A facile preparation of an octahydropyrrolo[2,3-c]pyridine enantiomer

Article abstract of DOI:10.1021/op700073g

A facile synthesis of octahydro-pyrrolo[2,3-c]pyridine 1 using an intramolecular [3+2]-cycloaddition of an azomethine ylide as the key step and employing DW-therm heat-transfer fluid as a solvent is disclosed. Enantiomerically pure 1 was obtained either via a chromatographic separation of the diastereoisomers 12 and 13 resulting from the cycloaddition with a chiral appendage or by a classical resolution of racemate 19.

Full text of DOI:10.1021/op700073g

Organic Process Research & Development 2007, 11, 711−715
A Facile Preparation of an Octahydropyrrolo[2,3-c]pyridine Enantiomer
Wen-Chung Shieh,* Guang-Pei Chen, Song Xue, Joseph McKenna, Xinglong Jiang, Kapa Prasad,* and Oljan Repicˇ
Process Research & DeVelopment, NoVartis Pharmaceuticals Corporation, One Health Plaza, East HanoVer,
New Jersey 07936, U.S.A.
Christopher Straub and Sushil K. Sharma
NoVartis Institutes for Biomedical Research, 250 Massachusetts AVenue, Cambridge, Massachusetts 02139, U.S.A.
Abstract:
of azomethine ylides (3) which are formed by thermolysis
of aziridines 4 (Scheme 1).2-7 This protocol (320-350 °C
in a sealed tube) is not convenient for scale-up purposes.
Lower temperature (e.g., 110 °C) led to significant decom-
position of aziridine 4 as reported earlier.4b,7
We utilized a two-pronged approach to provide the supply
of 1 in sufficient quantities. The first approach involved the
use of a chiral appendage to facilitate the chromatographic
separation of diastereomeric isomers resulting from the
cycloaddition. The second method was the use of classical
resolution for separating the enantiomers.
Approach Using a Chiral Appendage. Synthesis of 1
(Scheme 2) started with the alkylation of 4-bromo-1-butene
(5) with 2-phenylethylamine (6) in the presence of potassium
carbonate affording pure 7 (69%) as an oil after distillation
(70 °C/0.25 mmHg). For the second piece, alkylation of 2,3-
dibromopropionate (8) with (R)-naphthylethylamine (9) using
potassium carbonate as the base furnished aziridine ester 10
(96% yield) as an oil after purification by silica gel
chromatography. A three-step, one-pot operation involving
saponification of ester 10 with potassium trimethylsilanoate,
reaction of the resulting potassium carboxylate with pivaloyl
chloride, and condensation of the mixed anhydride formed
in situ with amine 7 generated aziridine amide 11 in
quantitative yield. For the cycloaddition reaction, we chose
to utilize an unconventional solvent DW-therm,8 typically
used as a commercial heat-exchange fluid. DW-therm, a
mixture of triethoxyalkylsilanes, is a nonviscous, nonhazard-
ous liquid with reported boiling and flash points of 240 °C
and 101 °C, respectively. From safety and temperature-
control points of view, this liquid is an ideal solvent for the
desired cycloaddition reaction. Heating 11 in DW-therm at
A facile synthesis of octahydro-pyrrolo[2,3-c]pyridine 1 using
an intramolecular [3+2]-cycloaddition of an azomethine ylide
as the key step and employing DW-therm heat-transfer fluid
as a solvent is disclosed. Enantiomerically pure 1 was obtained
either via a chromatographic separation of the diastereoisomers
12 and 13 resulting from the cycloaddition with a chiral
appendage or by a classical resolution of racemate 19.
Inhibitors of apoptosis proteins (IAPs) have been impli-
cated as having a role in cancer by blocking the activity of
caspases, thereby preventing programmed cell death of these
diseased cells. A proapoptotic mitochondrial protein, Smac,
is capable of neutralizing IAPs by binding to a peptide
binding pocket on the surface of a key domain (BIR3) of
the IAPs thereby precluding their interaction with Caspase
9.1 Utilizing structure-based drug design we have considered
and synthesized several peptidomimetic scaffolds of the Smac
ligand which exhibit good in vitro activity in multiple tumor
cell lines. One highly potent compound, contains the bicyclic
amine core structure 1, which presented a considerable
synthetic challenge. The research synthesis, which will be
discussed in a subsequent publication, was sufficient for
preparing small quantities of the compound. Further refine-
ment of the procedure has permitted the production of the
desired compound on large scale for further studies. The
culmination of our effort is the subject of this communication.
The initial synthesis of bicyclic amine 1 involved the use
(3) (a) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1991, 56, 3210-3211. (b) Sisko,
J.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4945-4951. (c)
Irie, O.; Samizu, K.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1999, 64,
587-595. (d) Hong, S.; Yang, J.; Weinreb, S. M. J. Org. Chem. 2006, 71,
2078-2089.
of bicyclic lactam 2 as the key intermediate.2 Bicyclic amines
such as 2 are often prepared on small scale via cycloaddition
(4) (a) Henke, B. R.; Kouklis, A. J.; Heathcock, C. H. J. Org. Chem. 1992, 57,
7056-7066. (b) Griffith, D. A.; Heathcock, C. H. Tetrahedron Lett. 1995,
36, 2381-2384.
* To whom correspondence may be sent. E-mail: prasad.kapa@novartis.com,
wen.shieh@novartis.com.
(5) DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309-
2315.
(1) (a) Du, C.; Fang, M.; Li, Y.; Li, L.; Wang, X. Cell. 2000, 102, 33-42. (b)
Verhagen, A. M.; Ekert, P. G.; Pakusch, M.; Silke, J.; Connolly, L. M.;
Reid, G. E.; Moritz, R. L.; Simpson, R. J.; Vaux, D. L. Cell 2000, 102,
43-53.
(2) Palermo, M. G.; Sharma, S. K.; Straub, C.; Wang, R.-M.; Zawel, L.; Zhang,
Y.; Chen, Z.; Wang, Y.; Yang, F.; Wrona, W.; Liu, G.; Charest, M. G.; He,
F. World Intellectual Property Organization WO 2005/097791 A1, 2005.
(6) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Am. Chem. Soc. 1987, 109,
5523-5524.
(7) Marx, M. A.; Grillot, A-L.; Louer, C. T.; Beaver, K. A.; Bartlett, P. A. J.
Am. Chem. Soc. 1997, 119, 6153-6167.
(8) DW-therm, a heat transfer fluid for Huber Cooling and Heating Unistats, was
purchased from the Huber Corporation of Germany at www.huber-online.
com.
10.1021/op700073g CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/13/2007
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711

Scheme 1
Scheme 2
240 °C (refluxing conditions) under a nitrogen atmosphere
for 20 min afforded a mixture of diastereoisomers 12 and
13 (1:1 ratio) in approximately 90% yield, superior to most
of the yields reported for this type of cycloaddition. After
the reaction, DW-therm was separated from the products by
vacuum distillation and, consistent with green chemistry
principles, could be reused. About 2 kg of the diastereomeric
mixture of 12 and 13 were produced in five runs using a
typical 5-L, three-necked reaction flask. The desired isomer
12 was isolated by silica gel chromatography in 94%
diasteromeric excess. Further purification by recrystallization
from tert-butyl methyl ether/heptane furnished lactam 12 with
99.5% optical purity and an overall yield of 61% of the
theoretical yield from 10. The absolute configuration of 12
was confirmed by a single-crystal X-ray (Figure 1). It is
noteworthy that the outcome of this cycloaddition employing
other high-boiling solvents such as DMSO (180 °C), 1,3,5-
triisopropylbenzene (230 °C), mineral oil (250 °C), or
tetramethylethylene sulfone (250-270 °C) was not satisfac-
tory.
hydrogenation with Pd(OH)2 as the catalyst furnished oc-
tahydro-pyrrolo[2,3-c]pyridine 1 in 85% yield with high
chemical (>99%) and optical (>99.9%) purity.
Resolution Approach. As observed above, the chiral
appendage employed in the first approach did not provide
any selectivity in favor of the desired isomer 12. Rather, the
only role it served was to enable the chromatographic
separation of the enantiomers 12 and 13. Therefore, we
turned our attention to a simpler strategy: using a racemic
precursor for the cycloaddition in anticipation that the final
octahydro-pyrrolo[2,3-c]pyridine 1 could be obtained by a
simple resolution of the corresponding racemate. Aziridine
amide 16 (Scheme 3) was prepared in good yield using a
similar approach to the preparation of 11. Cycloaddition of
Reduction of optically pure 12 with DIBAL, followed by
quenching with EtOAc and sat. aqueous NaHCO3 solution
furnished 14 as an oil in quantitative yield. This quench
procedure generates a granular aluminum salt that is easily
separated from the product by filtration. Oily 14 was purified
by silica gel chromatography to remove any residual metal
that could poison the subsequent catalytic hydrogenation
reaction. This resulted in an 84% recovery of 14 which
solidified upon standing. Removing the chiral appendage by
Figure 1.
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Scheme 3
16 in DW-therm at 240 °C furnished cis-bicyclic amide 17
in 80% yield as a racemic mixture. Reduction of 17 with
lithium aluminum hydride, and subsequent removal of the
benzyl group by hydrogenation provided the racemic oc-
tahydro-pyrrolo[2,3-c]pyridine 19 in 64% yield over two
steps. Resolution of 19 using (+)-dibenzoyl-D-tartaric acid
afforded the tartrate salt 20 with 99% ee in 92% of the
theoretical yield. Treating the tartrate salt with aqueous
NaOH solution afforded 1 in 97% yield and 99% ee.
In conclusion, we have developed a simple and efficient
(90% yield) protocol for the intramolecular [2+3] cycload-
dition of azomethine ylides using commercially available
DW-therm as a solvent and requiring no special equipment.
This methodology was employed successfully for manufac-
turing large quantities of enantiomerically pure octahydro-
pyrrolo[2,3-c]pyridine, 1, an important intermediate in the
preparation of IAP inhibitors.2
organic phases containing 7 were combined and evaporated
under vacuum. The remaining concentrate was distilled under
high vacuum to remove excess phenethylamine until its
content in the pot residue was 1% or less. The remaining
oil, compound 7, was used as is. 1H NMR (500 MHz, CDCl3)
δ 7.20-7.35 (m, 5H), 5.79 (m, 1H) 5.00-5.10 (m, 2H), 2.92
(m, 2H), 2.84 (t, J ) 6.8 Hz, 2H), 2.73 (t, J ) 6.8 Hz, 2H),
2.27 (m, 2H).
1-((R)-1-Naphthalen-1-yl-ethyl)aziridine-2-carboxylic
acid methyl ester (10). Into a 22-L, four-necked flask
equipped with a mechanical stirrer, a thermometer, and an
addition funnel were charged (R)-(+)-1-(1-naphthyl)ethyl-
amine 9 (823 g, 4.8 mol) and acetonitrile (12.5 L) under a
nitrogen atmosphere. To this solution were added potassium
carbonate (1.33 kg, 9.6 mol) and 2,3-dibromopropionate 8
(1.42 kg, 5.8 mol). The mixture was heated to 60 °C and
stirred for an additional 2 h. The mixture was cooled to rt
and stirred for another 16 h. Any solid was removed by
filtration. The filtrate was concentrated under vacuum to
obtain an oily residue. The oil was dissolved into tert-butyl
methyl ether (2 L) and hexane (1 L), filtered through a pad
of Celite, and concentrated under vacuum to yield a brown
oil (1.52 kg). The oil was purified by chromatography (silica
gel; ethyl acetate/heptane, 35:65) to obtain product 10 as an
oil (1.18 kg, 96% yield): 1H NMR (500 MHz, CDCl3) δ
7.75-8.05 (m, 4H), 7.50 (m, 3H), 3.84 (s, 1.2H), 3.72 (s,
1.8H), 3.35 (m, 1H), 2.50 (s, 0.6H), 2.37 (m, 0.4H), 2.25 (s,
0.4H), 2.10 (m, 0.6H), 1.95 (d, J ) 6.4 Hz, 0.6H), 1.60-
1.70 (m, 3.4H).
Experimental Section
General. Melting points were determined on a Thomas-
Hoover melting point apparatus and are uncorrected. NMR
spectra were recorded on a Bruker AVANCE DPX-500
spectrometer (1H NMR at 500 MHz). Reactions were carried
out under an atmosphere of nitrogen.
But-3-enyl-phenethylamine (7). Into a 12-L, four-necked
flask equipped with a mechanical stirrer, a thermometer and
an addition funnel were charged phenethylamine 6 (2 kg,
16.7 mol), potassium carbonate (766 g, 5.6 mol, 325 mesh),
and acetonitrile (8 L) under a nitrogen atmosphere. 4-Bromo-
1-butene 5 (576 g, 5 mol) was added slowly at 20-25 °C
over a period of 30 min. After the addition, the mixture was
heated to 50 °C and stirred for an additional 3 h. The mixture
was cooled to rt and stirred for an additional 12 h. The stirrer
was stopped, and any solid was allowed to settle. The
supernatant (organic solution) was separated from the solid
by siphoning. The remaining solid was filtered through a
pad of Celite, which was rinsed with acetonitrile (1 L). The
1-((R)-1-Naphthalen-1-yl-ethyl)aziridine-2-carboxylic
acid but-3-enyl-((3Z,5Z)-3-vinylhepta-3,5-dienyl)-amide
(11). Into a 22-L, four-necked flask equipped with a
mechanical stirrer, a thermometer, and an addition funnel
were charged aziridine 10 (1.11 kg, 4.35 mol) and THF (11
L) under a nitrogen atmosphere. To the solution was added
potassium trimethylsilanolate (558 g, 4.35 mol) over a period
of 20 min. After the addition, the mixture was stirred at rt
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for an additional 16 h. The mixture was concentrated under
vacuum at 30 °C to give an oily residue. The oil was
dissolved in dichloromethane (11 L) and cooled to 0 °C.
Pivaloyl chloride (551 g, 4.6 mol) was added slowly, and
the mixture was warmed to rt, and stirred for an additional
1 h. The mixture was cooled to 0-5 °C, and amine 7 (800
g, 4.57 mol) was added. The mixture was warmed to rt and
stirred for an additional 16 h. An aqueous solution of 1 N
NaOH (5 L) was added. The organic layer was separated,
dried over MgSO4, and concentrated under vacuum at 30
°C to obtain aziridine amide 11 as an oil (1.97 kg), which
was used for the next step without further purification.
(3aS,7aS)-1-((R)-1-Naphthalen-1-yl-ethyl)-6-phenethyl-
octahydropyrrolo[2,3-c]pyridin-7-one (12). Into a 2-L,
four-necked flask equipped with a mechanical stirrer, a
thermometer, and an addition funnel was charged DW-therm
(900 g, a mixture of triethoxyalkylsilane, purchased from
Huber Corporation8) under a nitrogen atmosphere. The
solvent was heated to 240 °C. A solution of aziridine amide
11 (443 g, 1.1 mol) in DW-therm (400 g) was added over a
period of 45 min, maintaining the batch temperature at 240
°C. After the addition, the mixture was stirred for an
additional 20 min. The mixture was cooled to rt and allowed
to settle into a two-phase solution. The thick bottom layer
was separated and purified by chromatography (silica gel;
EtOAc/heptane/diethylamine, 40:60:1) to isolate the first crop
of product 12 as a solid. This operation was repeated four
more times (3 × 443 g and 1 × 200 g). The combined upper
layers were concentrated under vacuum at 60-70 °C/0.5
mmHg until only a small amount of DW-therm was present.
The residual oil was purified by chromatography (silica gel;
EtOAc/heptane/diethylamine, 40:60:1) to isolate the second
crop of product 12. Both crops of 12 were combined and
recrystallized from a mixture of tert-butyl methyl ether and
heptane to afford bicyclic amide 12 as a solid (529 g, 61%
keeping the batch temperature at 20-35 °C. After the
addition, the batch was stirred at rt for an additional 1 h.
Any white solid was removed by filtration and rinsed with
EtOAc. The combined filtrate was washed with 15% aqueous
solution of NaCl and concentrated under vacuum at 35 °C
to yield an oil (44.3 g). The oil was purified by chromatog-
raphy (silica gel; EtOAc/heptane/diethylamine, 80:20:1) to
obtain product 14 as an oil (36.5 g, 95% yield): 1H NMR
(500 MHz, CDCl3) δ 8.62 (s, 1H), 7.85 (d, J ) 8.8 Hz, 1H),
7.75 (d, J ) 7.9 Hz, 1H), 7.62 (s, 1H), 7.32-7.52 (m, 3H),
7.10-7.32 (m, 5H), 4.56 (m, 1H), 3.15 (s, 1H), 2.48-2.85
(m, 8H), 2.25 (m, 3H), 1.65-1.90 (m, 4H), 1.55 (d, J ) 6.1
Hz, 3H).
1-Benzyl-aziridine-2-carboxylic acid methyl ester (15).
To a cool solution of benzyl amine (38.37 g, 360 mmol) in
methanol (250 mL) at 5-6 °C was slowly added a solution
of 2,3-dibromopropionate (25.27 g, 103 mmol) in methanol
(75 mL). The reaction mixture was warmed to 20-25 °C
and maintained at this temperature for 18 h. The reaction
mixture was concentrated; TBME (500 mL) and water (500
mL) were added. The organic layer with washed water, dried
over MgSO4, and concentrated to give yellow oil. The crude
was further purified with column chromatography on silica
gel (EtOAc/hexanes, 1:1) to give 15.43 g of 15 in 78% yield.
1H NMR (500 MHz, CDCl3) δ 7.28-7.36 (m, 5H), 3.73 (s,
3H), 3.55 (s, 2H), 2.28 (dd, J ) 1.9, 3.8 Hz, 1H), 2.23 (d,
J ) 1.9 Hz, 1H), 1.78 (d, J ) 3.8 Hz). MS (M + H+) 192.
1-Benzyl-aziridine-2-carboxylic acid but-3-enyl-phen-
ethyl-amide (16). To a solution of 15 (9.51 g, 49.75 mmol)
in THF (200 mL) was added KOTMS (6.38 g, 49.75 mmol).
The mixture was stirred overnight at room temperature. The
mixture was concentrated and the residue dissolved in
dichloromethane (200 mL) and cooled to 0 °C. Trimethyl-
acetyl chloride (5.94 g, 49.25 mmol) was added slowly, and
the mixture was warmed to room temperature over 2 h. The
mixture was cooled to -78 °C, and but-3-enyl-phenethyl-
amine (7, 8.63 g, 49.24 mmol) was added and stirred at -78
°C for 1.5 h. Saturated sodium bicarbonate (100 mL) was
added. The mixture was extracted with EtOAc (4 × 100 mL).
The organic extracts were combined, dried, and concentrated
under vacuum. The residue was purified by flash chroma-
tography (silica gel; hexane/EtOAc, 1:8) to provide 12.5 g
(76%) of the title compound 16. 1H NMR (500 MHz, CDCl3)
δ 6.92-7.24 (m, 10H), 5.6 (dd, J ) 4.2, 7.9 Hz, 1H), 4.83-
4.9 (m, 2H), 3.55 (s, 2H), 3.1 (t, J ) 4.2 Hz, 2H), 3H), 2.7
(t, J ) 4.2 Hz, 2H), 2.5 (t, J ) 3.8 Hz, 2H), 2.4 (t, J ) 3.8
Hz, 2H), 2.3 (dd, J ) 1.9, 3.9 Hz, 1H), 2.2 (d, J ) 1.9 Hz,
1H), 1.78 (d, J ) 3.9 Hz, 1H); MS (M + H+) 355.
1
yield from 10): mp 103-106 °C. H NMR (500 MHz,
CDCl3) δ 8.36 (m, 1H), 7.80 (m, 1H), 7.72 (d, J ) 8.2 Hz,
1H), 7.47 (d, J ) 7.3 Hz, 1H), 7.40 (m, 3H), 7.28 (m, 4H),
7.20 (m, 1H), 5.36 (q, J ) 6.7 Hz, 1H), 3.76 (m, 1H), 3.65
(m, 1H), 3.51 (d, J ) 8.2 Hz, 1H), 3.35 (m, 1H), 2.92-3.05
(m, 3H), 2.45-2.55 (m, 2H), 2.22 (m, 1H), 1.65-1.80 (m,
2H), 1.57 (d, J ) 6.7 Hz, 3H), 1.53 (m, 1H), 1.27 (m, 1H).
13C NMR (125 MHz, CDCl3) δ 170.0, 140.3, 139.7, 134.4,
132.9, 129.3, 129.0, 128.6, 128.7, 126.8, 125.7, 125.65,
125.61, 125.27, 124.0, 61.9, 52.1, 50.3, 45.6, 4.6, 36.7, 34.6,
29.6, 28.9, 9.5.
(3aR,7aS)-1-(R)-1-Naphthalen-1-ylethyl)-6-phenethyl-
octahydropyrrolo[2,3-c]pyridine (14). Into a 3-L, four-
necked flask equipped with a mechanical stirrer, a thermom-
eter, and an addition funnel were charged bicyclic amide 12
(40 g, 0.1 mol) and toluene (600 mL) under a nitrogen
atmosphere. The solution was cooled to -70 °C, and a
solution of 1.5 M DIBAL in toluene (200 mL, 0.3 mol) was
added slowly, maintaining the batch temperature at -70 °C.
The mixture was warmed to rt over a period of 45 min and
stirred for an additional 2 h. Ethyl acetate (200 mL) was
added, maintaining the batch temperature at 20-25 °C. A
saturated aqueous solution of NaHCO3 (100 mL) was added,
(3aS,7aS)-6-Phenethyloctahydropyrrolo[2,3-c]pyri-
dine (1). A 2.5-L Parr bottle was charged with 20% Pd-
(OH)2 on carbon (11.2 g, 50% wet) under nitrogen atmo-
sphere. A solution of compound 14 (56 g, 0.15 mol) in
methanol (1 L) was added. The mixture was hydrogenated
at 50 psi for 16 h until all 14 was consumed. The mixture
was filtered through a pad of Celite under a nitrogen
atmosphere, and then the filtrate was concentrated under
vacuum at 35 °C to give an oil. The oil containing 1 was
dissolved in ethyl acetate. A solution of 6 N HCl in isopropyl
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alcohol (27 mL) was diluted with EtOAc (60 mL) and added
to the solution containing 1 over a period of 40 min at 18-
27 °C. After the addition, the mixture was cooled to 0 °C
and stirred for an additional 1 h. Any solid was collected by
filtration to obtain 1 as a white hydrochloride salt (33 g,
82% yield): mp 172-178 °C. 1H NMR (500 MHz, CDCl3)
δ 7.12-7.32 (m, 5H), 3.50 (s, 1H), 3.15-3.35 (m, 2H),
2.45-2.95 (m, 8H), 2.20 (s, 2H), 1.95 (m, 1H), 1.70 (m,
2H), 1.45 (s, 1H). By treating the hydrochloride salt with
organic layers were combined and dried with MgSO4. The
solvent was removed under vacuum to afford 18 as a clear
amber oil (8.79 g, 92%): 1H NMR (500 MHz, CDCl3) δ
7.37-7.15 (m, 10H), 3.87 (d, J ) 13.4 Hz, 1H), 3.59 (d, J
) 13.4 Hz, 1H), 3.01 (m, 1H), 2.77 (m, 3H), 2.67-2.45 (m,
5H), 2.44-2.35 (m, 2H), 2.15 (m, 1H), 1.80 (m, 1H), 1.72
(dd. J ) 11.9 Hz and 6.4 Hz, 2H), 1.58 (m, 1H); MS (M +
H+) 321.
6-Phenethyloctahydropyrrolo[2,3-c]pyridine (19). Com-
pound 18 (8.65 g, 27 mmol) was dissolved in methanol (250
mL) and stirred with 10% palladium-on-carbon catalyst (1.1
g, 50% wet) under H2 (60 psi) at rt for 16 h. The reaction
mixture was filtered, and the solvent was removed under
aqueous 1 N NaOH solution, the free base of 1 was obtained
1
as an oil: [R]25 -11.5 (c ) 1, CH3CN); H NMR (500
Na
MHz, CDCl3) δ 7.15-7.35 (m, 5H), 3.05 (m, 1H), 2.96 (qAB
,
J ) 8.2 and 4.0 Hz, 1H), 2.87 (m, 2H), 2.70 (m, 2H), 2.60
(m, 1H), 2.49 (m, 2H), 2.40 (bs, 1H), 2.30 (dd, J ) 11.6
and 3.7 Hz, 1H), 2.02 (td, J ) 11.0, 3.0 Hz, 1H), 1.88 (m,
1H), 1.77 (m, 1H), 1.52 (m, 2H), 1.36 (m, 1H). 13C NMR
(125 Hz, CDCl3) δ 141.0, 129.1, 128.7, 126.3, 60.9, 58.6,
55.0, 53.0, 44.9, 36.6, 34.1, 31.9, 27.8.
1-Benzyl-6-phenethyloctahydropyrrolo[2,3-c]pyridine-
7-one (17). A solution of 16 (10.7 g, 32 mmol) in DW-
therm (8 mL) was added in 15 min to a flask containing
DW-therm (10 mL) at 240 °C. The mixture was stirred for
an additional 30 min. DW-therm was distilled off under
vacuum, and the residue was purified by flash chromatog-
raphy on silica gel (EtOAc/hexanes) to give racemic 17 as
an oil (7.5 g, 70% yield): 1H NMR (500 MHz, CDCl3) δ
7.43-7.17 (m, 10H), 4.45 (d, J ) 13.4 Hz, 1H), 3.76 (m,
1H), 3.62-3.36 (m, 3H), 3.00 (m, 2H), 2.89 (m, 3H), 2,49
(m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 1.74 (m, 1H), 1.51
(m, 2H); MS (M + H+) 335.
1-Benzyl-6-phenethyloctahydropyrrolo[2,3-c]pyri-
dine (18). A solution of lithium aluminum hydride (30 mmol,
1 M in THF) was slowly added to a solution of 17 (9.94 g,
30 mmol) in THF (220 mL). The mixture was warmed to
60 °C and stirred for 3 h. Water (1.1 g), 15% aqueous
solution of NaOH (1.1 mL), and water (3.4 mL) were added
in sequence while stirring continued. The resulting suspen-
sion was stirred for an additional 20 min. Any solid was
removed by filtration through a Celite bed. The filtrate was
washed with water and brine. The aqueous layers were
combined and extracted with tert-butyl methyl ether, and the
1
vacuum to obtain 19 as a yellow oil (6.28 g, 84%): H NMR
(500 MHz, CDCl3) δ 7.27 (t, J ) 7 Hz, 2H), 7.18 (m, 3H),
3.11 (m, 1H), 3.02 (dd, J ) 6.4 Hz and 3.7 Hz, 1H), 2.93
(m, 2H), 2.76 (m, 2H), 2.67 (m, 1H), 2.55 (m, 2H), 2.36
(dd, J ) 11.9 Hz and 3.7 Hz, 2H), 2.08 (td, J ) 11.0 Hz
and 2.8 Hz, 1H), 1.94 (m, 1H), 1.83 (m, 1H), 1.57 (m, 2H),
1.43 (m,1H); MS (M + H+) 231.
(3aS,7aS)-6-Phenethyloctahydropyrrolo[2,3-c]pyri-
dine (1). Compound 19 (16.1 g, 70 mol) was dissolved in a
solution of 2-propanol (85 mL) and anhydrous ethanol (127
mL). A solution of (+)-dibenzoyl-D-tartaric acid (25.1 g) in
ethanol (84 mL) was added slowly, followed by toluene (425
mL). The mixture was stirred at rt for 16 h. Any solid was
collected by filtration, rinsed with a solution of 2-propanol/
ethanol/toluene (1:2.5:5, 30 mL), and dried under vacuum
(50 °C) to furnish the tartrate salt of 20 (19.0 g): HPLC >
99%; [R]25Na +69.4 (c ) 1, CH3CN/H2O ) 1:1). The tartrate
salt was stirred in a mixture of aqueous 1 N NaOH solution
and tert-butyl methyl ether. The organic layer was separated,
washed with water, dried with MgSO4, filtered, and con-
centrated under vacuum to afford 1 (7.23 g, 90% theory) as
1
an oil: specific rotation, H- and 13C NMR spectra were
consistent with those of the authentic sample.
Received for review March 28, 2007.
OP700073G
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