solvent and col-
umn chromatography (AcOEt–cyclohexane, 1:3) gave 7
as a yellow oil (683mg, 56%). Rf (EtOAc) 0.55; 1H
NMR (300MHz, CDCl3) d 7.70–7.20 (6H, m), 4.92
(1H, A portion of AB system), 4.68 (1H, B portion of
AB system), 4.60–4.52 (1H, m), 3.90 (1H, br d,
J = 13Hz), 2.82–2.65 (5H, m), 2.57 (2H, br s), 1.98–
1.40 (6H, m), 1.45 (9H, s). 13C NMR (75.4MHz, CDCl3)
d 195.8, 169.8, 155.1, 136.6, 128.8 (2C), 128.0, 127.8
(3C), 118.5, 79.6, 50.2, 49.1, 39.8, 38.4, 30.7, 28.4 (3C),
27.5, 25.1, 18.8, 18.6. Anal. Calcd for C24H32N2O4: C,
69.88; H, 7.82; N, 6.79. Found: C, 69.93. H, 7.80. N,
C22H32N2O: C, 77.60; H, 9.47; N, 8.23. Found: C,
77.62; H, 9.49; N, 8.20. ½aŠ ¼ þ14( c 1, CHCl3).
25
D
6.82. EIMS 412 (6%), 356 (10%), 339 (16%),
25
D
312 (100%), 214(80%). ½aŠ ¼ ꢀ4 6 c( 1, CHCl3). Ee
4.1.8. N-Benzyl-aloperine 13. To a solution of 12
(361mg, 1.06mmol) in CH2Cl2 (40mL), PPh3 (695mg,
2.65mmol) and CBr4 (421mg, 1.27mmol) were added
and the reaction mixture was stirred at room tempera-
ture for 3h. Dry Et3N (361lL, 2.60mmol) was added
and, after 15h, the solution was poured into HCl 1N.
The aqueous solution was basified with NH4OH concd
and extracted with CH2Cl2. Evaporation of the solvent
and chromatographic purification (hexane–Et3N, 30:1)
gave 13 (153mg, 45%). Rf (AcOEt–hexane–Et3N,
90%. Chiral HPLC Analysis (Analytical). Column:
Chiracel OD; UV detector: k 254nm; solvent: petroleum
ether–i-PrOH, 9:1; flow rate: 0.7mL/min; retention time:
7, 14.02min; ent-7, 15.80min.
4.1.6. 1-Benzyl-2-oxo-6-piperidin-2-yl-1,2,3,4,6,7,8,8a-
octahydro-quinoline-8-carboxylic acid methyl ester
11. To a solution of 7 (424mg, 1.03mmol) in THF–
MeOH (1:2, 30mL), NaBH4 (56mg, 1.48mmol) was
added at 0ꢁC. After 2h, the reaction mixture was
poured into a NH4Cl(satd) and extracted with AcOEt.
The crude 8 was directly dissolved in toluene (10mL)
and refluxed in presence of pTSA (8mg, 0.043mmol)
and methyl acrylate (6mL, 66.7mmol). After 10days,
the solution was concentrated in vacuum and the mix-
ture of 9 and 10 was directly submitted to the next reac-
tion. 9: Rf (EtOAc) 0.46; 10: Rf (EtOAc) 0.42. To a
solution of 10 and 9 (417mg, 0.86mmol) in CH2Cl2
(28mL), CF3COOH (6.5mL, 83mmol) was added. After
2h at room temperature, water was added and the solu-
tion was basificated with NH4OH. Evaporation of the
organic layer and column chromatography (AcOEt–
1
15:10:1) 0.48; H NMR (300MHz, CDCl3) d 7.40–7.11
(5H, m), 5.58 (1H, d, J = 4.5Hz), 4.12 (1H, A portion
of AB system), 3.01 (1H, B portion of AB system),
2.98–1.25 (22H, m). 13C NMR (75.4MHz, CDCl3) d
139.6, 133.8, 128.6 (2C), 128.1 (2C), 127.9, 126.6, 65.6,
65.1, 57.8, 55.8, 52.5, 51.7, 35.7, 33.7, 32.6, 29.6, 25.6
(2C), 25.2, 23.5. Anal. Calcd for C22H30N2: C, 81.93;
H, 9.38; N, 8.69. Found: C, 81.90. H, 9.41. N, 8.73.
25
D
EIMS 322 (25%), 231 (100%). ½aŠ ¼ þ56 (c 0.7, EtOH).
4.1.9. (+)-Aloperine 1. To a solution of 13 (50mg,
0.15mmol) in THF (600lL) maintained at room tem-
perature, Et3N (1.20mL), lithium (53mg, 7.57mmol)

A. Barilli et al. / Tetrahedron: Asymmetry 15 (2004) 2921–2925
2925
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Silvani, A.; Danieli, B. Org. Lett. 2002, 4, 2925–2928.
6. Angoli, M.; Barilli, A.; Lesma, G.; Passarella, D.; Riva, S.;
Silvani, A.; Danieli, B. J. Org. Chem. 2003, 68, 9525–
9527.
7. (a) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A.
Chem. Commun. 2000, 139–163; (b) Ciriminna, R.; Bolm,
C.; Fey, T.; Pagliaro, M. Adv. Synth. Catal. 2002, 344,
159–163; For a brief review, see: (c) Ley, S. V.; Baxendale,
I. R.; Brusotti, G.; Caldarelli, G.; Massi, A.; Nesi, M.
Farmaco 2002, 57, 321–330.
and ethylendiamine (redistilled from Na, 123lL,
1.82mmol) were added. After 2h, THF (600lL), Et3N
(1.20mL) and ethylendiamine (123lL) were added.
After 3h, NH4Cl 5% (5mL) and water (5mL) were
added and the reaction mixture was stirred for 10min.
The aqueous layer was basified with Na2CO3 and ex-
tracted with CHCl3. After evaporation of organic layer,
a yellow oil was obtained. Chromatography purification
(AcOEt–MeOH–Et3N 15:5:2) gave 1 (28mg, 80%). Rf
(AcOEt–MeOH–Et3N 15:5:2) 0.15; 1H NMR
(300MHz, CD3COCD3) d 5.50 (1H, d, J = 6.5Hz),
3.22 (1H, d, J = 5.8Hz), 3.15–3.05 (1H, m), 2.90 (1H,
dd, J = 11.4, 6Hz), 2.87–2.75 (1H, m), 2.68 (1H, td,
J = 12.1, 2.8Hz), 2.65–2.45 (2H, m), 2.40–1.15 (16H,
m). 13C NMR (300MHz, CDCl3) d 136.1, 126.9, 60.1,
58.1, 55.1, 47.6, 46.0, 34.9, 32.5, 31.6, 29.6, 27.1, 25.4
(2C), 20.2. Anal. Calcd for C15H24N2: C, 77.53; H,
10.42; N, 12.05. Found: C, 77.58. H, 10.42. N, 12.02.
25
D
½aŠ ¼ þ68 (c 1, EtOH).
8. DÕAcunzo, F.; Baiocco, P.; Fabbrini, M.; Galli, C.;
Gentili, P.; Macchitella, D. Eur. J. Org. Chem. 2002,
4195–4201.
Acknowledgements
9. (a) Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D.
Tetrahedron Lett. 2001, 42, 7551–7553; (b) Fabbrini, M.;
Galli, C.; Gentili, P. J. Mol. Catal. B: Enzym. 2002, 231–
240; (c) Cantarella, G.; Galli, C.; Gentili, P. J. Mol. Catal.
B; Enzym. 2002, 135–144.
The authors express their gratitude to Ministero dellÕIst-
´
ruzione dellÕUniversita e della Ricerca for the financial
support. The work was partially supported by DGI-
CYT, Spain (BQU2000-0651).
10. (a) Nicotra, S.; Intra, A.; Ottolina, G.; Riva, S.; Danieli,
B. Tetrahedron: Asymmetry 2004, 15, in this issue.
doi:10.1016/j.tetasy.2004.06.034; (b) Nicotra, S.; Cram-
arossa, M. R.; Mucci, A.; Pagnoni, U. M.; Riva, S.; Forti,
L. Tetrahedron 2004, 60, 596–600.
References
1. Lupinine family includes also N-methyl and N-allyl
aloperina.