Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H

Article abstract of DOI:10.1016/j.tet.2010.04.037

The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (+)-2-tropinone, the enantioselective syntheses have establ

Full text of DOI:10.1016/j.tet.2010.04.037

Tetrahedron 66 (2010) 4428e4433
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H
*
Hong Shu, April R. Noble, Suhong Zhang, Lei Miao, Mark L. Trudell
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have
been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (þ)-2-
tropinone, the enantioselective syntheses have established the absolute configuration of these alkaloids
as (þ)-(2R,5S) and (ꢀ)-(5S,2R).
Received 2 March 2010
Received in revised form 2 April 2010
Accepted 6 April 2010
Available online 10 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amphibian alkaloids
Ant venom alkaloids
Pyrrolidine
Enantioselective synthesis
1. Introduction
R1
R2
R2
R1
N
H
N
H
Alkaloids isolated from amphibian skin extracts are repre-
sented by over 20 structural classes with over 800 unique com-
pounds identified as of 2005.1 The amphibian alkaloids have
provided valuable leads toward the development of new thera-
peutic agents and have been attractive targets for synthesis.2 The
unsymmetrical 2,5-disubstituted pyrrolidine alkaloids (1) are
a unique class of alkaloids in that these simple monocyclic amines
have been isolated from two very distinct sources.1 Initially, the
2,5-disubstituted pyrrolidine alkaloids were isolated from the
venom of several ant species and thought to serve as a chemical
defense mechanism against predators.3 More recently, the 2,5-
disubstitited pyrrolidine alkaloids have been found in the skin
extracts of various neotropical amphibian species.4 With few ex-
ceptions, the 2,5-disubstituted pyrrolidine alkaloids are rare in
amphibian species and when present are only obtained in trace
amounts. However, the 2,5-disubstituted pyrrolidine alkaloid 197B
(2) was found to be the major alkaloid in the skin extracts of one
population of Columbian frog (Dendrobates histrionicus).4 The
source of these anuran alkaloids has been presumed to be diet-
ary3d, although feeding studies have shown that pyrrolidine al-
kaloids are not readily accumulated in amphibian skin.5 This
suggests that a rather remarkable ecological and perhaps evolu-
tionary relationship exists between ant and frog species living in
neotropical environments (Fig. 1).
trans-1
cis-1
2N
5
N
H
H
(+)-197B (2)
225H (3)
Figure 1. Pyrrolidine Alkaloids.
Among, the 2,5-disubstituted pyrrolidine alkaloids that have
been isolated, the trans-isomers (e.g., 2) have been shown to be
exclusively found in ant extacts3 and predominate over the cis-
isomers in anuran extracts.1,4 As such the trans-2,5-disubstituted
pyrrolidine alkaloids have been the subject of numerous studies,
ranging from the development of synthetic methods6 and total
synthesis7 to pharmacological evaluation.2 However, due to the
paucity of the cis-isomers (e.g., 225H, 3), these alkaloids have not
been fully characterized and the absolute configurations of these
molecules are unknown.1 In addition, these alkaloids have not re-
ceived much attention from the synthetic community.8 As part of
program aimed at CNS drug discovery based upon novel molecular
scaffolds it was of interest to develop an enantioselective synthetic
approach that would allow for the unequivocal determination of
the absolute configuration of both enantiomers of the 2,5-di-
substituted pyrrolidine alkaloid cis-225H 3 and ent-3. Herein we
describe the synthesis of both enantiomers of cis-225H from
a common intermediate.
* Corresonding author. E-mail address: mtrudell@uno.edu (M.L. Trudell).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.037

H. Shu et al. / Tetrahedron 66 (2010) 4428e4433
4429
2. Results and discussion
Since the demethylation step was clearly problematic with
CbzCl, we elected to explore an alternative route to 6. We envisaged
that a separate demethylation step prior to introduction of the Cbz-
group would give higher overall yields of 6. In the revised synthetic
route (Scheme 1), demethylation was attempted first. Treatment of
confiscated grade cocaine12 with ethyl chloroformate provided 8 in
98% yield. Subsequent hydrolysis and concomitant dehydration of 8
in concentrated HCl at reflux for 12 h afforded noranhy-
droecognine$HCl (9) in quantitative yield. The carboxylic acid
moiety of 9 was then reacted with diphenylphosphoryl azide cat-
alyzed by 4-dimethylaminopyridine in dichloromethane giving the
intermediate acyl azide, which then underwent a Curtius rear-
rangement in 1 N HCl at reflux. The crude mixture was treated with
CbzCl to furnish 6 in 84% overall yield. The yield of this one-pot
three-step heterogeneous reaction was closely related to the dry-
ness of the intermediate 9. Thoroughly drying the acid 9 and
grinding it into a fine powder was found to greatly facilitate the
formation of the acyl azide and as a result led to a higher overall
yield of the Cbz-2-tropinone 6.
Previous work in our laboratory has shown that the pyrrolidine
derivative 4, was a useful chiral building block for the construction
of amphibian alkaloid skeletons containing a cis-pyrrolidine sub-
unit.9 The orthogonal reactivity of the side chain functional groups
and the nitrogen atom protecting group of 4 offered easy access to
more complicated ring systems. In addition, we had shown pre-
viously that the S-configuration at C5 of 4 was inert to a wide va-
riety of functional group transformations and could be exploited
without worry of epimerization. Readily prepared from (þ)-(1R)-2-
tropinone (5)10, the versatility of 4 for enantioselective synthesis
seemed well suited for the preparation of both enantiomers of cis-
225H (3 and ent-3, Fig. 2).
2
5
CO2CH3
OBn
O
N
O
4
With 6 in hand, our attention was focused on the preparation
of pyrrolidine 4. The tropinone 6 was treated with a THF solution
of NaH followed by the addition of TBSCl to furnish silyl enol
ether 10 in 89% yield. Compared with the methyl enol ether
employed in earlier studies,9 the silyl enol ether was more stable
toward chromatography and was readily purified prior to the
ozonolysis step. Ozone was slowly bubbled through a solution of
enol ether 10 in dichloromethane/methanol (9:1) at ꢀ78 ꢂC.
Treatment of the intermediate ozonide with sodium borohydride
followed by addition of diazomethane (from DiazaldÒ) furnished
the pyrrolidine 11, in 67% yield over the three steps. Subsequent
Swern oxidation of 11 provided the cis-pyrrolidine 4 in 98% yield
(Scheme 2).
5
5
2N
2
C5H11
C6H13
C6H13
C5H11
N
H
H
ent-3
3
Figure 2. Retrosynthetic approach.
Starting from (þ)-2-tropinone (5) it was our intent to prepare
4 by direct demethylation/acylation with benzyl chloroformate
(CbzCl) followed by subsequent conversion into the cis-pyrroli-
dine derivative. The (þ)-tropinone 5 was readily obtained from
(ꢀ)-cocaine10 or via resolution of (ꢁ)-2-tropinone with
L-tartaric
O
BnO
acid.11 As we had previously shown, the direct demethylation/
acylation of 5 only gave a modest yield (56%) of the desired Cbz-
2-tropinone 6.9 This was disappointing since the corresponding
ethyl carbamate 7, could be obtained in 98% yield employing
ethyl chloroformate under similar conditions (Scheme 1). Al-
though 7 was a viable starting point, the ethyl carbamate would
not provide the overall efficiency that was desired, due to
deprotection chemistry that would be required late in the syn-
thetic sequence.
N
a
b, c, d
OTBS
6
10 (89%)
OH
O
e
CO2CH3
OBn
11 (67%)
CO2CH3
OBn
4 (98%)
N
N
O
O
O
RO
Scheme 2. Reagents and conditions: (a) TBSCl, NaH, THF, 0 ꢂC. (b) O3, CH2Cl2/CH3OH,
ꢀ78 ꢂC. (c) NaBH4, 0 ꢂC. (d) CH2N2, Et2O, 0 ꢂC. (e) (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢂC,
then Et3N.
N
N
O
O
a or b
5
6 R = Bn (56%)
7 R = Et (98%)
The conversion of the intermediate ozonide to the alcohol de-
rivative 11 and subsequent oxidation to 4 was preferable to the
direct conversion of 10 into the aldehyde moiety (e.g., using
dimethylsufide or triphenylphosphine to reduce the ozonide). This
indirect method gave more reliable yields and furnished 4 with
fewer byproducts and impurities. This revised synthetic route gave
the pyrrolidine building block 4 in a 49% overall yield from
(ꢀ)-cocaine and was a significant improvement over our previous
method.9
The pyrrolidine 4 existed as a mixture (3:1) of conformational
isomers due to hindered rotation about the NeCbz bond (rotam-
ers). Since the presence of rotamers significantly complicated the
NMR spectrum it was practical to advance subsequent in-
termediates to a point where the conformational isomers did not
contribute to the complexity of the molecule before a meaningful
structural characterization was made.
EtO
O
N
N
CO2CH3
OCOPh
(-)-cocaine
CO2CH3
b
OCOPh
8 (98%)
O
BnO
H
d,e,f
c
•HCl
CO2H
N
N
O
6 (87%)
9 (99%)
Scheme 1. Reagents and conditions: (a) CbzCl, K2CO3, toluene, reflux. (b) EtOCOCl,
K2CO3, toluene, reflux. (c) 12 N HCl, reflux. (d) DMAP, (PhO)2PON3, Na2CO3, CH2Cl2. (e)
1 N HCl, reflux. (f) CbzCl, Na2CO3, CH3OH/H2O.

4430
H. Shu et al. / Tetrahedron 66 (2010) 4428e4433
25
The construction of the C2 and C5 alkyl appendages of 225H was
levorotatory enantiomer {[
a]
ꢀ20.6} (c 0.5, CH3OH) and estab-
D
envisaged to employ an iterative process of olefination. Subsequent
hydrogenation would then provide the saturated side chains as well
simultaneously remove the Cbz-protecting group to give pyrroli-
dine alkaloid 225H. As illustrated in Scheme 3, treatment of the 4
with the Wittig ylide generated from a solution of n-butyl-
triphenylphosphonium bromide and KH in THF at 0 ꢂC afforded the
Z-olefin 12 in 85% isolated yield. The carboxyl moiety of 12 was then
reduced with diisobutylaluminium hydride (DIBALH) in toluene at
ꢀ78 ꢂC, and concomitant Wittig olefination furnished the diene 13
as an unresolvable mixture of geometrical isomers in 85% yield for
the two-step process.
lished the absolute configuration of ent-3 as 2S, 5R.
a
b, c
4
CO2CH3
N
Cbz
14 (87%)
d
N
H
N
Cbz
(-)-3 (95%)
15 (81%)
a
b, a
4
CO2CH3
N
Cbz
Scheme 4. Reagents and conditions: (a) Ph3P(CH2)2CH3Br, KH, THF, 0 ꢂC. (b) DIBALH,
CH2Cl2, ꢀ78 ꢂC. (c) Ph3P(CH2)4CH3Br, KH, THF, 0 ꢂC. (d) H2 (1 atm), 10% Pd/C, CH3OH.
12 (85%)
Since both pyrrolidines 3 and ent-3 were clearly cis-isomers and
based upon the similar but opposite optical rotations, it was clear
that the syntheses proceeded with a similar degree of enantiose-
lectivity. Because it was unlikely that epimerization of either ster-
eocenter would lead to a cis-isomer over the more stable trans-
isomers, we were comfortable with the assignments of the absolute
configurations of the (þ)-(2R, 5S) 225H and (ꢀ)-(2S,5R) 225H.
c
N
H
N
Cbz
(+)-3 (99%)
13 (85%)
Scheme 3. Reagents and conditions: (a) Ph3P(CH2)3CH3Br, KH, THF, 0 ꢂC. (b) DIBALH,
CH2Cl2, ꢀ78 ꢂC. (c) H2 (1 atm), 10% Pd/C, CH3OH.
3. Conclusion
Conceivably, these steps could have resulted in some epimeri-
zation of the stereocenter at C2 due to the potentially labile nature
of the intermediate aldehyde moiety toward the basic reaction
conditions of either the reduction or the Wittig reaction. However,
minor epimerization was of little concern at this point since we
envisaged that any 2,5-trans-pyrrolidines formed as byproducts
could be quite easily separated from the cis-isomer by chroma-
tography after the final steps of the synthesis. The mixture of
conformational and geometrical isomers of diene 13 was exposed
to a hydrogen atmosphere (1 atm) in the presence of 10% palladium
on activated carbon. Simultaneous hydrogenation of the two alkene
moieties and hydrogenolysis of the Cbz-group afforded the pyrro-
lidine 225H (3) in quantitative yield. From these results it could be
In summary, the efficient and expeditious syntheses of both
enantiomers of the amphibian alkaloid cis-pyrrolidine 225H ex-
ploits the inherent stereochemistry of a (1R)-tropane ring system of
(ꢀ)-cocaine for the construction of the core cis-2,5-disubstituted
pyrrolidine. Utilizing the intermediate 4 as a common building
block, the enantioselective syntheses of both of the (þ)-cis-225H
(72% yield) and (ꢀ)-cis-225H (67% yield) were achieved. This has
served to establish the absolute configurations of both the dex-
trorotatory and the levorotatory isomers of cis-225H.
4. Experimental section
4.1. General methods
then established that 3 was the dextrorotatory isomer, (þ)-cis-
25
225H {[
a
]
D
þ21.9} (c 1.0, CH3OH) and thus had the absolute con-
figuration of 2R, 5S.
All chemicals were purchased from Aldrich Chemical Company
and used as received unless otherwise noted. Anhydrous
dichloromethane was purchased from Mallinckrodt Baker, Inc.
Chromatography refers to flash chromatography on silica gel
While it was clear from the NMR spectra of 3 that no trans-
isomers were present, attempts to confirm the enantiomeric purity
using the NMR chiral shift reagent 1,10-binaphthyl-2,20-diylphos-
phoric acid were inconclusive.13,14 Since the specific rotation data
for the naturally occurring cis-pyrrolidine 225H has not been pre-
viously reported we decided to synthesize the other enantiomer
ent-3 for comparison. It was envisaged that the synthesis of the
levorotatory isomer would not only validate the enantioselectivity
of the approach it would also demonstrate the versatility of the
pyrrolidine building block 4.
Because of the asymmetry of the side chains of 4, we had to
slightly modify our approach for construction of the C2 and C5 ap-
pendages of ent-3 (Scheme 4). Treatment of 4, with the Wittig ylide
generated from n-propyltriphenylphosphonium bromide in a THF
solution of KH provided the Z-alkene 14 in 89% yield. Homologation
of the ester moiety of 14 was achieved in similar fashion to that
described previously for 3. Reduction of the carboxylate with
DIBALH to the corresponding aldehyde and concomitant Wittig
olefination with the ylide generated from n-pentyltriphenyl-
phosponium bromide furnished 15 as an unresolvable mixture of
geometrical and conformational isomers in 81% yield for the two-
steps. Hydrogenation of the mixture then conveniently furnished
the ent-3 in 95% yield. It was determined that ent-3 was the
ꢀ
(Sorbtech, Inc.: 40e62 A, 230e400 mesh). Proton and carbon NMR
were recorded on a Varian-400 MHz nuclear magnetic resonance
spectrometer at ambient temperature in CDCl3 from Cambridge
Isotope Laboratories, Inc. 1H NMR chemical shifts are reported as
d
values (ppm) relative to tetramethylsilane. 13C NMR chemical
shifts are reported as
d values (ppm) relative to chloroform-
d (77.0 ppm). Optical rotations were measured on Autopol III po-
larimeter at the sodium D line (2 mL sample cell). Melting points
(mp) were measured with an Electrothermal R Mel-Temp appara-
tus and are uncorrected.
4.1.1. (1R,5S)-8-Ethoxycarbonyl-8-azabicyclo[3.2.1]octan-2-one (7).
To a solution of 510 (0.64 g, 4.6 mmol) and K2CO3 (380 mg,
2.3 mmol) in toluene (8 mL) was added ethyl chloroformate
(2.2 mL, 23 mmol). The reaction mixture was heated to reflux for
24 h. The solvent was removed under vacuum and the resulting
residue was dissolved in water (9 mL). The aqueous layer was
extracted with dichloromethane (3ꢃ10 mL). The organic layers
were combined and dried over Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by

H. Shu et al. / Tetrahedron 66 (2010) 4428e4433
4431
chromatography (SiO2, CH2Cl2/hexane, 3:7) to yield 7 (0.89 g, 98%)
with the evolution of gas. The aqueous solution was then heated in
a preheated oil bath (120 ꢂC) for 40 min until the carbon dioxide
and nitrogen gas evolution ceased. The aqueous solution was
concentrated under reduced pressure and the residue was basified
(pH 9.5e10) by the addition of a saturated solution of Na2CO3. The
aqueous solution was then extracted with dichloromethane
(2ꢃ50 mL). The combined organic portions were washed with
brine (50 mL), dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The residue without further purification was dis-
solved in the mixture of methanol (108 mL) and water (12 mL) and
cooled to 0 ꢂC. Solid sodium bicarbonate (4.6 g) was added por-
tionwise followed by the addition of benzyl chloroformate (2.4 mL).
The reaction mixture was allowed to warm to room temperature
and stirred for 5 h. The solvent was removed under reduced pres-
sure and the aqueous solution was diluted with water (50 mL) and
extracted with dichloromethane (2ꢃ50 mL). The combined organic
fractions were washed by brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The residue was purified by
20
as a pale yellow oil. [
CDCl3)
a
]
D ꢀ15.4 (c 0.4, CH3OH). 1H NMR (400 MHz,
d
4.47 (s, 1H), 4.40 (s, 1H), 4.10e4.14 (m, 2H), 2.35e2.45 (m,
2H), 2.17e2.22 (m, 3H), 1.78e1.84 (m, 3H), 1.23 (t, J 6.8 Hz, 3H). 13C
NMR (400 MHz, CDCl3) 14.6, 30.6 (2), 32.5 (2), 52.8, 61.5, 64.1,
d
154.3, 205.7. Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10.
Found: C, 60.90; H, 7.67; N, 7.10.
4.1.2. (1R,2R,3S,5S)-3-(Benzoyloxy)-2-methoxycarbonyl-8-ethoxy-
carbonyl-8-azabicyclo[3.2.1]octane (8). Confiscated (ꢀ)-cocaine
hydrochloride (20 g) was dissolved in water (50 mL). The aqueous
solution was washed with ether to remove any trace organic im-
purities. A saturated solution of Na2CO3 was added until the solu-
tion was at pH 10. The resultant slurry was extracted with
dichloromethane (100 mL). The aqueous portion was discarded.
The organic solution was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo to furnish (ꢀ)-cocaine (18.1 g, 100%).
(ꢀ)-Cocaine (9.76 g, 32.1 mmol) and NaHCO3 (4.05 g,
48.3 mmol) were added to anhydrous toluene (100 mL). To the
suspension was added ethyl chloroformate (17.5 g, 15.3 mL,
161 mmol). The reaction mixture was heated to reflux for 12 h, then
another portion of ethyl chloroformate (10.5 g, 9.18 mL, 96.5 mmol)
was added. Stirring and heating were continued for an additional
12 h. Toluene was removed under reduced pressure and the residue
was portioned between ethyl acetate (100 mL) and water (100 mL).
The aqueous layer was separated and extracted with ethyl acetate
(2ꢃ100 mL). The combined organic portions were washed with
saturated Na2CO3 solution (100 mL), brine (100 mL), dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue
was purified by chromatography (SiO2, EtOAc/hexanes, 1:2)
affording 8 (11.4 g, 98%) as a slightly yellow oil. Rf¼0.34 (EtOAc/
chromatography (SiO2, EtOAc/hexanes, 1:2) to afford 6 (3.84 g, 87%)
25
as a clear oil. [
d
a
]
ꢀ5.9 (c 1.0, CH3OH). 1H NMR (400 MHz, CDCl3)
D
7.39e7.27 (m, 5H), 5.19e5.07 (m, 2H), 4.54e4.44 (m, 2H),
2.48e2.42 (m, 2H), 2.38e2.32 (m, 2H), 2.25e2.18 (m, 2H), 1.86e1.77
(m, 2H). 13C NMR (CDCl3)
d
205.5, 154.0, 136.5, 128.6, 128.2, 128.0,
67.2, 64.3, 53.0, 32.6, 30.6, 28.0, 27.2. Anal. Calcd for C15H17NO3: C,
69.48; H, 6.61; N, 5.40. Found: C, 69.65; H, 6.65; N, 5.29.
4.1.5. (1R,5S)-8-Benzyloxycarbonyl 2-(tert-butyl-dimethylsilyloxy)-
8-azabicyclo[3.2.1]oct-2-ene
(10). Sodium
hydride
(60 mg,
2.5 mmol) was suspended in anhydrous THF (4 mL) under nitrogen
atmosphere at 0 ꢂC. A solution of ketone 9 (130 mg, 0.50 mmol) in
dry THF (2 mL) was added dropwise and stirred for 2 h. Then tert-
butyl(chloro)dimethylsilane (1.0 M in THF, 1 mL) was added
dropwise and stirred overnight at room temperature. The mixture
was cooled to 0 ꢂC, the reaction was quenched by a slow addition
of water (10 mL) and diluted with ethyl ether (20 mL). The organic
fraction was separated and the aqueous portion was extracted
with ethyl ether (2ꢃ20 mL). Combined organic portions were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by chromatography
hexanes, 1:2). [
a
]
25 ꢀ30.4 (c 1.0, CH3OH). 1H NMR (400 MHz, CDCl3)
D
d
7.98e7.90 (m, 2H), 7.59e7.51 (m, 1H), 7.42e7.37 (m, 2H),
5.50e5.41 (m, 1H), 4.76e4.41 (m, 2H), 4.20e4.00 (m, 2H), 3.63 (s,
3H), 3.09 (br s, 1H), 2.61e2.56 (m, 1H), 2.18e1.72 (m, 5H), 1.30e1.19
(m, 3H). 13C NMR (CDCl3)
d 170.4, 166.0, 153.9, 133.3, 129.7, 128.5,
66.7, 61.2, 61.1, 54.9, 54.6, 52.6, 52.4, 52.0, 51.6, 49.4, 48.9, 33.7, 33.3,
28.9, 28.2, 27.9, 27.3, 14.8. Anal. Calcd for C19H23NO6: C, 63.15; H,
6.41; N, 3.88. Found: C, 63.22; H, 6.49; N, 3.91.
(SiO2, EtOAc/hexanes, 5:95) to afford 10 (166 mg, 89% yield) as
25
4.1.3. Noranhydroecognine HCl (9). The carbamate
8
(10.1 g,
a colorless oil. [
a]
ꢀ43.5 (c 1.2, CH3OH). 1H NMR (400 MHz,
D
28.5 mmol) was added to concentrated hydrochloric acid (12 N,
100 mL). The mixture was heated to reflux for 6 h. After cooling to
room temperature, the aqueous solution was extracted with ethyl
ether (2ꢃ50 mL) and the organic extracts were discarded. The
aqueous portion was concentrated under reduced pressure at ele-
vated temperature. The remaining water was removed by suspen-
sion of the slurry in toluene followed by azeotropic distillation
under reduced pressure. The resultant solid was dried in a vacuum
oven (80 ꢂC, 30 mmHg,) for 12 h. The solid was ground into a fine
powder and heated under vacuum for an additional 12 h. This
afforded 9 (5.41 g, 99%) as a white powder. Mp 260e262 ꢂC (dec).
Anal. Calcd for C8H12ClNO2: C, 50.67; H, 6.38; N, 7.39. Found: C,
50.38; H, 6.39; N, 7.27.
CDCl3) d 7.28e7.35 (m, 5H), 5.09e5.19 (m, 2H), 4.11e4.49 (m,
2.5Hrotamers), 2.61e2.79 (m, 0.5Hrotamers), 1.94e2.18 (m, 3H), 1.74
(dd, J 16.4, 4.6 Hz, 1H), 1.58e1.67 (m, 2H), 0.90 (s, 9H), 0.14 (m, 6H).
13C NMR (75 MHz, CDCl3)
d 154.8, 154.4, 137.1, 128.6, 128.1, 128.0,
97.3, 66.8, 57.7, 52.5, 34.4, 33.7, 32.4, 31.4, 30.2, 29.4, 25.8, 18.2,
ꢀ4.5, ꢀ4.1, Anal. Calcd for C21H31NO3Si: C, 67.52; H, 8.36; N, 3.79.
Found: C, 67.73; H, 8.58; N, 3.79.
4.1.6. (2R,5S)-1-Benzyloxycarbonyl-2-methoxycarbonyl-5-(2-hy-
droxyethyl)pyrrolidine (11). Silyl ether 10 (781 mg, 2.1 mmol,
1.0 equiv) was dissolved in a solution of dichloromethane (50 mL)
and methanol (5 mL). At ꢀ78 ꢂC, O3 was bubbled into the solution
until a light blue color was observed and persisted. A stream of
nitrogen was bubbled through the solution for 10 min. At ꢀ78 ꢂC,
NaBH4 (250 mg) was added by one portion. After 30 min, another
portion of NaBH4 (300 mg) was added and the reaction was
warmed to room temperature. The solvent was removed under
reduced pressure. The residue was triturated with 2 N HCl (25 mL)
to pH 1. The aqueous solution was extracted with dichloromethane
(3ꢃ20 mL). The combined organic portions were dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pressure to
afford a light yellow oil. The oil was dissolved in ethyl ether (20 mL)
and diazomethane was freshly prepared from p-toluenesulpho-
nylmethylnitrosamide (Diazald) and bubbled through the solution
at 0 ꢂC. When a yellow color persisted, diazomethane stream was
4.1.4. (1R,5S)-8-Benzyloxycarbonyl-8-azabicyclo[3.2.1]octan-2-one
(6). The finely powdered 9 (3.22 g, 17.0 mmol) and sodium car-
bonate (4.50 g, 42.5 mmol) were suspended in anhydrous
dichloromethane (100 mL) followed by the addition of 4-dime-
thylaminopyridine (104 mg, 0.84 mmol). The suspension was
purged with N2, sealed, and stirred for 15 min before diphenyl-
phosphoryl azide (5.71 g, 4.48 mL, 20.7 mmol) was added drop-
wise. The stirring was continued for 48 h at room temperature. The
solvent was removed under reduced pressure and the residue was
dissolved in water (40 mL). The mixture was cooled to 0 ꢂC,
hydrochloric acid (1 N, 120 mL) was added slowly and carefully

4432
H. Shu et al. / Tetrahedron 66 (2010) 4428e4433
removed and nitrogen was bubbled through the solution for 5 min.
The mixture was allowed to warm to room temperature and the
solvent was removed under reduced pressure. The residue was
purified by chromatography (SiO2, hexanes/EtOAc, 4:6) affording
4.1.9. (2S,5R)-1-Benzyloxycarbonyl 2-(hex-2-enyl)-5-(1-pentenyl)-
pyrrolidine (13). Methyl ester 12 (142 mg, 0.41 mmol) was dis-
solved in anhydrous dichloromethane (15 mL) and cooled to
ꢀ78 ꢂC. Diisobutylaluminium hydride (1 M in toluene, 0.50 mL)
was added dropwise over 30 min. After completion of the addition,
the reaction mixture was stirred at ꢀ78 ꢂC for 2 h until the starting
material was no longer observed by TLC. The reaction was
quenched by the addition of methanol (0.5 mL) and warmed to
room temperature. The mixture was poured into ice-cold hydro-
chloric acid (1 N, 2 mL). The aqueous layer was extracted with
dichloromethane (2ꢃ20 mL). The combined organic portions were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The aldehyde was typically
carried on to the next step without further purification.
ester 11 (430 mg, 67% yield, three steps) as a colorless oil. [
a
]
25 þ52
D
(c 0.6, CH3OH). 1H NMR (400 MHz, CDCl3)
d
7.28e7.37 (m, 5H),
5.03e5.22 (m, 2H), 4.37 (t, J 8.3 Hz, 1H), 3.93 (dd, J 9.8, 4.6 Hz, 1H),
3.64e3.82 (m, 3H), 3.60 (s, 3H), 2.30e2.37 (m, 1H), 1.95e2.11 (m,
2H), 1.61e1.82 (m, 3H). 13C NMR (75 MHz, CDCl3)
d 173.6, 156.1,
136.4, 128.7, 128.3, 127.9, 67.8, 59.9, 59.1, 55.8, 52.4, 37.8, 30.9, 29.2.
Anal. Calcd for C16H21NO5: C, 62.53; H, 6.89; N, 4.56. Found: C,
62.28; H, 7.00; N, 4.49.
4.1.7. (2R,5S)-1-Benzyloxycarbonyl-2-methoxcarbonyl-5-(2-oxo-
ethyl)pyrrolidine (4). To a solution of oxalyl chloride (150 mg,
0.1 mL, 1.18 mmol) in dichloromethane (30 mL) at ꢀ78 ꢂC was
added dimethyl sulfoxide (184 mg, 0.17 mL, 2.25 mmol) dropwise.
The mixture was stirred at ꢀ78 ꢂC for 10 min before a solution of
the alcohol 11 (300 mg, 0.98 mmol) in dichloromethane (2 mL) was
added slowly. The mixture was stirred for 15 min, then triethyl-
amine (541 mg, 0.75 mL, 5.35 mmol) was added and the mixture
was warmed to room temperature. Water (30 mL) was added and
the organic layer was separated and the aqueous layer was
extracted with dichloromethane (2ꢃ30 mL). The combined organic
portions were washed by brine, dried over anhydrous MgSO4, fil-
tered, and concentrated. The residue was purified by chromatog-
Potassium hydride (40% in mineral oil) was washed by anhy-
drous hexanes and dried by a stream of argon. Potassium hydride
(50 mg, 1.3 mmol) and Ph3P(CH2)3CH3Br (663 mg, 1.7 mmol) were
suspended in 10 mL of anhydrous THF. The reaction was stirred
under the atmosphere of nitrogen at room temperature for 30 min
and then cooled to 0 ꢂC. A solution of the aldehyde (131 mg,
0.42 mmol) in THF (1 mL) was added dropwise. Upon completion of
the addition the reaction mixture was stirred at room temperature
for 1 h. The reaction was quenched by the addition of saturated
solution of ammonium chloride (1 mL). The reaction was then
partitioned between ethyl acetate (20 mL) and water (20 mL) and
the organic layer was separated. The aqueous layer was extracted
with ethyl acetate (2ꢃ20 mL). Combined organic fractions were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
chromatography (SiO2, EtOAc/hexanes, 1:11) to afford 13 (116 mg,
raphy (SiO2, EtOAc/hexanes,1:1) to afford 4 (294 mg, 98%) as a clear
25
oil. [
a
]
D
þ23.6 (c 1.0, CH3OH). 1H NMR (400 MHz, CDCl3)
d 9.81
(s, 0.6Hrotamers), 9.71 (s, 0.4Hrotamers), 7.35e7.27 (m, 5H), 5.19e5.03
(m, 2H), 4.50e4.32 (m, 2H), 3.74 (s, 1.2Hrotamers), 3.61 (s,
1.8Hrotamers), 3.24 (dd, J 20.1, 3.7 Hz, 0.6Hrotamers), 3.05 (dd, J 20.1,
3.7 Hz, 0.4Hrotamers), 2.72e2.62 (m, 1H), 2.27e2.16 (m, 2H),
85% two steps). 1H NMR (400 MHz, CDCl3)
d 7.40e7.23 (m, 5H),
5.55e5.30 (m, 4H), 5.12 (s, 2H), 4.61e4.57 (m, 1H), 3.95e3.85 (m,
1H), 2.62e2.51 (m, 2H), 2.20e1.80 (m, 6H), 1.80e1.60 (m, 4H),
2.03e1.94 (m, 1H), 1.75e1.66 (m, 1H). 13C NMR (CDCl3)
d 200.9,
200.7, 173.2, 173.0, 154.3, 153.9, 136.3, 136.1, 128.5, 128.4, 128.2,
128.1, 128.0, 127.6, 67.3, 67.0, 59.9, 59.5, 54.0, 53.2, 52.3, 52.1, 48.9,
48.2, 31.0, 30.2, 28.9, 28.0, 22.2. Anal. Calcd for C16H19NO5: C, 62.94;
H, 6.27; N, 4.59. Found: C, 62.51; H, 6.53; N, 4.49.
1.51e1.18 (m, 4H),1.00e0.85 (m, 4H). 13C NMR (CDCl3)
d 155.5, 137.1,
133.2, 130.5, 130.1, 128.4, 128.1, 128.0, 125.9, 67.7, 59.0, 56.2, 32.9,
31.7, 30.0, 22.8, 14.3. Anal. Calcd for C23H33NO2: C, 77.70; H, 9.36; N,
3.94. Found: C, 77.66; H, 9.49; N, 4.08.
4.1.8. (2R,5S,Z)-1-Benzyloxycarbonyl 2-methoxycarbonyl-5-(hex-2-
enyl)-pyrrolidine (12). Potassium hydride (40% in mineral oil) was
washed with anhydrous hexanes and dried by a stream of argon.
Potassium hydride (47.3 mg, 1.18 mmol) and Ph3P(CH2)3CH3Br
(628 mg, 1.57 mmol) were suspended in of anhydrous THF (10 mL).
The reaction mixture was stirred under the atmosphere of nitrogen
at room temperature for 30 min and then cooled to 0 ꢂC. A solution
of aldehyde 4 (120 mg, 0.39 mmol) in THF (1 mL) was added drop-
wise. Upon completion of the addition, the reaction mixture was
stirred at room temperature for 1 h. The reaction was quenched by
theaddition ofsaturated solutionof ammoniumchloride(1 mL). The
mixture was then partitioned between ethyl acetate (20 mL) and
water (20 mL). The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (2ꢃ20 mL). The combined
organic portions were washed with brine, dried on anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography (SiO2, EtOAc/hexanes, 1:4)
4.1.10. (þ)-cis-225H (3). A solution of diene 13 (45 mg, 0.13 mmol)
10% palladium on activated carbon (10 mg) in methanol (10 mL)
was stirred under a hydrogen atmosphere (1 atm) overnight. The
solution was filtered through a pad of Celite and washed with ethyl
acetate (20 mL) and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (SiO2, CH3OH/CH2Cl2,
1:10) to provide (þ)-cis-225H 3 (32 mg, 99%) as a light yellow oil.
25
[a
]
þ21.9 (c 1.0, CH3OH). 1H NMR (400 MHz, CDCl3)
d 2.98e2.88
D
(m, 2H), 1.87e1.79 (m, 2H) 1.54e1.21 (m, 22H), 0.92e0.84 (m, 5H).
13C NMR (CDCl3)
d 59.6, 37.0, 36.9, 32.3, 32.0, 31.5, 29.7, 27.7, 27.4,
22.8, 22.8, 14.3, 14.3. Anal. Calcd for C15H31N: C, 79.92; H, 13.86; N,
6.21. Found: C, 79.68; H, 13.97; N, 6.18.
4.1.11. (2R,5S,Z)-1-Benzyloxycaarbonyl-2-methoxy-carbonyl-5-
(pent-2-enyl)pyrrolidine (14). Potassium hydride (40% in mineral
oil) was washed with anhydrous hexanes and dried by a stream of
argon. Potassium hydride (60 mg, 1.5 mmol) and Ph3P(CH2)2CH3Br
(770 mg, 2.0 mmol) were suspended in anhydrous THF (10 mL).
The reaction was stirred under an atmosphere of nitrogen at room
temperature for 30 min and then cooled to 0 ꢂC. A solution of
aldehyde 4 (153 mg, 0.50 mmol) in of THF (1 mL) was added
dropwise. Upon completion of the addition the reaction mixture
was stirred at room temperature for 1 h. The reaction was
quenched by the addition of a saturated solution of ammonium
chloride (1 mL). The reaction was then partitioned between ethyl
acetate (20 mL) and water (20 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with ethyl acetate
(2ꢃ20 mL). The combined organic layers were washed with brine,
affording the Z-alkene 12 (115 mg, 85%). Rf¼0.44 (EtOAc/hexanes,
25
1:4). [
d
a
]
þ15.6 (c 1.0, CH3OH). 1H NMR (400 MHz, CDCl3)
D
7.39e7.22 (m, 5H), 5.53e5.44 (m, 2H), 5.43e5.29 (m, 2H),
4.41e4.30 (m, 1H), 4.00e3.83 (m, 1H), 3.77 (s, 1.4H), 3.61 (s, 1.6H),
2.84e2.62 (m, 1H), 2.31e2.13 (m, 2H), 2.10e1.87 (m, 4H), 1.84e1.70
(m, 1H), 1.42e1.34 (m, 2H), 0.93 (t, J 0.7 Hz, 1.6Hrotamers), 0.84 (t, J
0.7 Hz, 1.4Hrotamers). 13C NMR (CDCl3)
d 173.5, 173.3, 154.9, 154.1,
136.6,136.5,132.4,132.2,128.4,128.3,128.0,127.8,127.6,125.6,125.3,
67.2, 66.8, 60.2, 59.8, 59.2, 58.6, 52.1, 52.0, 32.0, 31.2, 29.4, 29.3, 29.0,
28.7, 28.0, 22.7, 22.6,13.7,13.6. Anal. Calcd for C20H27NO4: C, 69.54; H,
7.88; N, 4.05. Found: C, 69.34; H, 8.01; N, 4.21.

H. Shu et al. / Tetrahedron 66 (2010) 4428e4433
4433
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by chromatography
d
2.96e2.88 (m, 2H), 1.80e1.70 (m, 2H) 1.59e1.21 (m, 22H),
0.95e0.85 (m, 5H). 13C NMR (CDCl3)
d
58.9, 37.0, 36.9, 32.3, 32.0,
(SiO2, EtOAc/hexanes. 1:4) to furnish the Z-alkene 14 (146 mg,
31.5, 29.7, 27.7, 27.4, 22.8, 22.8, 14.3, 14.2. Anal. Calcd for C15H31N: C,
79.92; H, 13.86; N, 6.21. Found: C, 79.84; H, 14.20; N, 6.05.
25
87%). Rf¼0.4 (EtOAc/hexanes¼1:4). [
a
]
þ13.0 (c 1.0, CH3OH). 1H
D
NMR (400 MHz, CDCl3)
d
7.39e7.22 (m, 5H), 5.55e5.44 (m, 2H),
5.33e5.27 (m, 2H), 4.41e4.30 (m, 1H), 4.00e3.83 (m, 1H), 3.77 (s,
1.4H), 3.61 (s, 1.6H), 2.84e2.62 (m, 1H), 2.31e2.13 (m, 2H),
2.13e1.87 (m, 4H), 1.78e1.70 (m, 1H), 2.32e2.14 (m, 2H), 1.23 (t, J
0.6 Hz, 1.6Hrotamers), 1.19 (t, J 0.6 Hz, 1.4Hrotamers). 13C NMR (CDCl3)
Acknowledgements
This research was supported by the National Institute on Drug
Abuse (DA11528), and the University of New Orleans, Office of
Research and Sponsored Programs. We wish to thank Mr. Kevin
Gormley, Division of Basic Research National Institute on Drug
Abuse for providing the confiscated cocaine hydrochloride.
d
173.5, 173.3, 154.9, 154.1, 136.6, 136.5, 132.4, 132.2, 128.4, 128.3,
128.0, 127.8, 127.6, 125.6, 125.3, 67.2, 66.8, 60.2, 59.8, 59.2, 58.6,
52.1, 52.0, 32.0, 31.2, 29.4, 28.7, 28.0, 20.7, 20.6, 13.9, 13.7. Anal.
Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 69.04; H,
7.44; N, 4.21.
Supplementary data
4.1.12. (2R,5S)-1-Benzyloxycarbonyl 2-(hex-1-enyl)-5-(pent-2-enyl)
pyrrolidine (15). The ester 14 (86 mg, 0.26 mmol) was taken up in
15 mL of anhydrous dichloromethane and cooled to ꢀ78 ꢂC in a dry
ice/acetone bath. At ꢀ78 ꢂC, diisobutylaluminium hydride (1 M in
toluene, 0.276 mL) was added dropwise over 30 min. After com-
pletion of the addition, the reaction mixture was stirred at ꢀ78 ꢂC
for 2 h. The reaction was quenched by the addition of methanol
(0.5 mL) and warmed to room temperature. The mixture was
poured into ice-cold hydrochloric acid (1 N, 2 mL). The aqueous
layer was extracted with dichloromethane (2ꢃ20 mL). The com-
bined organic portions were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The aldehyde was typically carried on to the next step.
Potassium hydride (40% in mineral oil) was washed with an-
hydrous hexanes and dried by a stream of argon. Potassium hy-
dride (28.8 mg, 0.72 mmol) and Ph3P(CH2)4CH3Br (409 mg,
0.96 mmol) were suspended in 10 mL of anhydrous THF. The re-
action was stirred under the atmosphere of nitrogen at room
temperature for 30 min and then cooled to 0 ꢂC. A solution of al-
dehyde (72 mg, 0.24 mmol) in THF (1 mL) was added dropwise.
Upon completion of the addition the reaction mixture was stirred
at room temperature for 1 h. The reaction was quenched by the
addition of saturated solution of ammonium chloride (1 mL). The
reaction was then partitioned between ethyl acetate (20 mL) and
water (20 mL) and the organic layer was separated. The aqueous
layer was extracted with ethyl acetate (2ꢃ20 mL). Combined or-
ganic fractions were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (SiO2, EtOAc/
hexanes, 1:11) to afford the diene 15 (75 mg, 81% two steps). 1H
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.037.
References and notes
1. Daly, J. W.; Garraffo, H. M.; Spande, T. F. J. Nat. Prod. 2005, 68, 1556e1575.
2. (a) Daly, J. W. J. Med. Chem. 2003, 46, 445e452; (b) Daly, J. W. In The Alkaloids;
Cordell, G. A., Ed.; Academic: New York, NY, 1998; Vol. 50, pp 141e169; (c) Daly,
J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell, G. A., Ed.; Academic:
New York, NY, 1993; Vol. 43, pp 186e188.
3. (a) Jones, T. H.; Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38, 1949e1958; (b)
Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.; Academic: New York, NY,
1987; Vol. 31, pp 193e315; (c) Jones, T. H.; DeVries, P. J.; Escoubas, P.J. Chem.
Ecol. 1991, 17, 2507e2517; (d) Jones, T. H.; Gorman, J. S. T.; Snelling, R. R.; De-
labie, J. H. C.; Blum, M. S.; Garraffo, H. M.; Jain, P.; Daly, J. W.; Spande, T. F. J.
Chem. Ecol. 1999, 25, 1179e1193; (e) Jones, T. H.; Zottig, V. E.; Robertson, H. G.;
Snelling, R. R. J. Chem. Ecol. 2003, 29, 2721e2727; (f) Jones, T. H.; Voegtle, H. L.;
Miras, H. M.; Weatherford, R. G.; Spande, T. F.; Garraffo, H. M.; Daly, J. W.;
Davidson, D. W.; Snelling, R. R. J. Nat. Prod. 2007, 70, 160e168.
4. Daly, J. W.; Whittaker, N.; Spande, T. F.; Highet, R. J.; Feigl, D.; Nishimori, N.;
Tokuyama, T.; Meyers, C. W. J. Nat. Prod. 1986, 49, 265e280.
5. Daly, J. W.; Secunda, S. I.; Garraffo, H. M.; Spande, T. F.; Wisnieski, A.; Cover, J. F.
Toxicon 1994, 32, 657e663.
6. (a) For example syntheses of trans-2,5-pyrrolidines, see Gribkov, D. V.;
Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748e3759; (b) Davis, F.
A.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71, 2779e2786; (c) Vasse, J.-L.;
Joosten, A.; Denhez, C.; Szymoniak, J. Org. Lett. 2005, 7, 4887e4889; (d) Ryu, J.
S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3, 3091e3094; (e) Katritzky, A. R.;
Cui, X.-L.; Yang, B.; Steel, P. J. J. Org. Chem. 1999, 64, 1979e1985; (f) Arredondo,
V. M.; Tan, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121,
3633e3639; (g) Celimene, C.; Dhimane, H.; Lhommet, G. Tetrahedron 1998, 54,
10457e10468; (h) Bloch, R.; Brillet-Fermandez, C.; Mandville, G. Tetrahedron:
Asymmetry 1994, 5, 745e750; (i) Machinaga, N.; Kibayashi, C. J. Org. Chem. 1991,
€
56, 1386e1393; (j) Backvall, J. E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990,
55, 826e831; (k) Takahata, H.; Takehara, H.; Ohkubo, N.; Momose, T. Tetrahe-
dron: Asymmetry 1990, 1, 561e566; (l) Gessner, W.; Takahashi, K.; Brossi, A.;
Kowalski, M.; Kaliner, M. A. Helv. Chim. Acta 1987, 70, 2003e2010; (m) Jones, T.
H.; Blum, M.; Murray, S.; Fales, H. M. Tetrahedron Lett. 1979, 12, 1031e1034.
7. For a recent reviews of pyrrolidine and related alkaloid synthesis see: (a)
Michael, J. P. Nat. Prod. Rep. 2004, 21, 625e649; (b) Cheng, Y.; Huang, Z.-T.;
Wang, M.-X. Curr. Org. Chem. 2004, 8, 325e351; (c) Pyne, S. G.; Davis, A. S.;
Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett 2004,
2670e2680; (d) Michael, J. P. Alkaloids 2001, 55, 91e258.
8. (a) For example syntheses of cis-2,5-pyrrolidines, see Raziullah, S.; Moloney, M.
G. Org. Biomol. Chem. 2006, 4, 2600e2615; (b) Llamas, T.; Gomez, R. A.; Car-
retero, J. C. Org. Lett. 2006, 8, 1795e1798; (c) Pandey, G.; Reddy, P. Y.; Bhalerao,
U. T. Tetrahedron Lett. 1991, 32, 5147e5150.
NMR (400 MHz, CDCl3)
d 7.40e7.23 (m, 5H), 5.65e5.40 (m, 4H),
5.17 (s, 1H), 5.12 (s, 1H), 4.61e4.57 (m, 1H), 3.79e3.85 (m, 1H),
2.62e2.51 (m, 2H), 2.20e1.80 (m, 4H), 1.77e1.62 (m, 4H), 1.51e1.11
(m, 4H), 1.11e0.83 (m, 6H). 13C NMR (CDCl3)
d 155.5, 137.1, 133.2,
130.5, 130.1, 128.4, 128.1, 128.0, 125.9, 67.7, 59.0, 56.2, 32.9, 31.7,
30.0, 22.8, 14.3. Anal. Calcd for C23H33NO2: C, 77.70; H, 9.36; N,
3.94. Found: C, 77.66; H, 9.49; N, 4.08.
9. Zhang, S.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72,
3133e3136.
10. Zhang, C.; Lomenzo, S. A.; Ballay, C.; Trudell, M. L. J. Org. Chem. 1997, 62,
7888e7889.
11. Lomenzo, S. A.; Enmon, J.; Troyer, M. C.; Trudell, M. L. Synth. Commun. 1995, 25,
3681e3690.
12. Confiscated grade (ꢀ)-cocaine hydrochloride was provided by NIDA Drug
Supply System , Research Technology Branch, National Institute on Drug Abuse.
A DEA Schedule II license was required.
4.1.13. (ꢀ)-cis-225H (ent-3). A solution of diene 15 (57 mg,
0.080 mmol) 10% palladium on activated carbon (10 mg) in meth-
anol (10 mL) was stirred under a hydrogen atmosphere (1 atm)
overnight. The solution was filtered through a pad of Celite and
washed with ethyl acetate (20 mL) and concentrated in vacuo. The
residue was purified by chromatography (SiO2, CH3OH/CH2Cl2,
1:10) to provide (ꢀ)-cis-pyrrolidine 225H (17 mg, 95%) as a light
13. Ravard, A.; Crooks, P. A. Chirality 1996, 8, 295e299.
14. Miao, L.; DiMaggio, S.; Shu, H.; Trudell, M. L. Org. Lett. 2009, 11, 1579e1582.
25
yellow oil. [
a]
ꢀ20.6 (c 0.5, CH3OH). 1H NMR (400 MHz, CDCl3)
D