Additives promote noyori-type reductions of a β-keto-γ-lactam: Asymmetric syntheses of serotonin norepinephrine reuptake inhibitors

Article abstract of DOI:10.1021/jo400589j

Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on β-keto-γ-lactam 8 to afford β-hydroxy-γ-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(l)-tartaric acid diastereomeric salt 16 enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9, it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was reducing faster to 9 than the equilibration of the stereocenter of 8.

Full text of DOI:10.1021/jo400589j

Note
pubs.acs.org/joc
Additives Promote Noyori-type Reductions of a β‑Keto-γ-lactam:
Asymmetric Syntheses of Serotonin Norepinephrine Reuptake
Inhibitors§
Nicholas A. Magnus,*,† Bret A. Astleford,† Dana L. T. Laird,‡ Todd D. Maloney,† Adam D. McFarland,†
John R. Rizzo,† J. Craig Ruble,‡ Gregory A. Stephenson,† and James P. Wepsiec†
†Eli Lilly and Company, Small Molecule Design and Development Division, Indianapolis, Indiana 46285, United States
‡Eli Lilly and Company, Discovery Chemistry Research and Technology Division, Indianapolis, Indiana 46285, United States
S
* Supporting Information
ABSTRACT: Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a
dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on β-keto-γ-lactam 8 to afford β-hydroxy-γ-
lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(L)-tartaric acid diastereomeric salt 16
enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9,
it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-
hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was
reducing faster to 9 than the equilibration of the stereocenter of 8.
were separated by chromatography. Finally, the required ether
erotonin and norepinephrine have been implicated as
Smodulators of endogenous analgesic mechanisms in linkages in 1 and 2 were made via SNAr chemistry and the
resulting molecules deprotected (Scheme 1).3 Although this
descending pain pathways and serotonin norepinephrine
route facilitated SAR studies and led to rapid synthesis of lead
derivatives, it had several drawbacks for multigram-scale
preparations of 1 and 2. Further, since only one of the 4
possible stereoisomers of 1 and 2 was desirable for potential
clinical evaluations, the development of stereoselective
syntheses was attractive.
Our stereoselective routes to prepare 1 and 2, illustrated in
Schemes 2 and 4, are based on the precedent chemistry of
Takasago International Corporation where the two stereo-
centers are derived from a dynamic kinetic resolution (DKR)
accompanied by enantio- and diastereoselective hydrogenation
of a β-keto-γ-lactam.5 Preparations of β-keto-γ-lactams via
Claisen condensation are typically run under cryogenic
conditions (−78 °C) by adding the γ-lactam to the base to
mitigate self-condensation.6 To avoid cryogenic conditions and
take advantage of the insolubility of intermediate enolate 7, we
chose to combine N-benzyl-γ-lactam 5 with ethyl isovalerate 6
in 2-MeTHF and add the mixture to LDA at −10 to 5 °C
(Scheme 2). This caused enolate 7 to precipitate, and heptane
was added to further induce the precipitation. The precipitate
reuptake inhibitors (SNRIs) have shown efficacy in the
treatment of chronic painful conditions such as diabetic
peripheral neuropathic pain and fibromyalgia.1 Therefore, the
pyrrolidine ether SNRIs 12 and 2,3 illustrated in Figure 1, have
been studied at Lilly for the potential treatment of pain.
The original routes used at Lilly to prepare compounds 1 and
2 started with (S)-N-tert-butoxycarbonylpyrrolidine-3-carbox-
ylic acid 3, which had been prepared in 5 steps featuring a 1,3-
dipolar cyclo-addition, manipulation of protection groups, and
an enzyme resolution.4 The acid 3 was converted via a 3-step
sequence to the diastereomers of secondary alcohol 4 which
Figure 1. Structures of serotonin norepinephrine reuptake inhibitors 1
and 2.
Received: March 27, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400589j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Original Route to 1 and 2
Scheme 2. Diastereoselective Synthesis of 1
was filtered off to afford a purification, but enolate 7 was not
stable enough for long-term storage, so it was subjected to an
acidic workup to give a 79% yield of β-keto-γ-lactam 8 as an oil.
Diastereoselective hydrogenation of β-keto-γ-lactam 8 in the
which are ( )-15 (Scheme 3). The aldol chemistry depicted in
Scheme 3 between N-benzyl-γ-lactam 5 and 3-methylbutanal
Scheme 3. Synthesis of Diastereomer Reference Standards
7
presence of (PPh3)3RuCl2 required an absorbent (Siliabond
triaminetetraacetate sodium salt (TAAcONa))8 treatment to
remove green color caused by residual rhodium affording a 77%
yield of ( )-9 as a solid. Vitride (sodium bis(2-methoxyethoxy)
aluminum hydride) reduction of ( )-9 in toluene afforded
( )-10 as a crude oil, which was taken directly into a
hydrogenation with Pd(OH)2 on carbon in EtOH to remove
the benzyl protection group giving ( )-11 also as a crude oil.5
The alcohol ( )-11 was dissolved in NMP and reacted with
1,3-dichloro-4-fluorobenzene 12 and tBuOK to induce an SNAr
reaction and provide ( )-1 as an oil, that was purified by
selective extraction into aqueous D,L-tartaric acid, in 81% overall
yield from ( )-9.2 The ( )-1 was resolved by forming the
diastereomer salt 13 with di-p-toluoyl-L-tartaric acid in a
mixture of EtOAc/EtOH in an initial yield of 34% with 92% ee,
and a recrystallization from the same solvent system gave an
85% recovery with >98% ee. The absolute S,S-stereochemical
configuration of 1 was confirmed by single crystal X-ray analysis
of 13 (see Supporting Information, SI).
gave a stereochemical mixture of β-hydroxy-γ-lactams ( )-9
and ( )-14. Fractional crystallization from MTBE/heptanes at
23 °C afforded isolation of ( )-9, cooling of the resulting
liquors to 0 °C gave a crop of crystals containing a mixture of
( )-9 and ( )-14, and finally cooling the liquors to −15 °C
gave crystals of ( )-14. Vitride reduction of ( )-14 afforded
( )-15.
In order to evaluate the enantio- and diastereoselectivity of
the DKR-hydogenation of β-keto-γ-lactam 8 and the stereo-
chemical “upgrade” of pyrrolidine 10 via crystallization of a
diastereomeric salt, we first needed to prepare these reference
standards: the diastereomers of β-hydroxy-γ-lactams ( )-9
which are ( )-14, and the diastereomers of pyrrolidines ( )-10
B
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The Journal of Organic Chemistry
Note
Table 1. DKR-hydrogenation Screen of Silica Gel Purified 8 to Selectively Produce 9
a
b
c
d
d
e
e
e
entry
catalyst
S/C
LiCl
HCl
solvent
8
%ee
9.8
%de
1
Ru(OAc)2[(S)-BINAP]
260
260
280
280
295
295
280
280
280
280
280
280
280
280
280
280
280
0
0
0
0
0
0
0
0
0
0
0
6
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
EtOH
IPA
67.3
0
50.5
81.4
29.9
88.1
69.5
90.7
8.8
2
Ru(OAc)2[(S)-BINAP]
89.4
14.2
93.4
4.5
3
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-xyl-BINAP]
Ru(OAc)2[(S)-xyl-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
Ru(OAc)2[(S)-tol-BINAP]
0
80.0
0
4
6
5
0
73.8
0
6
6
87.0
19.8
94.8
31.1
98.2
96.7
96.3
96.3
96.3
23.8
98.4
96.1
7
0
81.2
0
8
6
93.1
17.0
93.6
94.7
93.9
95.3
93.6
74.4
98.4
96.3
9
0
86.5
42.2
35.1
33.3
0
10
11
12
13
14
15
16
17
18
19
6
IPA
0.01
0.1
1
6
IPA
6
IPA
6
IPA
10
6
IPA
24.3
88.0
73.1
2.5
1
1
1
1
1
0
IPA
2
IPA
10
6
IPA
f
g
g
470
IPA
95.1
98.0
NA
NA
NA
NA
f
g
g
1400
6
IPA
a
b
Screening reactions run with 8 (400 mg), catalyst load (5 mg), and solvent (5 mL) at 65 °C under 70−85 psi of H2 for 16.0 h. Diacetato[(S)-
(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium(II) (Ru(OAc)2[(S)-BINAP)]), diacetato[(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-
binaphthyl]ruthenium(II) (Ru(OAc)2[(S)-tol-BINAP)]), diacetato[(S)-(−)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl]ruthenium(II) (Ru-
(OAc)2[(S)-xyl-BINAP)]). Substrate to catalyst mole ratio. Mole percent relative to 8. Unreacted 8, enantio- and diastereoselectivities
c
d
e
f
g
determined by chiral HPLC (see SI). Entry 18 catalyst load (3 mg) and entry 19 catalyst load (1 mg). Not applicable (too small to accurately
measure).
Our initial hydrogenation reactions to convert β-keto-γ-
lactam 8 into β-hydroxy-γ-lactam 9 indicated that the catalyst
diacetato[(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-
binaphthyl]ruthenium(II) (Ru(OAc)2[(S)-tol-BINAP)])9 at a
substrate to catalyst ratio (S/C) of 280 reliably gave high
stereochemical selectivity (>95% ee and >94% de) and
complete conversion of 8 to 9 at 65 °C under 70−85 psi of
H2 in IPA in the presence of about 6 mol % HCl.10 In order to
study the DKR-hydrogenation reaction in more detail via
online NMR and chiral HPLC, we further purified the β-keto-γ-
lactam 8 by silica gel column chromatography.11 Unfortunately,
after the silica gel purification β-keto-γ-lactam 8 would no
longer completely convert to β-hydroxy-γ-lactam 9 (Table 1,
entry 10). Perplexed by this development, we wondered if
residual lithium from the preparation of 8 was playing a role in
the catalysis since lithium has been shown to enhance the
reactivity of ruthenium-BINAP catalytic systems.12 Prior to
chromatography 8 was found to be contaminated with very low
levels of lithium ((0.11 μg/g) (lithium was below our ICP
detection limit of 0.02 μg/g after chromatography)), so it
seemed doubtful that lithium was the sole culprit in crude 8 for
enhanced catalysis. However, in an attempt to more completely
convert silica gel purified 8 into 9 LiCl12a was added to the
DKR-hydrogenation reactions and improved conversions were
observed (Table 1, entries 11−14).
70−85 psi of H2. These experiments investigate the effects of
(1) varying the methyl substitution on the aryl groups on the
phosphorus atom of the BINAP catalysts, (2) MeOH, EtOH,
and IPA solvent systems, and (3) the additives LiCl and HCl.
Hydrogenations to convert 8 to 9 with Ru(OAc)2[(S)-
BINAP)], Ru(OAc)2[(S)-tol-BINAP)], and Ru(OAc)2[(S)-xyl-
BINAP)] in MeOH were examined with and without catalytic
HCl (Table 1, entries 1−6). These experiments indicated that
the Ru(OAc)2[(S)-tol-BINAP)] catalyst gives the highest ee
(80.7%) and de (90.7%) and that adding 6 mol % HCl
promotes complete conversions of 8 to 9. The Ru(OAc)2[(S)-
tol-BINAP)] catalyst was also screened in EtOH and IPA with
and without catalytic HCl (entries 7−10), which indicated that
IPA gives higher ee and de (96.4 and 94.9) than EtOH (94.8
and 93.1) and again that HCl is required for high conversions.
However, while the conversion of 8 to 9 was 100% in EtOH
with 6 mol % HCl (entry 8), it was only 57.8% in IPA with 6
mol % HCl (entry 10). Next, the Ru(OAc)2[(S)-tol-BINAP)]
catalyst was screened in IPA with 6 mol % HCl adding LiCl at
0.01, 0.1, 1, and 10 mol % levels (entries 11−14). Adding 0.01
and 0.1 mol % of LiCl gave small increases in conversion. While
adding 1.0 mol % of LiCl gave complete conversion, and 10
mol % LiCl resulted in incomplete conversion of 8 to 9
(75.7%). Again with the Ru(OAc)2[(S)-tol-BINAP)] catalyst in
IPA, the LiCl amount was set at 1.0 mol %, and now the added
HCl was varied at 0, 2, and 10 mol % (entries 15−17). At 0−2
mol % HCl the conversion of 8 to 9 was only 12−26.9%, and
Table 1 is a list of DKR-hydrogenation experiments that start
with silica gel purified β-keto-γ-lactam 8 run at 65 °C under
C
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The Journal of Organic Chemistry
Note
Scheme 4. DKR-hydrogenation-based Synthesis of 2
with 10 mol % HCl the conversion was 97.5%. In the IPA
system with 1 mol % LiCl and 6 mol % HCl, the
Ru(OAc)2[(S)-tol-BINAP)] substrate to catalyst ratio (S/C)
was varied from the apparently optimal 280 (entry 13; 100%
conversion; 96.3% ee and 95.3% de) to 470 and 1400 (entries
18−19) giving only 4.9 to 2% conversion of 8 to 9, respectively.
When DKR-hydrogenation reactions to convert 8 to 9 were
incomplete, the ratio of the enantiomers of 8 was 1:1, racemic
by chiral HPLC, and we wondered if this was the case during
the course of the reaction (i.e., were the enantiomers of 8
nonracemic during the DKR-hydrogenation). With access to a
hydrogenation reactor with a flow loop to a NMR probe and a
HPLC system, we became interested in observing the rate and
equilibrium of the DKR-hydrogenation online by NMR and
chiral HPLC. Due to the high viscosity of IPA relative to
MeOH, and the need to pump the reaction effectively through
these systems, the aforementioned studies were conducted with
MeOH as the reaction solvent. The 1HNMR experiment
starting with 8, catalytic Ru(OAc)2[(S)-BINAP)] (S/C of 170),
and HCl (3 mol %) at 65 °C under 70 psi of H2 in MeOH gave
complete conversion to 9 and 14 in about 30 min (see SI). It
took about 30 min to cycle a sample from the reactor to the
chiral HPLC for complete analysis. Therefore, a replicate
reaction was run at 40 °C to slow the reaction down for HPLC
analyses. It was observed that the racemic starting material (8)
had enriched to a ratio of about 2:1 (36% ee) after 6 cycles (3.0
h), indicating that one of the enantiomers of 8 was reducing
faster to 9 and 14 than the equilibration of the stereocenter of 8
(see SI).
To synthesize pyrrolidinyl ether 2, β-keto-γ-lactam 8 was
converted to β-hydroxy-γ-lactam 9 via hydrogenation in the
presence of catalytic Ru(OAc)2[(S)-tol-BINAP] in IPA
containing catalytic HCl (6 mol %) and LiCl (1 mol %) with
complete conversion (96% ee and 94% de; 93% yield) (Scheme
4).13 Reduction of 9 with Vitride in toluene gave pyrrolidine 10
as an oil which was purified via a crystalline diastereomeric salt
16 formed with dibenzoyl-(L)-tartaric acid (L-DBTA) in
MeOAc in 75% overall yield (100% ee and de). The salt 16
was freebased into MTBE with aqueous NaHCO3 in the
presence of TEA (necessary to improve solubility) to afford
purified 10 in 95% yield. Pyrrolidine 10 was reacted with
tBuOK and 6-chloro-3-fluoro-2-methylpyridine14 17 in DMF to
give the SNAr adduct 18 in 65% yield. Chloride 18 was treated
with KOMe in DMSO to install the methoxy moiety of 19 in
98% yield. Hydrogenation of 19 over Pd/C in EtOH gave a
94% yield of 2 (2 was prepared in 8 steps and 31% overall yield
starting from γ-lactam 5 (Scheme 2)).
CONCLUSION
■
Asymmetric syntheses of SNRIs 1 and 2 have been
demonstrated utilizing diastereoselective hydrogenation, and
enantio- and diastereoselective DKR-hydrogenation of β-keto-
γ-lactam 8. DKR-hydrogenation screening experiments starting
with 8 to produce β-hydroxy-γ-lactam 9 revealed that
Ru(OAc)2[(S)-tol-BINAP] gave greater stereoselectivity than
Ru(OAc)2[(S)-BINAP)] and Ru(OAc)2[(S)-xyl-BINAP)], and
that selectivity was better in IPA than EtOH or MeOH. In
addition, adding catalytic amounts of HCl and LiCl to the
DKR-hydrogenation reactions in IPA gave more complete
conversions of 8 to 9. Diastereoselective salt resolutions via
tartrates afforded separation of the diastereomers of pyrrolidinyl
ether 1 and upgraded the ee and de of intermediate pyrrolidine
10 toward the synthesis of 2. Finally, the required aromatic
rings of 1 and 2 were installed utilizing SNAr reactions.
EXPERIMENTAL SECTION
HRMS measurements were made with an ion trap mass analyzer. All
reactions were run under a nitrogen atmosphere unless otherwise
stated.
■
1-Benzyl-3-(3-methylbutanoyl)pyrrolidin-2-one (8). Diisopro-
pylamine (32.00 g; 316.2 mmol) was combined with 2-MeTHF (135
mL), cooled to −7 °C, and 2.5 M n-BuLi in hexanes (125.0 mL; 312.5
mmol) was added over 0.5 h. 1-Benzylpyrrolidin-2-one 5 (25.20 g;
143.8 mmol), ethyl 3-methylbutanoate 6 (22.50 g; 172.8 mmol), and
2-MeTHF (110 mL) were combined and added to the LDA/2-
MeTHF mixture over 0.5 h, while maintaining the reaction
temperature between −10 to 5 °C, to afford a yellow slurry. After
0.75 h, heptane (250 mL) was added to the mixture over 0.5 h at −5
to 5 °C. The slurry was filtered and the off-white solids (7) were rinsed
with 1:1 2-Me-THF/heptane (50 mL). The solids were suspended in
MTBE (250 mL), aqueous 10% citric acid (250 mL) added, and the
mixture stirred for 0.5 h to give two homogeneous phases (aq. phase
pH 4−5). MTBE (100 mL) was added and the organic phase was
separated, washed with water (2 × 100 mL), dried (MgSO4), and
concentrated to afford 8 as a yellow oil (29.8 g, 79%). Note: due to the
air instability of 7 only the 1H NMR spectrum was collected: 1H NMR
(400 MHz, DMSO-d6) δ 7.33−7.28 (m, 1H), 7.25−7.17 (m, 2H), 4.25
(s, 2H), 3.03 (dd, J = 8.7, 7.1 Hz, 2H), 2.56 (dd, J = 8.7, 7.1 Hz, 2H),
2.08−1.95 (m, 1H), 1.81 (d, J = 7.0 Hz, 2H), 0.87 (d, J = 6.7 Hz, 6H).
Spectra for 8: 1H NMR (400 MHz, DMSO-d6) δ 7.34 (m, 2H), 7.30−
7.24 (m, 1H), 7.22−7.16 (m, 2H), 4.41 (d, J = 14.9 Hz, 1H), 4.34 (d, J
= 14.9 Hz, 1H), 3.75 (dd, J = 9.3, 6.6 Hz, 1H), 3.21 (m, 2H), 2.72 (dd,
J = 17.4, 7.4 Hz, 1H), 2.52 (dd, J = 17.4, 7.4 Hz, 1H), 2.26 (m,1H),
2.12−1.94 (m, 2H), 0.89 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H).
D
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The Journal of Organic Chemistry
Note
13C NMR (100 MHz, DMSO-d6) δ 206.3, 170.2, 137.0, 129.0, 128.0,
128.0, 55.0, 51.3, 46.2, 45.2, 23.8, 22.9, 22.6, 20.1. A small amount of
the enol tautomer appears in the NMR spectra of 8 and the following
1.77 (m, 1H), 1.70−1.58 (m, 1H), 1.51 (m, 1H), 1.25 (ddd, J = 13.9,
9.7, 4.3 Hz, 1H), 1.02 (ddd, J = 13.6, 9.4, 2.9 Hz, 1H), 0.86 (d, J = 6.7
Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ
70.6, 50.2, 47.1, 46.6, 46.1, 28.5, 24.3, 24.3, 22.1. IR (film) 3293, 3237,
3145, 2952, 2914, 2863 cm−1. HRMS (ESI+) calcd for C9H20NO
158.1539, found 158.1539.
1
assignments were made: H NMR (500 MHz, DMSO-d6) δ 11.88 (s,
1H), 4.40 (s, 2H), 3.28 (dd, J = 7.5, 7.3 Hz, 2H), 2.59 (dd, J = 7.5,7.3
Hz, 2H), 0.91 (d, J = 6.4 Hz, 6H). 13C NMR (125 MHz, DMSO-d6) δ
19.5, 23.0, 25.6, 40.6, 44.3, 45.5, 100.4, 163.2, 172.5. IR (film) 2957,
2871, 1714, 1682 cm−1. HRMS (ESI+) calcd for C16H22NO2
260.1645, found 260.1647.
(S)-3-((S)-1-(2,4-Dichlorophenoxy)-3-methylbutyl)-
pyrrolidine ( )-1. Crude ( )-11 (from previous experiment)
(assumed 9.03 g; 57.4 mmol) was dissolved in NMP (45 mL) and
cooled to 0 °C. 1,3-Dichloro-4-fluorobenzene 12 (9.50 g; 57.6 mol)
(R)-1-Benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-
one (( )-9). Ketone 8 (24.65 g; 95.05 mmol), (PPh3)3RuCl2 (0.91 g;
0.94 mmol), and MeOH (250 mL) were combined under 350 psi of
H2 and heated to 50 °C for 24.0 h. The reaction was concentrated to
give green solids which were combined with CH3CN (250 mL) and
stirred at 22 °C to produce a thin green slurry. Siliabond
triaminetetraacetate sodium salt (TAAcONa) (23.3 g) was added
and the resulting mixture stirred at 22 °C for 16.0 h. The resulting
slurry was filtered through a plug of TAAcONa (26.0 g) capped with a
layer of Celite and the plug was rinsed with CH3CN (750 mL). The
resulting filtrate was concentrated to give a light yellow solid which
was triturated in MTBE (150 mL) at 22 °C for 2.25 h. Heptane (150
mL) was added to the slurry over 0.5 h and the resulting mixture
cooled to 0 °C and stirred for 1.0 h. The slurry was filtered, the solids
rinsed with cold (0 °C) 1:1 MTBE/heptane (25 mL), and dried to
afford ( )-9 as an off-white solid (19.2 g; 77%). Mp 113.2−114.6 °C.
1H NMR (400 MHz, DMSO-d6) δ 7.32 (m, 2H), 7.28−7.19 (m, 3H),
4.60 (d, J = 6.1 Hz, 1H), 4.43 (d, J = 15.0 Hz, 1H), 4.33 (d, J = 15.0
Hz, 1H), 4.06−3.95 (m, 1H), 3.20−3.07 (m, 2H), 2.36 (ddd, J = 10.1,
7.8, 2.6 Hz, 1H), 2.08−1.93 (m, 1H), 1.88 (m, 1H), 1.71 (m, 1H),
1.34 (ddd, J = 13.6, 9.4, 5.3 Hz, 1H), 1.16 (ddd, J = 13.4, 8.6, 4.5 Hz,
1H), 0.89 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H). 13C NMR (100
MHz, DMSO-d6) δ 174.7, 137.0, 128.4, 127.4, 127.0, 66.4, 47.3, 45.5,
44.8, 44.5, 24.0, 23.4, 22.0, 17.3. IR (solid) 3357, 2959, 2949, 2928,
2867, 1666 cm−1. HRMS (ESI+) calcd for C16H24NO2 262.1802,
found 262.1803.
(S)-1-((S)-1-Benzylpyrrolidin-3-yl)-3-methylbutan-1-ol
( )-10. Lactam ( )-9 (15.20 g; 58.16 mmol) was dissolved in toluene
(150 mL), cooled to 0 °C, and ≥65 wt % Vitride in toluene (37.22 g;
128.9 mmol) was combined with toluene (100 mL) and added over
0.5 h, giving a maximum temperature of 10 °C, and the resulting
mixture warmed to 22 °C. After 22.0 h, the reaction mixture was added
to a cold (0 °C) aqueous 10% Rochelle’s salt solution (150 mL) and
toluene (25 mL) added. The mixture was warmed to 22 °C and stirred
for 3.0 h (slight emulsion). Water (150 mL) was added to the mixture
and stirring continued for 0.75 h giving 2 phases. Aqueous 10%
Rochelle’s salt (50 mL) and toluene (50 mL) were added, the aqueous
phase was removed, and the organic phase washed with water (2 ×
150 mL). The organic phase was dried (MgSO4) and concentrated to
afford crude ( )-10 as an orange oil (100% yield assumed and
material taken directly into the next step). 1H NMR (400 MHz,
DMSO-d6) δ 7.33−7.19 (m, 5H), 4.38 (br, 1H), 3.54 (d, J = 13.0 Hz,
1H), 3.49 (d, J = 13.0 Hz, 1H), 3.29 (ddd, J = 9.5, 6.4, 2.7 Hz, 1H),
2.55 (m, 2H), 2.30 (m, 1H), 2.12−1.93 (m, 2H), 1.84−1.59 (m, 2H),
1.21 (ddd, J = 13.8, 9.8, 4.2 Hz, 1H), 0.98 (ddd, J = 13.8, 9.6, 2.8 Hz,
1H), 0.85 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H). 13C NMR (100
MHz, DMSO-d6) δ 139.4, 128.3, 128.0, 126.6, 70.4, 59.8, 56.8, 53.5,
45.0, 44.2, 26.2, 23.9, 21.6. IR (film) 3386, 2953, 2921, 2868, 2799
cm−1. HRMS (ESI+) calcd for C16H26NO 248.2009, found 248.2009.
(S)-3-Methyl-1-((S)-pyrrolidin-3-yl)butan-1-ol ( )-11. Crude
( )-10 (from previous experiment) (assumed 14.2 g; 57.4 mmol)
was dissolved in EtOH (150 mL) and 20% Pd(OH)2 on carbon 50%
water wet (2.15 g; 15.3 mmol) added. The mixture was subjected to 50
psi of H2 at 22 °C for 7 days to reach full conversion (H2 leakage
prolonged the reaction time). The reaction mixture was filtered
through glass fiber filter paper, rinsed through with EtOH (50 mL),
and concentrated to afford ( )-11 as a colorless oil. The oil was
dissolved in toluene (50 mL) and concentrated to remove residual
EtOH in preparation for the next step (100% yield assumed). 1H
NMR (400 MHz, DMSO-d6) δ 3.30 (ddd, J = 9.6, 6.5, 3.0 Hz, 1H),
2.80−2.60 (m, 3H), 2.39 (dd, J = 10.5, 7.3 Hz, 1H), 1.86 (m, 1H),
t
and solid BuOK (13.00 g; 115.9 mmol) were added to the reaction
mixture causing the temperature to rise briefly to 19 °C and return to
0 °C. After stirring for 2.0 h at 0 °C, the mixture was warmed to 22 °C
and held for 16.0 h. The mixture was combined with heptane (200
mL) and water (80 mL), and the organic phase separated and washed
with water (2 × 80 mL). The organic phase was combined with
aqueous 10% D,L-tartaric acid (150 mL) and the aqueous phase
separated. The aqueous phase was combined with MTBE (200 mL)
and 5 M NaOH (50 mL) and the organic phase separated, washed
with water (2 × 50 mL), dried (MgSO4), and concentrated to afford
( )-1 (14.20 g, 81% yield over 3 steps) as a light yellow oil. 1H NMR
(400 MHz, DMSO-d6) δ 7.51 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.9, 2.6
Hz, 1H), 7.23 (d, J = 9.0 Hz, 1H), 4.52 (ddd, J = 7.3, 5.8, 4.2 Hz, 1H),
2.84 (dd, J = 10.7, 7.9 Hz, 1H), 2.81−2.64 (m, 2H), 2.48 (dd, J = 10.7,
7.5, 1H), 2.29 (m, 1H), 1.79−1.46 (m, 4H), 1.45−1.33 (m, 1H), 0.87
(d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 153.2, 129.3, 128.0, 124.0, 123.2, 116.1, 79.5, 48.9, 46.5,
43.6, 41.8, 27.8, 24.2, 23.2, 22.3. IR (film) 2956, 2870, 1585, 1568
cm−1. HRMS (ESI+) calcd for C15H22NOCl2 302.1073, found
302.1076.
(S)-3-((S)-1-(2,4-Dichlorophenoxy)-3-methylbutyl)-
pyrrolidine Di-p-toluoyl-L-tartrate (13). Pyrrolidine ( )-1 (14.20
g; 46.98 mmol) was dissolved in EtOAc (42 mL) and EtOH (42 mL)
and di-p-toluoyl-L-tartaric acid (18.3 g; 47.4 mmol) was added to the
mixture. The mixture was warmed to 50 °C and EtOAc (240 mL)
containing seeds (5 mg of 13) was slowly added to the mixture. This
produced a hazy yellow mixture that was cooled to 30 °C and stirred
for 16.0 h to give a thick slurry. The slurry was cooled to 22 °C, stirred
for 4.0 h, and the solids filtered and washed with 20:3 EtOAc/EtOH
(25 mL). After drying the white solids (11.23 g), chiral HPLC analysis
indicated 92.8% ee. The solids were suspended in 20:3 EtOAc/EtOH
(110 mL) and the thick slurry warmed to 50 °C to give a thin slurry.
After 1.0 h, the slurry was cooled to 22 °C and stirred for 16.0 h. The
solids were filtered, rinsed with 20:3 EtOAc/EtOH (22 mL), and dried
25
to afford 13 (9.46 g; 29%) with 98.2% ee by chiral HPLC. [α]D
1
−80.0 (MeOH, c = 2.5). Mp 175.6−176.3 °C. H NMR (400 MHz,
DMSO-d6) δ 9.49 (bs, 3H), 7.83 (d, J = 8.2 Hz, 4H), 7.55 (d, J = 2.6
Hz, 1H), 7.32 (dd, J = 9.0, 2.6 Hz, 1H), 7.30 (d, J = 8.1 Hz, 4H), 7.25
(d, J = 9.0 Hz, 1H), 5.62 (s, 2H), 4.64 (dt, J = 7.0, 5.0 Hz, 1H), 3.26
(dd, J = 11.3, 8.1 Hz, 1H), 3.16 (ddd, J = 11.2, 8.4, 4.5 Hz, 1H), 3.05
(ddd, J = 11.2, 8.7, 7.5 Hz, 1H), 2.78 (dd, J = 11.4, 9.2 Hz, 1H), 2.49
(m, 1H), 2.36 (s, 6H), 1.89 (m, 1H), 1.75 (m, 1H), 1.64−1.43 (m,
2H), 1.32 (ddd, J = 13.9, 7.6, 4.8 Hz, 1H), 0.85 (d, J = 6.4 Hz, 3H),
0.80 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 168.5(2),
164.9(2), 152.7, 143.7(2), 129.5, 129.3(4), 129.2(4), 128.1, 127.0(2),
124.5, 123.3, 116.4, 77.2, 72.6(2), 45.6, 44.2, 41.7, 41.4, 25.3, 24.0,
22.9, 22.3, 21.2(2). IR (solid) 2956, 2870, 1717, 1669, 1611, 1586
cm−1. HRMS (ESI+) calcd for C15H22NOCl2 302.1073, found
302.1076.
(R)-1-Benzyl-3-((R)-1-hydroxy-3-methylbutyl)pyrrolidin-2-
one (( )-14). 1-Benzylpyrrolidin-2-one 5 (25.00 g, 142.7 mmol) was
combined with 2-MeTHF (200 mL) and the resulting solution cooled
to −78 °C. A 2.0 M solution of LDA in THF/heptane/ethylbenzene
(Aldrich) (80.00 mL; 160.0 mmol) was added to the reaction mixture
keeping the temperature between −60 to −75 °C. After 1.0 h, 3-
methylbutanal (12.50 g; 145.1 mmol) in 2-MeTHF (25 mL) was
added to the reaction mixture keeping the temperature between −60
to −75 °C. The mixture was warmed to 0 °C and aqueous 10% citric
acid (150 mL) was added. The organic phase was separated, washed
with water (2 × 150 mL), and concentrated to give a yellow solid. The
E
dx.doi.org/10.1021/jo400589j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
solids were added to MTBE (50 mL) at 23 °C to form a thin slurry
and heptane (200 mL) was slowly added. After 1.5 h, the solids were
filtered and dried to afford 16.00 g (42% yield) of the diastereomer
( )-9 as a white powder. The liquors were cooled to 0 °C and seeded
with ( )-9 to afford a further 4.80 g of ( )-9 contaminated with the
diastereomer ( )-14. The resulting liquor was cooled to −15 °C for
5.0 h to give white plate crystals which were filtered and dried to afford
5.46 g (14% yield) of the diastereomer ( )-14. Mp 57.3−58.5 °C. 1H
NMR (400 MHz, DMSO-d6) δ 7.38−7.19 (m, 5H), 4.81 (d, J = 4.1
Hz, 1H), 4.43 (d, J = 14.9 Hz, 1H), 4.30 (d, J = 14.9 Hz, 1H), 3.78 (m,
1H), 3.15 (t, J = 7.1 Hz, 2H), 2.58−2.50 (m, 1H), 2.08−1.93 (m, 1H),
1.86−1.66 (m, 2H), 1.44 (ddd, J = 14.0, 10.0, 4.4 Hz, 1H), 1.00 (ddd, J
= 12.9, 9.4, 2.9 Hz, 1H), 0.86 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.7 Hz,
3H). 13C NMR (100 MHz, DMSO-d6) δ 174.5, 136.8, 128.5(2),
127.7(2), 127.2, 69.4, 47.0, 45.5, 44.9, 42.1, 23.8, 23.8, 21.5, 20.3. IR
(solid) 3407, 2951, 2925, 2867. 1652, 1643, and 1431 cm−1. HRMS
(ESI+) calcd for C16H24NO2 262.1802, found 262.1803.
(R)-1-((S)-1-Benzylpyrrolidin-3-yl)-3-methylbutan-1-ol
(( )-15). Lactam ( )-14 (4.90 g; 18.8 mmol) and toluene (50 mL)
were combined, cooled to 0 °C, and ≥65 wt % Vitride (sodium bis(2-
methoxyethoxy)aluminum hydride or Red-Al) in toluene (12.41 g =
12.00 mL; 42.96 mmol) diluted with toluene (40 mL) was added over
0.25 h giving a maximum temperature of 10 °C. The mixture was
warmed to 22 °C and stirred for 22.0 h. The reaction was cooled to 0
°C and 20% aqueous Rochelle’s salt (50 mL) and toluene (15 mL)
were added. After 1.0 h, the organic phase was separated, washed with
water (2 × 50 mL), and concentrated to give ( )-15 as a colorless oil
(4.18 g; 90%). 1H NMR (400 MHz, DMSO-d6) δ 7.26 (m, 4H), 7.19
(m, 1H), 4.60−4.00 (br, 1H), 3.49 (d, J = 1.8 Hz, 2H), 3.24 (ddd, J =
10.0, 7.6, 2.7 Hz, 1H), 2.58−2.40 (m, 2H), 2.39−2.30 (m, 2H), 1.98
(m, 1H), 1.74 (m, 2H), 1.33 (m, 1H), 1.16 (ddd, J = 13.8, 9.7, 4.2 Hz,
1H), 1.06 (ddd, J = 13.3, 9.6, 2.7 Hz, 1H), 0.83 (d, J = 6.7 Hz, 3H),
0.80 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 139.4,
128.4(2), 128.0(2), 126.6, 71.1, 60.0, 56.5, 53.8, 45.0, 44.5, 27.4, 24.0,
23.9, 21.6. IR (film) 3387, 2954, 2923, 2868, 2796, 1469, and 1453
cm−1. HRMS (ESI+) calcd for C16H26NO 248.2009, found 248.2009.
(R)-1-Benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-
one (9). To a solution of ketone 8 (10.00 g, 38.56 mmol) in IPA (120
mL) was added 0.1 M LiCl in IPA (3.75 mL; 0.38 mmol), and 10%
con. HCl (35%) in IPA (2.0 mL; 2.3 mmol). The mixture was purged
with N2 followed by the addition of Ru(OAc)2[(S)-tol-BINAP) (0.125
g, 0.139 mmol). The reactor was purged with N2 (5 × 85 psi), then
purged with H2 (3 × 85 psi), and heated to 65 °C for 16.0 h. The
reactor was vented and held under N2 for HPLC analysis which
indicated less than 50% conversion to 9. Another charge of
Ru(OAc)2[(S)-tol-BINAP) (0.125 g, 0.139 mmol) was made followed
by purging with H2 (3 × 85 psi) and placing the reaction mixture
under 85 psi of H2 with heating to 65 °C for 20.0 h to afford a
complete conversion of 8 to 9 with 96.4% ee and 94.3% de. The
reaction mixture was cooled to 22 °C and concentrated to give crude 9
as a greenish/yellow oil, which was purified via column chromatog-
raphy using the following conditions: Crude 9 dissolved in 5% EtOH/
25% MTBE in heptanes (130 mL) and loaded onto a silica column
using Merck 9385, 60A., 230−400 mesh (700 g) eluting with 5%
EtOH/25% MTBE in heptanes to afford 9.39 g (93% yield) of 9 as a
yellow waxy oil (see ( )-9 for NMR and HRMS data). IR (film) 2957,
2871, 1714, 1682 cm−1.
L-tartaric acid (DBTA) (5.67 g; 15.50 mmol) added. The mixture was
heated to 50 °C to give a thin slurry, and a mixture of DBTA (5.67 g;
15.5 mmol) dissolved in MeOAc (15 mL) was added to the slurry over
0.5 h. After 17.0 h, the slurry was cooled to 21 °C over 2.0 h, and the
solids filtered, washed with MeOAc (2 × 50 mL), and dried. The
DBTA salt 16 (14.08 g; 75% yield) was isolated as an off-white solid. A
sample of the DBTA salt 16 was freebased to give 10 according to the
procedure below and analyzed by chiral HPLC which indicated 100%
ee and de. [α]D −63.1 (MeOH, c = 2.5). Mp 148.2−150.5 °C. H
NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.0 Hz, 4H), 7.65 (t, J =
7.4 Hz, 2H), 7.52 (t, J = 7.7 Hz, 4H), 7.45 (dd, J = 7.7, 1.8 Hz, 2H),
7.39−7.27 (m, 3H), 5.70 (s, 2H), 4.13 (s, 2H), 3.40 (dt, J = 9.0, 4.0
Hz, 1H), 3.22−2.88 (m, 3H), 2.74 (t, J = 10.0 Hz, 1H), 2.18 (dq, J =
15.8, 8.1, 7.2 Hz, 1H), 1.80 (q, J = 7.6 Hz, 2H), 1.75−1.60 (m, 1H),
1.21 (ddd, J = 14.0, 9.6, 4.7 Hz, 1H), 0.91 (ddd, J = 13.1, 9.2, 3.4 Hz,
1H), 0.83 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H) (exchangeable
protons not observed). 13C NMR (100 MHz, DMSO-d6) δ 168.4(2),
164.9(2), 133.5(2), 132.1, 130.2(2), 129.6(2), 129.3(4), 128.8,
128.7(4), 128.5(2), 72.9(2), 67.3, 56.7, 54.2, 52.4, 44.6, 42.6, 23.9,
23.5(2), 21.7. IR (solid) 3239.5, 2954, 2870, 1749, 1734, 1706, 1612,
and 1451 cm−1. HRMS (ESI+) calcd for C16H26NO 248.2009, found
248.2009.
25
1
(S)-1-((S)-1-Benzylpyrrolidin-3-yl)-3-methylbutan-1-ol (10).
Salt 16 (20.00 g; 33.02 mmol; 100% de and ee) was suspended in
MTBE (200 mL) at 22 °C. To the slurry was added TEA (64.0 mL;
330 mmol), followed by 50% saturated aqueous NaHCO3 (200 mL).
The mixture was stirred for 1.0 h to give two homogeneous phases.
The organic layer was removed, washed with 50% saturated aqueous
NaHCO3 (200 mL), water (200 mL), saturated brine (200 mL), dried
(Na2SO4), and concentrated to afford 10 (7.82 g, 95.7%) as an orange
25
oil. [α]D 1.8 (MeOH, c = 2.75). See ( )-10 spectra.
3-((S)-1-((S)-1-benzylpyrrolidin-3-yl)-3-methylbutoxy)-6-
chloro-2-methylpyridine (18). At 22 °C, solid tBuOK (1.51 g; 12.9
mmol) was added to DMF (25 mL) followed by alcohol 10 (2.00 g;
8.08 mmol) to afford a thin yellow slurry. After 16.0 h, 6-chloro-3-
fluoro-2-methylpyridine 17 (1.30 g; 8.89 mmol) was added to the
mixture giving a green color and a brief endotherm to 19 °C. After
24.0 h, water (50 mL) and MTBE (50 mL) were added to the
reaction, the organic phase separated, and the aqueous phase extracted
with MTBE (20 mL). The organic phases were combined, washed
with water (2 × 20 mL) and saturated brine (20 mL), dried (Na2SO4),
and concentrated to give an orange oil. The oil was purified by column
chromatography over silica gel eluting with 20% EtOAc/hexanes to
afford 18 as an orange oil (1.98 g) in 65% yield. [α]D25 12.3 (MeOH, c
1
= 2.2). H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 8.7 Hz, 1H),
7.32−7.17 (m, 6H), 4.48 (dt, J = 7.8, 4.7 Hz, 1H), 3.56 (d, J = 13.0 Hz,
1H), 3.46 (d, J = 13.1 Hz, 1H), 2.61−2.38 (m, 4H), 2.30 (s, 3H), 2.20
(dd, J = 8.9, 6.9 Hz, 1H), 1.90−1.77 (m, 1H), 1.71−1.50 (m, 3H),
1.39 (ddd, J = 13.9, 7.8, 4.2 Hz, 1H), 0.87 (d, J = 6.4 Hz, 3H), 0.84 (d,
J = 6.4 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 152.2, 148.7,
139.2, 138.9, 128.2(2), 128.0(2), 126.6, 122.6, 121.9, 78.2, 59.6, 55.6,
53.4, 41.2, 41.1, 25.5, 24.3, 23.1, 22.4, 18.9. IR (film) 2956, 2870, 2791,
1577, and 1438 cm−1. HRMS (ESI+) calcd for C22H30N2OCl
373.2041, found 373.2043.
3-((S)-1-((S)-1-Benzylpyrrolidin-3-yl)-3-methylbutoxy)-6-me-
thoxy-2-methylpyridine (19). At 22 °C, MeOK (0.94 g; 12.9
mmol) was added to chloride 18 (1.20 g; 3.22 mmol) in DMSO (10
mL) giving a dark pink color. The mixture was heated to 100 °C for
1.0 h and cooled back to 22 °C. Water (50 mL) was added to the
reaction and the mixture extracted twice with MTBE (50 and 20 mL).
The combined organic phases were washed with water (2 × 5 mL) and
saturated brine (10 mL), dried (Na2SO4), and concentrated to afford
19 as a light yellow oil (1.17 g) in 98% yield. [α]D25 12.8 (MeOH, c =
(S)-1-((S)-1-Benzylpyrrolidin-3-yl)-3-methylbutan-1-ol Di-
benzoyl-L-tartrate (16). Lactam 9 (8.10 g; 31.0 mmol; 96.4% ee
and 94.3% de) and toluene (80 mL) were combined, cooled to 0 °C,
and Vitride (13.51 mL; 68.18 mmol) diluted with toluene (80 mL)
was added over 0.5 h giving a maximum temperature of 10 °C. The
mixture was warmed to 22 °C and stirred for 18.0 h. The reaction was
cooled to 0 °C and a mixture of saturated aqueous Rochelle’s salt (100
mL) and water (50 mL) were added over 0.3 h. The mixture was
warmed to 22 °C, stirred vigorously for 6.5 h, MTBE (100 mL) added,
and stirring continued for 16.0 h. The organic phase was separated,
washed with water (2 × 100 mL), brine (100 mL), dried (Na2SO4),
and the solvent removed to give crude 10 as an orange oil (7.34 g). At
22 °C, the crude 10 was dissolved in MeOAc (85 mL) and dibenzoyl-
1
3.4). H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 8.9 Hz, 1H),
7.32−7.17 (m, 5H), 6.56 (d, J = 8.8 Hz, 1H), 4.26 (dt, J = 7.9, 4.7 Hz,
1H), 3.76 (s, 3H), 3.56 (d, J = 13.0 Hz, 1H), 3.48 (d, J = 13.1 Hz, 1H),
2.61−2.52 (m, 2H), 2.41 (m, 2H), 2.26 (s+m, 4H), 1.88−1.74 (m,
1H), 1.71−1.56 (m, 2H), 1.51 (ddd, J = 13.6, 7.8, 5.6 Hz, 1H), 1.35
(ddd, J = 14.3, 8.1, 4.3 Hz, 1H), 0.86 (d, J = 6.6 Hz, 3H), 0.84 (d, J =
6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 156.5, 147.4, 144.3,
F
dx.doi.org/10.1021/jo400589j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
139.3, 128.2(2), 128.0(2), 126.6, 125.2, 107.4, 78.7, 59.6, 55.6, 53.5,
52.9, 41.4, 41.2, 25.7, 24.3, 23.2, 22.4, 19.0. IR (film) 2955, 2869, 2790,
1471, and 1427 cm−1. HRMS (ESI+) calcd for C23H33N2O2 369.2537,
found 369.2540.
Zarrinmayeh, H.; Thomas, C. E.; Joshi, E.; Iyengar, S.; Johansson, A.
M. ACS Med. Chem. Lett. 2013, DOI: 10.1021/ml400049p.
(4) Mendiola, J.; García-Cerrada, S.; de Frutos, O.; de la Puente, M.
L.; Gu, R. L.; Khau, V. V. Org. Process Res. Dev. 2009, 13, 292.
(5) (a) Yuwasa, Y.; Sotoguchi, T.; Seido, N. Eur. Pat. Appl., EP
855390 A1 19980729; Takasago International Corporation, Japan,
1998. (b) Hattori, K.; Yamada, A.; Kuroda, S.; Toshiyuki Chiba, T.;
Murata, M.; Sakane, K. Bioorg. Med. Chem. Lett. 2002, 12, 383. This
related paper appeared during the preparation of this manuscript:
(c) Lall, M. S.; Hoge, G.; Tran, T. P.; Kissel, W.; Murphy, S. T.;
Taylor, C.; Hutchings, K.; Samas, B.; Ellsworth, E. L.; Curran, T.;
Showalter, H. D. H. J. Org. Chem. 2012, 77 (10), 4732.
(6) (a) Babudrif, F.; Ciminalel, F.; Di Nunno, L.; Florio, S.
Tetrahedron 1982, 38 (4), 557. (b) Christoffers, J.; Werner, T.; Unger,
S.; Frey, W. Eur. J. Org. Chem. 2003, 425. (c) Magnus, P.; Fielding, M.
R.; Wells, C.; Lynch, V. Tetrahedron Lett. 2002, 43, 947.
(7) Wilkinson, G.; Osborn, J. A.; Jardine, F. H.; Young, J. F. J. Chem.
Soc., Sect. A: Inorg., Phys., Theor. 1966, 12, 1711.
(8) Siliabond triaminetetraacetate sodium salt (TAAcONa) pur-
chased from SiliCycle is a supported version of ethylenediaminetetra-
acetic acid (EDTA) in its sodium salt form (silica bound metal
scavenger).
(9) Nara, H.; Sayo, N.; Fujiwara, T. Eur. Pat. Appl., EP 2166014 A2
20100324; Takasago International Corporation, Japan, 2010.
(10) King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J.
Org. Chem. 1992, 57, 6689.
6-Methoxy-2-methyl-3-((S)-3-methyl-1-((S)-pyrrolidin-3-yl)-
butoxy)pyridine (2). To a glass pressure vessel was charged 20 wt %
Pd/C (10% wet, 0.50 mg) followed by a solution of 19 (2.57 g, 6.97
mmol) in EtOH (26 mL). The reaction vessel was purged with H2 gas
(3 × 50 psi), and the vessel placed under 50 psi of H2 and warmed to
60 °C causing the pressure to increase to 55 psi. After 24.0 h, the
reaction mixture was cooled to 22 °C and filtered through Celite (wet
with MeOH to avoid ignition of the Pd/C), followed by washing of
the Celite with MeOH (30 mL). The filtrate was concentrated to give
2 (1.83 g; 94.3%) as a light yellow oil. [α]D25 −5.4 (MeOH, c = 3.0).
1H NMR (400 MHz, DMSO-d6) δ 7.40 (d, J = 8.9 Hz, 1H), 6.57 (d, J
= 8.8 Hz, 1H), 4.30 (dt, J = 7.6, 5.0 Hz, 1H), 3.76 (s, 3H), 3.33 (br,
1H), 2.86 (dd, J = 10.6, 8.0 Hz, 1H), 2.82−2.67 (m, 2H), 2.53 (dd, J =
10.7, 7.1 Hz, 1H), 2.34−2.20 (m, 1H), 2.27 (s, 3H), 1.78−1.43 (m,
4H), 1.35 (ddd, J = 13.3, 8.1, 4.4 Hz, 1H), 0.87 (d, J = 6.6 Hz, 3H),
0.84 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 156.5,
147.4, 144.3, 125.3, 107.3, 78.6, 53.0, 48.8, 46.5, 43.4, 42.0, 27.7, 24.3,
23.2, 22.4, 19.0. IR (film) 2955, 2869, 1583, 1471, and 1426 cm−1.
HRMS (ESI+) calcd for C16H27N2O2 279.2067, found 279.2070.
ASSOCIATED CONTENT
* Supporting Information
■
S
(11) β-Keto-γ-lactam 8 was further purified via silica gel
chromatography eluting with EtOAc (21−25%)/heptane.
(12) (a) Inoue, T.; Sato, D. PCT Int. Appl., WO 2006054644 A1
20060526; Nippon Soda Co LTD, Japan, 2006. (b) Ohkuma, T.;
Kurono, N. Synlett 2012, 23, 1865. (c) Kurono, N.; Yoshikawa, T.;
Yamasaki, M.; Ohkuma, T. Org. Lett. 2011, 13 (5), 1254.
(13) 10 g scale reactions to convert 8 to 9 required more catalyst and
time, than the 400 mg scale screening reactions, to reach completion
due to the need to use larger pressure reactors with less efficient mass
transfer.
The chiral HPLC method and chromatograms for 9, 10, 13,
and Table 1. NMR spectra for Scheme 2, 3, and 4 compounds,
and X-ray data for 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: magnus_nicholas_a@lilly.com.
■
(14) Sasse, K.; Fischer, R.; Santel, H. J.; Schmidt, R. R. Ger. Offen.,
DE 3614846 A1 19871105; Bayer AG, Germany, 1987.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Daneen T. Angwin, Steven E.
Bandy, John L. Bowers, Jonas Y. Buser, Lauren E. Click, and
Thomas Z. Gunter for analyses, assistance with analytical
method development, and chromatographic purifications.
DEDICATION
■
§Dedicated to Professor Philip D. Magnus, F.R.S., The
University of Texas at Austin, on the occasion of his 70th
birthday.
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