General strategy for the construction of enantiopure pyrrolidine-based alkaloids. Total synthesis of (-)-monomorine

Article abstract of DOI:10.1021/jo062532p

(Chemical Equation Presented) An enantiopure cis-2,5-disubstituted pyrrolidine building block was prepared from cocaine. The synthetic utility of this compound as a chiral building block was demonstrated by a short and efficient synthesis of the pyrrolidi

Full text of DOI:10.1021/jo062532p

bicyclic 3,5-disubstituted indolizidines 1 or simply as the major
structural element in the monocyclic 2,5-disubstituted pyrrolidine
alkaloids 2. In lieu of these structural similarities, it was of
interest to develop a general and enantioselective synthetic
method that would allow access to these as well as other novel
classes of alkaloids.6
General Strategy for the Construction of
Enantiopure Pyrrolidine-Based Alkaloids. Total
Synthesis of (-)-Monomorine
Suhong Zhang, Liang Xu, Lei Miao, Hong Shu, and
Mark L. Trudell*
Department of Chemistry, UniVersity of New Orleans,
New Orleans, Louisiana 70148
mtrudell@uno.edu
ReceiVed December 11, 2006
There are numerous reports describing the syntheses of the
more common trans-2,5-disubstituted pyrrolidine moiety found
in numerous pyrrolidine or indolizidine alkaloids.7 However,
there are only a few methods that have been reported that
stereoselectively furnish cis-2,5-disubstituted pyrrolidine deriva-
tives, and these methods are somewhat limited to fairly simple
substitution patterns.7i,8 Therefore, it was of interest not only
to develop an enantioselective approach but also to develop a
general strategy that would allow for the preparation of complex
natural as well as nonnatural indolizidine and/or pyrrolidine
alkaloids that could be used in future structure-activity studies.
The synthetic strategy for the preparation of an enantiopure
cis-2,5-disubstituted pyrrolidine building block was envisaged
to proceed from an intermediate derived from cocaine (3). The
approach would exploit the inherent stereochemistry at C1 and
C5 of cocaine, such that via a sequence of degradation reactions
an unsymmetrical cis-2,5-disubstituted pyrrolidine 5 could be
obtained (Scheme 1). Although not commercially available,
confiscated grade cocaine can be obtained from the National
Institute on Drug Abuse with appropriate DEA licensing in
sufficient quantities to provide useful amounts of chiral building
blocks. As described in some of our previous work, cocaine
can be readily converted into (+)-2-tropinone (4).9 It was
An enantiopure cis-2,5-disubstituted pyrrolidine building
block was prepared from cocaine. The synthetic utility of
this compound as a chiral building block was demonstrated
by a short and efficient synthesis of the pyrrolidine-based
alkaloid (-)-monomorine (six steps, 37% overall yield).
Alkaloids isolated from neotropical frogs have become
important targets for synthesis due to their vast array of structural
diversity and biological activity.1 For many of the over 500
alkaloids that represent nearly 20 different structural classes,
the stereochemical assignment and absolute configurations have
yet to be unequivocally determined. The paucity of natural
material has made total synthesis the only available avenue to
obtain material for study of the structure and activity of these
novel compounds. As part of an ongoing study in our labora-
tories, we have been very interested in the amphibian alkaloids
that exhibit pharmacological activity mediated by nicotinic
receptor ion channels.2,3 Nicotinic receptor ligands have been
identified as having potential therapeutic value for the treatment
of Alzheimer’s disease, Parkinson’s disease, acute and chronic
pain, as well as smoking cessation.4,5 Several classes of the
amphibian alkaloids have been reported to be noncompetitive
blockers at nicotinic receptor ion channels.1 Of these alkaloids,
two classes share the common structural feature of a cis-2,5-
disubstituted pyrrolidine ring system. This ring system can be
found either incorporated in complex molecules such as the
(6) For recent reviews of pyrrolidine and related alkaloid synthesis, see:
(a) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625. (b) Cheng, Y.; Huang,
Z.-T.; Wang, M.-X. Curr. Org. Chem. 2004, 8, 325. (c) Pyne, S. G.; Davis,
A. S.; Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M.
Synlett 2004, 15, 2670. (d) Michael, J. P. Alkaloids 2001, 55, 91.
(7) For example syntheses of trans-2,5-pyrrolidines, see: (a) Gribkov,
D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. (b)
Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71, 2779. (c)
Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Org. Lett. 2005, 7,
4887. (d) Ryu, J. S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3,
3091. (e) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org. Chem.
1999, 64, 1979. (f) Arredondo, V. M.; Tan, S.; McDonald, F. E.; Marks, T.
J. J. Am Chem. Soc. 1999, 121, 3633. (g) Celimene, C.; Dhimane, H.;
Lhommet, G. Tetrahedron 1998, 54, 10457. (h) Bloch, R.; Brillet-
Fermandez, C.; Mandville, G. Tetrahedron: Asymmetry 1994, 5, 745. (i)
Machinaga, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 1386. (j) Ba¨ckvall,
J. E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990, 55, 826. (k) Takahata,
H.; Takehara, H.; Ohkubo, N.; Momose, T. Tetrahedron: Asymmetry 1990,
1, 561. (l) Gessner, W.; Takahashi, K.; Brossi, A.; Kowalski, M.; Kaliner,
M. A. HelV. Chim. Acta 1987, 70, 2003. (m) Jones, T. H.; Blum, M.; Murray,
S.; Fales, H. M. Tetrahedron Lett. 1979, 12, 1031.
(1) (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. J. Nat. Prod. 2005,
68, 1556. (b) Daly, J. W. J. Med. Chem. 2003, 46, 445. (c) Daly, J. W.;
Garraffo, H. M.; Spande, T. F. In The Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Amsterdam, 1999; pp 1-161.
(2) Banner, E. J.; Stevens, E. D.; Trudell, M. L. Tetrahedron Lett. 2004,
45, 4411.
(3) Zhang, C.; Trudell, M. L. J. Org. Chem. 1996, 61, 7189.
(4) Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem. 1997, 40,
4169.
(5) Decker, M.; Arneric, S. P. In Neuronal Nicotinic Receptors:
Pharmacology and Therapeutic Opportunities; Arnernic, S. P., Brioni, J.
D., Eds.; Wiley-Liss: New York, 1999; pp 395-411 and references cited
therein.
(8) For example syntheses of cis-2,5-pyrrolidines, see: (a) Moloney, M.
G.; Raziullah, S. Org. Biomol. Chem. 2006, 4, 2600. (b) Llamas, T.; Gomez,
R. A.; Carretero, J. C. Org. Lett. 2006, 8, 1795. (c) Celimene, C.; Dhimane,
H.; Saboureau, A.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 1585.
(d) Pandey, G.; Reddy, P. Y.; Bhalerao, U. T. Tetrahedron Lett. 1991, 32,
5147.
(9) Zhang, C.; Lomenzo, S. A.; Ballay, C.; Trudell, M. L. J. Org. Chem.
1997, 62, 7888.
10.1021/jo062532p CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/16/2007
J. Org. Chem. 2007, 72, 3133-3136
3133

SCHEME 1
SCHEME 3
SCHEME 2
complexity of the molecule and a meaningful structural char-
acterization could be performed.
The orthogonal reactivity of the aldehyde, the ester, and the
N-Cbz protecting group as well as the asymmetry of cis-2,5-
appendages of pyrrolidine 8 offered the flexibility desired of a
chiral building block for the syntheses of a variety of alkaloids.
To demonstrate the synthetic utility of 8 as a building block
for the construction of pyrrolidine-based alkaloids, (-)-mono-
morine (12) was selected as our initial target (Scheme 3). The
natural alkaloid (+)-monomorine, isolated from ants (Mono-
morium pharaonis)10 and more recently detected in amphibian
skin extracts (Melanophryniscus stelzneri),11 has been the target
of a variety of synthetic efforts.12 Both the natural isomer13 and
the unnatural antipode14 have been enantioselectively synthe-
sized and well characterized. Therefore, (-)-monomorine (12)
was deemed an ideal target to evaluate the chemical and
stereochemical efficiency of our approach.
envisaged that further manipulation of this enantiopure tropane
derivative could provide a useful intermediate for the total
synthesis of 3,5-disubstituted indolizidine and/or cis-2,5-disub-
stituted pyrrolidine alkaloids.
Our initial task was to develop a synthetic sequence for the
preparation of an enantiopure cis-2,5-disubstituted pyrrolidine
building block from (+)-2-tropinone (4). The selection of (+)-
2-tropinone (4) to be used as an early intermediate was based
upon its availability and relative ease of preparation in our
laboratory.9 Confiscated grade (-)-cocaine was readily con-
verted into (+)-2-tropinone (4) in 80% overall yield. This one-
pot two-step procedure was typically performed on a 35 g scale
and furnished 10 g quantities of optically pure 4. As illustrated
in Scheme 2, the 2-tropinone 4 was then N-demethylated and
the nitrogen atom was simultaneously protected as the Cbz-
carbamate 6 (56% yield) by heating 4 at reflux in a solution of
Cbz-Cl and toluene. This step was necessary to reduce the
nitrogen atom basicity and protect it from oxidation during
ozonolysis in the succeeding step. The N-Cbz-2-tropanone 6
was then converted into the methyl enol ether 7 with trimethyl
orthoformate catalyzed by PTSA. The intermediate enol ether
7 was obtained in 95% yield but was unstable to chromatography
and thus required purification by vacuum bulb-to-bulb distil-
lation. Because of its relative instability, the enol ether 7 was
immediately subjected to ozonolysis conditions. The double
bond of 7 was cleaved by ozone at -78 °C, and subsequent
reductive workup with triphenylphosphine furnished the enan-
tiopure cis-2,5-disubstituted pyrrolidine 8 in 74% yield. The
pyrrolidine 8 existed as a mixture (3:1) of two conformers due
to hindered rotation about the N-Cbz bond (rotomers). The
formation of rotomers significantly complicated the NMR
spectroscopy of later intermediates. As a result, it was difficult
to spectroscopically characterize intermediate compounds. There-
fore, it was often practical to advance intermediates to a point
where the conformational isomers did not contribute to the
Construction of the C3 side chain of (-)-monomorine prior
to ring closure to form the indolizidine ring system was deemed
preferable to the alternative sequence. This approach would
avoid protection of reactive functionality during the late stages
of the synthesis and has been successful in recent syntheses of
(10) Ritter, F. J.; Rotgans, I. E. M.; Tulman, E.; Verwiel, P. E. J.; Stein,
F. Experientia 1973, 29, 530.
(11) Garraffo, H. M.; Spande, T. F.; Daly, J. W.; Baldessari, A.; Gros,
E. G. J. Nat. Prod. 1993, 56, 357.
(12) (a) Wantanabe, Y.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989, 54,
4088. (b) Jefford, C. W.; Tang, Q.; Zaslona, A. HelV. Chim. Acta 1989, 72,
1749. (c) Yamaguchi, R.; Hatta, E.; Matsuki, T.; Kawanisi, M. J. Org. Chem.
1987, 52, 2094. (d) Iida, H.; Wantanabe, Y.; Kibayashi, C. Tetrahedron
Lett. 1986, 27, 5513. (e) Stevens, R. V.; Lee, A. W. M. J. Chem. Soc.,
Chem. Commun. 1982, 102. (f) Macdonald, T. L. J. Org. Chem. 1980, 45,
193. (g) Oliver, J. E.; Sonnet, P. E. J. Org. Chem. 1974, 39, 2662.
(13) (a) Conchon, E.; Gelas-Mialhe, Y.; Remuson, R. Tetrahedron:
Asymmetry 2006, 17, 1253. (b) Ito, M.; Kibayashi, C. Tetrahedron Lett.
1990, 31, 5065.
(14) (a) Jefford, C. W.; Sienkiewicz, K.; Thornton, S. R. Tetrahedron
Lett. 1994, 35, 4759. (b) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem.
Soc. 1991, 113, 3513. (c) Royer, J.; Husson, H.-P. J. Org. Chem 1985, 50,
670.
3134 J. Org. Chem., Vol. 72, No. 8, 2007

(+)-monomorine and related indolizidine alkaloids.15 This
approach would then require the initial conversion of the C2
ester moiety of 8 into the butyl side chain at C3 of indolizidine
12. Thus, the aldehyde moiety of 8 was protected as the acetal
with trimethyl orthoformate catalyzed by cerric chloride to afford
9 in 92% yield. Reduction of the ester with DIBAL-H to the
aldehyde followed by concomitant Wittig olefination afforded
the four-carbon unit necessary for the indolizidine C3 side chain.
Conversion of the butenyl group of 10 into the required butyl
group was deemed unnecessary at this stage because this could
ultimately be achieved during the deprotection/indolizidine ring-
forming steps. Therefore, subsequent hydrolysis of the acetal
moiety with PTSA‚H2O in acetone gave the Z-alkenal 10 in
55% overall yield.
dried over Na2SO4. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography
(EtOAc/hexane, 1:1) to yield 6 as a colorless oil (3.42 g, 56%).
1
[R]20 -5.7 (c 2.5, MeOH). H NMR (CDCl3) δ 7.36-7.27 (m,
D
5H), 5.17-5.11 (m, 2H), 4.51-4.45 (m, 2H), 2.48-2.42 (m, 2H),
2.38-2.32 (m, 2H), 2.25-2.18 (m, 2H), 1.86-1.77 (m, 2H). 13C
NMR (CDCl3) δ 205.3, 153.8, 136.2, 128.4, 128.2, 128.0, 127.8,
67.0, 64.1, 52.8, 32.4, 30.4, 27.8. Anal. Calcd for C15H17NO3: C,
69.48; H, 6.61; N, 5.40. Found: C, 69.65; H, 6.74; N, 5.62.
(1R)-N-Benzyloxycarbonyl-2-methoxy-8-azabicyclo[3.2.1]oct-
2-ene (7). A solution of trimethyl orthoformate (3.4 g, 32 mmol),
6 (5.5 g, 21 mmol), and PTSA‚H2O (400 mg, 2 mmol) was stirred
vigorously at 80 °C under nitrogen for 5 h. The mixture was cooled
to rt, and the solvent was evaporated to dryness under reduced
pressure. The residue was purified via bulb-to-bulb distillation under
a vacuum (1 mmHg) to afford 7 as a colorless oil (5.5 g, 95%). 1H
NMR (CDCl3) 7.33 (brs, 5H), 5.13 (qAB, JAB ) 12 Hz, ∆ν ) 2
Hz, 2H), 4.39 (m, 1H), 4.25 (m, 2H), 3.54 (s, 3H), 2.68 (m, 1H),
2.13-1.98 (m, 3H), 1.80 (dd, J ) 15.2, 4.4 Hz, 1H), 1.64 (m, 1H).
13C NMR (CDCl3) δ161.0, 155.3, 136.6, 128.4, 128.0, 127.3, 92.8,
67.0, 54.5, 54.4, 52.2, 28.8, 28.0, 25.3. HRMS(EI) calcd for
C16H19NO3 273.1365, found 273.1358.
(2R,5S)-N-Benzyloxycarbonyl-2-methoxylcarbonyl-5-(2-oxo-
ethyl)-pyrrolidine (8). Ozone was bubbled through a solution of
7 (5.3 g, 19 mmol) in CH2Cl2 (40 mL) at -78 °C until a slight
blue color persisted. The mixture was then flushed with nitrogen
for 10 min. Triphenylphosphine (10 g, 39 mmol) was then added
to the solution, and the mixture was stirred overnight. The solvent
was evaporated under reduced pressure, and the residue was purified
by flash column chromatography (EtOAc/hexane, 1:1) to yield 8
as a colorless oil (4.4 g, 74%). [R]20D +18.5 (c 2.5, MeOH). Major
conformer: 1H NMR (CDCl3) 9.83 (s, 1H), 7.34-7.30 (m, 5H),
5.20-5.04 (m, 2H), 4.58-4.38 (m, 1H), 3.62 (s, 3H), 3.33 (m,
1H), 2.73-2.62 (m, 2H), 2.23-2.19 (m, 2H), 2.03-1.99 (m, 2H).
13C NMR (CDCl3) δ 200.7, 173.1, 153.8, 136.2, 128.2, 127.9, 127.5,
66.9, 59.8, 59.4, 53.9, 48.1, 30.1, 28.0. Minor conformer: 1H NMR
(CDCl3) 9.73 (s, 1H), 7.34-7.30 (m, 5H), 5.20-5.04 (m, 2H),
4.58-4.38 (m, 1H), 3.76 (s, 3H), 3.15 (m, 1H), 2.73-2.62 (m,
2H), 2.23-2.19 (m, 2H), 2.03-1.99 (m, 2H). Anal. Calcd for
C16H19NO5‚1/2H2O: C, 61.13; H, 6.41; N, 4.46. Found: C, 61.35;
H, 6.32; N, 4.45.
The indolizidine ring system was constructed by exploiting
a common synthetic strategy of side-chain elongation via
olefination followed by a simultaneous hydrogenation/reductive
amination sequence.13a As illustrated in Scheme 3, olefination
of 10 with trimethylphosphonoacetate, lithium chloride, and
DBU gave the enone 11 in 80% yield as a mixture of rotomers
and isomers. Separation of the isomers was not pursued because
the planned hydrogenation/ring-closing reaction sequence was
envisaged to give a single product regardless of olefin geometry.
The hydrogenation of the two olefin moieties, simultaneous
deprotection of the pyrrolidine nitrogen atom, and concomitant
reductive amination/ring closure was achieved smoothly by
hydrogenation (55 psi) over 10% Pd-carbon. This one-pot
transformation furnished (-)-monomorine (12) in 87% yield
as a single enantiomer. It is noteworthy that only R-stereo-
chemistry was obtained at C5 of the indolizidine system. This
result was consistent with previous reports that describe the
delivery of hydrogen to the intermediate imine double bond,
syn to the C8a H-atom.13a The relative stereochemistry and
absolute configuration of the (-)-monomorine was confirmed
1
by comparison to the published H NMR spectrum,13C NMR
spectrum, and the specific rotation, respectively, and all were
in excellent agreement.14
In summary, we have developed a synthetic route that exploits
the natural stereochemistry inherent to cocaine for the synthesis
of an enantiopure cis-2,5-pyrrolidine building block (8). The
enantiopure building block 8 was ideally suited for the construc-
tion of more complex pyrrolidine-based alkaloids due to the
asymmetry of the appendages and the orthogonal reactivity of
the functional/protecting groups. The utility of this compound
as a chiral building block was demonstrated by the short and
efficient synthesis of (-)-monomorine (12, six steps, 37%
overall yield from 8). This approach will undoubtedly be equally
as effective for providing other natural and nonnatural deriva-
tives for structure-activity studies and will be the subject of
future investigations.
(2R,5S)-N-Benzyloxycarbonyl-2-methoxycarbonyl-5-(2,2-
dimethoxyethyl)-pyrrolidine (9). Trimethylorthoformate (2.5 g,
24 mmol) was added to a solution of aldehyde 8 (0.8 g, 2.6 mmol)
and CeCl3‚7H2O (1.0 g, 2.7 mmol) in methanol (10 mL) for 30
min. The reaction was quenched with saturated NaHCO3 (5 mL),
and the mixture was extracted with EtOAc (2 × 10 mL). The
combined organic layers were washed with brine solution, dried
over Na2SO4, and evaporated to dryness under reduced pressure.
This afforded the acetal 9 (0.90 g, 92%) in sufficient purity for use
1
in the next step. H NMR (CDCl3) δ 7.34-7.30 (m, 5H), 5.24-
5.10 (m, 2H), 4.58-4.38 (m, 1H), 4.19 (m, 1H), 3.67 (s, 3H), 3.33-
2.73 (m, 7H), 2.73-2.62 (m, 2H), 2.23-2.19 (m, 2H), 2.03-1.99
(m, 2H). 13C NMR (CDCl3) δ 173.1, 153.8, 136.2, 128.2, 127.9,
127.5, 101.2, 66.9, 59.8, 59.4, 48.1, 42.1, 39.0, 26.6, 22.5.
HRMS(EI) calcd for C18H25NO6 351.1682, found 351.1658.
Experimental Section
(2R,5S)-N-Benzyloxycarbonyl-2-(1-butenyl)-5-(3-oxoethyl)-
pyrrolidine (10). A solution of DIBAL-H (1.0 M in toluene, 1.1
mL, 1.1 mmol) was added dropwise over 30 min to a solution of
9 (0.20 g, 0.60 mmol) in toluene (3 mL) at -78 °C. After 10 min,
Et2O (5 mL), H2O (2 mL), and 15% NaOH (3 mL) were added to
the reaction mixture and stirred for 30 min. The reaction mixture
was extracted with Et2O (2 × 10 mL), washed with brine solution,
dried over Na2SO4, and evaporated to dryness under reduced
pressure. The residue was dissolved in toluene (3 mL) and added
to a previously prepared solution of CH3CH2CH2PPh3Br (0.44 g,
1.1 mmol) and t-BuOK (0.12 g, 1.1 mmol) in toluene (5 mL) that
had been stirred at rt for 1.5 h. The mixture was stirred at rt for 8
(1R)-N-Benzyloxycarbonyl-2-oxo-8-azabicyclo[3.2.1]octane (6).
Benzyl chloroformate (18 mL, 128 mmol) was added to a solution
of 4 (3.6 g, 26 mmol) and potassium carbonate (180 mg, 1.3 mmol)
in toluene (80 mL). The solution was heated to reflux for 48 h.
The solvent was removed under reduced pressure, and the residue
was dissolved in water (50 mL). The aqueous mixture was extracted
with CH2Cl2 (3 × 50 mL), and the combined organic layers were
(15) (a) Pilli, R. A.; Dras, C.; Maldaner, A. O. J. Org. Chem. 1995, 60,
717. (b) Fleurant, A.; Celerier, J. P.; Lhommet, G. Tetrahedron: Asymmetry
1993, 4, 1429.
J. Org. Chem, Vol. 72, No. 8, 2007 3135

h, then EtOAc (20 mL) and saturated Na2S2O3 solution (10 mL)
were added to the reaction mixture. The reaction mixture was
extracted with EtOAc (2 × 10 mL), washed with brine, dried over
Na2SO4, and evaporated to dryness under reduced pressure. The
residue (0.11 g) was dissolved in acetone (10 mL). PTSA‚H2O
(0.012 g, 0.06 mmol) was added, and the mixture was stirred for
30 min. The solvent was evaporated, and the residue was dissolved
in CH2Cl2 (20 mL). The organic solution was washed with saturated
NaHCO3 solution, dried over Na2SO4, and evaporated to dryness
under reduced pressure. The residue was purified by flash chro-
matography (EtOAc/hexane, 1:1) to yield 10 as a colorless oil (0.086
(-)-Monomorine (12). A solution of 11 (70 mg, 0.2 mmol) and
10% Pd/C (14 mg) in CH3OH (10 mL) was hydrogenated at 55 psi
for 24 h on a Parr hydrogenation apparatus. The solids were
removed by filtration through a pad of celite, and the solvent was
removed under reduced pressure. The residue was purified by
chromatography using a short column of silica gel (CH3OH/CHCl3),
and a light yellow oil was obtained. The oil was dissolved in CH2Cl2
(10 mL), washed with saturated NaHCO3 solution (10 mL), and
dried over Na2SO4. The solvent was removed under reduced
pressure to provide 12 (35 mg, 87%) as a light yellow oil. [R]20
D
-35.6 (c 0.5, n-hexane), lit. [R]20D -35.8 (c 1.35, n-hexane).14c 1
H
1
g, 55% overall). H NMR (CDCl3) δ 9.78 (s, 1H), 5.42 (brs, 1H),
NMR δ (CDCl3) 2.54-2.44 (m, 1H), 2.25-2.20 (m, 1H), 2.08-
2.01 (m, 1H), 1.86-1.42 (m, 8H), 1.40-1.26 (m, 8H), 1.13 (d, J
) 6.4 Hz, 3H), 0.89 (t, J ) 7.0 Hz, 3H). 13C NMR (CDCl3) δ
67.1, 62.8, 60.2, 39.7, 35.8, 30.8, 30.3, 29.7, 29.4, 24.8, 22.8, 22.6,
14.4.
5.29-5.24 (m, 1H), 4.61 (brs, 1H), 4.37-4.31 (m, 1H), 4.11 (q, J
) 7.2 Hz, 2H), 2.94 (brs, 1H), 2.56-2.49 (m, 1H), 2.18-1.99 (m,
2H), 1.73-1.64 (m, 4H), 1.51-1.33 (m, 2H), 1.18 (t, J ) 7.2 Hz,
3H), 0.92 (t, J ) 7.2 Hz, 3H). 13CNMR (CDCl3) δ 200.6, 153.8,
136.2, 132.4, 128.4, 128.2, 127.9, 127.5, 66.9, 55.2, 53.9, 48.1,
30.1, 28.0, 26.7, 15.1. HRMS(EI) calcd for C18H23NO3 301.1678,
found 301.1685.
Acknowledgment. We thank the National Institute on Drug
Abuse (DA12703) for the financial support of this research. We
also wish to thank Professor Gregory Fu, the Department of
Chemistry at MIT, Professor Edwin Vedejs, and the Department
of Chemistry at the University of Michigan for all of the
assistance provided to Mr. Miao and Ms. Shu during the
evacuation of New Orleans due to Hurricane Katrina.
(2R,5S)-N-Benzyloxycarbonyl-2-(1-butenyl)-5-(4-oxopent-2-
enyl)-pyrrolidine (11). To a stirred solution of lithium chloride
(15 mg, 0.4 mmol) in CH3CN (10 mL) was added dimethyl (2-
oxopropyl)phosphonate (125 mg, 0.8 mmol), DBU (0.4 mL, 0.3
mmol), and 10 (105 mg, 0.3 mmol). The mixture was stirred under
nitrogen for 24 h. The solvent was evaporated to dryness under
reduced pressure, and the residue was purified by flash column
chromatography (EtOAc/hexane, 1:1) to yield 11 as a colorless oil
1
(83 mg, 80%). H NMR (CDCl3) δ 7.38-7.30 (m, 5H), 6.80-
Supporting Information Available: Copies of 1H NMR spectra
for compounds 7-11. This material is available free of charge via
the Internet at http://pubs.acs.org.
6.72 (m, 1H), 6.11-6.04 (m, 1H), 5.31-5.19 (m, 1H), 5.15-5.08
(m, 1H), 4.62 (brs, 1H), 4.08 (brs, 1H), 2.70 (brs, 1H), 2.40 (brs,
1H), 2.20 (s, 3H), 2.09-2.05 (m, 2H), 2.00-1.92 (m, 2H), 1.71-
1.61 (m, 4H), 1.11-0.84 (m, 3H). HRMS(EI) calcd for C21H27NO3
341.1991, found 341.1983.
JO062532P
3136 J. Org. Chem., Vol. 72, No. 8, 2007