Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl) propanenitrile

Article abstract of DOI:10.1021/jo3004716

(S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966,(1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S _N2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1′-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.

Full text of DOI:10.1021/jo3004716

Article
pubs.acs.org/joc
Stereoselective Synthesis of (S)-3-(Methylamino)-3-((R)-pyrrolidin-3-
yl)propanenitrile
Manjinder S. Lall,*,† Garrett Hoge,‡ Tuan P. Tran,† William Kissel,§ Sean T. Murphy,⊥ Clarke Taylor,¶
Kim Hutchings,# Brian Samas,† Edmund L. Ellsworth,∥ Timothy Curran,∇ and H. D. Hollis Showalter○
†Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
‡Dr. Reddy’s, Cambridge, Cambridgeshire CB40PE, U.K.
§Ironwood Pharmaceuticals, Cambridge, Massachusetts 02142, United States
⊥Takeda California, San Diego, California 92121, United States
¶Lycera Corp., Ann Arbor, Michigan 48109, United States
#AstraZeneca, Waltham, Massachusetts 02451, United States
∥Pfizer Worldwide Research and Development, Portage Street, Kalamazoo, Michigan 49007, United States
∇Vertex Pharmaceuticals, Cambridge, Massachusetts 02139, United States
○University of Michigan, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: (S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of
PF-00951966,1 a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract
infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and
stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key
transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II)
complex to afford β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization
and (b) SN2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1′-position in
high yield (80%), after efficient purification using a simple acid/base extraction protocol.
fluoroquinolone core by way of their ring nitrogen to give
highly active broad spectrum antibacterial agents.
In this article we disclose an efficient and stereoselective
synthesis of diamine 1, which is a key intermediate in the
preparation of PF-00951966, a novel broad-spectrum fluo-
roquinolone antibiotic discovered at Pfizer (Figure 1).
INTRODUCTION
■
The discovery and development of new antibacterial agents has
drawn considerable attention in recent years due to the
alarming rise of resistant bacteria.2 The relentless increase in
antibiotic resistance to many now common-place bacterial
pathogens such as Staphylococcus aureus, Streptococcus pneumo-
niae, Enterococcus faecalis, methicillin-resistant Staphylococcus
aureus (MRSA), penicillin-resistant pneumococcus, and vanco-
mycin-resistant Enterococcus faecalis (VRE) is proving difficult
to treat effectively.3 Perhaps more concerning is the emergence
of multidrug resistant (MDR) bacteria.4 Thus, there is an
important need to introduce effective antibiotics to add to our
current arsenal. Fluoroquinolone antibacterial agents have
shown promise as an important class of therapeutically useful
compounds.2c Most of the fluoroquinolone agents that show
broad spectrum activity are substituted at the 7-position of the
quinolone with cyclic aliphatic amines, especially diamine side
chains.5 Two diamines that have been particularly effective
are N-methyl-N-{(1S)-1-[(3R)-pyrolidinon-3-yl]ethyl}amine6a
and 3-aminopyrrolidine,6b both of which are attached to the
Figure 1. Structures of diamine 1 and fluoroquinolone PF-00951966.
PF-00951966 has a unique efficacy profile against pathogens
causing community-acquired respiratory tract infections including
Received: March 13, 2012
Published: April 23, 2012
© 2012 American Chemical Society
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Scheme 1
Scheme 2
Scheme 3
multidrug resistant organisms. The original route to prepare 1
employed a nonstereoselective 1,4-conjugate addition to racemic
α,β-unsaturated nitrile 2, followed by extensive chromatographic
purification to isolate the title compound (Scheme 1).1
Although this route facilitated SAR studies and led to rapid
optimization of lead derivatives, it had several drawbacks for
multigram-scale preparation of PF-00951966. Further, since the
other three stereoisomers of PF-00951966 are much less active
as antibacterial agents, the development of a stereoselective
synthesis of intermediate diamine 1 was paramount.
we were confident that 5 would be amenable to purification by
crystallization.
The β-keto amide substrate 10 for the catalytic asymmetric
hydrogenation reaction was prepared in good yield (75%) via a
modified Claisen (amide) condensation, through reacting
commercially available 1-benzyl-2-pyrrolidinone with freshly
prepared lithium diisopropylamine in THF at −78 °C, followed
by quenching with benzyloxyacetyl morpholine 9 (Scheme 3).
Initially we attempted to quench the lithiated 1-benzyl-2-
pyrrolidinone anion with benzyloxyacetyl chloride 8; however,
this reaction gave 10 in low yield (45−55%) with numerous
side-products10 making purification difficult. With β-keto amide
10 in hand, the stage was set to investigate the asymmetric
hydrogenation reaction. Dynamic kinetic resolution is an im-
portant consideration for the reduction of β-dicarbonyl com-
pounds, such as 10, with epimerizable substituents at the α-
position.11 Although the BINAP-Ru(II) system has been
recognized as an efficient and general catalyst for the hydro-
genation of β-keto substrates,8c we obtained low enantiose-
lectivity in the hydrogenation of amide 10 as shown in Table 1
(entries 1−3). However, utilizing the comparatively more
recent DM-SEGPHOS-Ru(II)8a,d,e,12 catalyst to hydrogenate
amide 10 resulted in improved enantioselectivity (Table 1,
entry 4). Furthermore, the enantioselectivity was highly dependent
on reaction temperature as well as pressure, and lowering these
parameters greatly enhanced enantioselectivity (Table 1, entry 5).
We also observed that good stereoselectivity was obtained in
multiple solvents (Table 1, entries 5−7). As anticipated, the crude
reaction mixture from the asymmetric hydrogenation could be
recrystallized from acetone and H2O (1:1) to afford β-hydroxy
amide 11b in good yield (73%) and enriched purity (de 98%, ee
>99%) as white crystals.
RESULTS AND DISCUSSION
■
Our stereoselective route to prepare 1 is outlined in Scheme 2.
We envisioned setting the absolute stereochemistry early on
using a catalytic asymmetric hydrogenation approach from
readily accessible β-keto amide 4.
Ruthenium catalysts containing chiral phosphine ligands are
uniquely capable of hydrogenating β-keto amides to give
homochiral β-hydroxy amides, such as 5, with extremely high
enantioselectivity and efficiency.7,8 After reduction of carbox-
amide 5 to the corresponding amine, the next key objective in
the synthesis would involve activation of the hydroxyl group to
form an appropriate leaving group followed by an SN2 sub-
stitution reaction with methylamine to provide product 7 with
inversion of configuration at the 1′-position. A variety of
methods and examples are known for this type of displacement
reaction.9 Amine 7 should then readily convert to the desired
diamine 1, enlisting standard reagents and conditions.
Interestingly, asymmetric hydrogenation of β-keto amides
followed by reduction of the amide to the amine functionality
is a practical route to prepare optically active 3-amino alcohols
but has only been sparsely reported in the literature.7 Further-
more, because most primary and secondary amides are solids,
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Table 1. Catalytic Asymmetric Hydrogenation of β-Keto Amide 10
a
b
c
d
entry
catalyst
RuCl2[(R)-BINAP]
S/C
solvent
H2 (atm)
temp (°C)
time (h)
11 de (%)
11 ee (%)
1
2
3
4
5
6
7
100
100
100
100
100
100
100
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
EtOAc
24
24
24
24
7
80
80
80
80
60
60
80
15
15
15
15
20
20
15
67
71
95
92
88
89
86
50
59
66
79
93
96
87
[RuCl(cymene)((R)-BINAP)]Cl
[RuCl(cymene)((R)-DM-BINAP)]Cl
[RuCl(cymene)((R)-DM-SEGPHOS)]Cl
[RuCl(cymene)((R)-DM-SEGPHOS)]Cl
[RuCl(cymene)((R)-DM-SEGPHOS)]Cl
[RuCl(cymene)((R)-DM-SEGPHOS)]Cl
7
7
a
BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; DM-BINAP = 2,2′-bis(di-3,5-(CH3)2C6H3-phosphino)-1,1′-binaphthyl; DM-SEGPHOS =
b
c
(4,4′-bi-1,3-benzodioxole)-5,5′-diyl-bis(di-3,5-(CH3)2C6H3-phosphine); cymene = 4-isopropyltoluene. Substrate/catalyst mole ratio. The
diastereomeric excess was determined on a crude reaction aliquot by chiral HPLC13 and H NMR analysis; for details, see the Experimental
1
Section. The enantiomeric excess was determined on a crude reaction aliquot by chiral HPLC;13 for details, see the Experimental Section.
d
The stereochemical purity of 11b was assessed directly by
chiral HPLC, using an analytical CHIRALCEL OJ-H column
(0.46 × 25 cm, 15% isopropanol-hexane, 0.8 mL/min), in
comparison with a sample mixture containing all four
stereoisomers (11a/b/c/d). The stereoisomeric mixture
(11a/b/c/d) was prepared by reduction of β-keto amide 10
in the presence of Raney Ni (methanol, 23 °C, 3.5 atm, 20 h,
80%), which gave a 1:1:1:1 mixture of stereoisomers (Scheme 4).13
Scheme 5
Scheme 4
followed by an SN2 substitution reaction with methylamine, to
furnish 14 with inversion of configuration at the 1′-position.16
A
suitable choice of reagents and conditions for nucleophilic
substitution reactions demands careful consideration to the
steric and electronic requirements of both the attacking
nucleophile and the electrophile.16 Consequently, the hydroxyl
group of compound 12 was activated with a variety of sulfonate
leaving groups (e.g., mesylate, nosylate, triflate)17 and screened
for successful displacement reaction with methylamine or a
methylamine surrogate (i.e., Bn(Me)NH, MeO(Me)NH,18a
CF3CONHMe,18b NaN3).19 The amine displacement screen
identified the p-nosylate group as a good leaving group because
the reaction favored the desired amine product over a side-
product, which was identified as olefin 15 resulting from elim-
ination. In addition, the p-nosylate 13 intermediate was a solid
and thought to be amenable to purification via recrystallization
for future development. The initial displacement screen also
identified methylamine as the amine of choice because the
other amine surrogates offered no enhancement in desired
product to olefin side-product ratio.20 Moreover, methylamine
is the preferred amine for synthetic convenience, which ulti-
mately streamlines the synthesis by limiting additional synthetic
steps.
With the choice of electrophile (13) and nucleophile
(methylamine) secured, we focused our attention on opti-
mizing the ratio of desired amine product (14) to olefin side-
product (15). We observed that the 14/15 product distribution
was critically dependent on solvent; Table 2 compiles the
optimized results from the solvent screen. In general, polar
solvents such as methanol and DMF gave amine 14 in dis-
appointingly low ratio (Table 2, entries 1 and 2, respectively).
Interestingly, the formation of desired amine 14 was better with
the polar protic solvent methanol (Table 2, entry 1) than with
DMF. This result may explain the superior selectivity observed
with neat methylamine21 (Table 2, entry 3). Despite the
favorable ratio obtained in entry 3 (Table 2), a problem that was
The diastereoisomers from the Raney Ni reduction could be
separated by SiO2 chromatography (dichloromethane−
methanol 3%) to give diastereoisomer 11a/b as a white solid
racemic mixture and the other diastereoisomer 11c/d as a clear
oil racemic mixture. The single enantiomer 11b, prepared from
the asymmetric hydrogenation reaction, coeluted by chiral
HPLC with one of the products (i.e., 11a/b white solid racemic
mixture) from the Raney Ni reduction having a retention time
of 17.2 min. The other three stereoisomers eluted with
retention times of 13.3, 20.8, and 24.3 min.13 The relative
stereochemistry of amide 11a/b was confirmed by single-crystal
X-ray analysis (Scheme 4).14
The remarkably high syn-diastereoselectivity observed with
amide 11b (prepared from the asymmetric hydrogenation reac-
tion) has been previously rationalized with other similar amides
in terms of a sterically constrained tricyclic transition state,11d
where the chiral arrangement of the DM-SEGPHOS phenyl
rings determines the absolute configuration of the new stereo-
center.15
The carbonyl group of β-hydroxy amide 11b is efficiently
reduced with lithium aluminum hydride in refluxing THF,
to provide optically active 3-amino alcohol 12 in excellent
yield (97%) with sufficient purity for the subsequent step
(Scheme 5).
The next key objective in the synthesis involved activation of
the hydroxyl group in 12 with an appropriate leaving group
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base (NaOH) extraction protocol, using dichloromethane
as extracting solvent. Presumably, the protonated amine 15
is reasonably soluble in dichloromethane, which is extracted
into the organic solvent (DCM) with other organic impurities.
Basification of the aqueous layer with 1 M NaOH liberates
diamine 14, which is extracted into dichloromethane and
recovered with high purity and yield (80%) after solvent removal.
With diamine 14 in hand and a method developed for
purification secured, our efforts focused on the remaining steps
required to complete the synthesis of pyrrolidine 1 (Scheme 6).
Hydrogenolysis of the benzyl ether and benzyl amine protec-
ting groups in 14 was accomplished under acidic (2 equiv HCl)
conditions to give alcohol 16 as the bis-hydrochloride salt in
good yield. Reduction in the absence of acid was problematic,
leading to incomplete or slow debenzylation. Alcohol 16 was
treated with benzyl chloroformate in the presence of NaOH to
provide the bis-benzyl carbamate (Cbz) derivative 17. The next
transformation involved activating alcohol 17 with methane-
sulfonyl chloride to give the mesylate adduct, followed by
displacement with a cyanide source. Our initial displacement
conditions (0.07 M mesylate in acetonitrile, 2 equiv KCN,
70 °C, 90 min) gave mainly oxazolidinone 1922 side-product
and nitrile 18 as the minor constituent. Enlisting the prescribed
reaction conditions (0.2 M mesylate in MTBE, 2 equiv
(n-Bu)4NCN, 50 °C, 3 h, 93% over two steps) gave smooth
conversion to nitrile 18 with no detection of the oxazolidinone
1922 side-product by TLC or LCMS. The prepared nitrile 18
sample was identical in all respects in comparison to an authentic
sample,1,23 confirming that the desired stereoselectivity was
attained in the asymmetric hydrogenation reaction and that the
methylamine substitution reaction proceeded with inversion of
configuration at the 1′-position in 14.24 The penultimate nitrile
18 underwent selective hydrogenolysis of the Cbz group
utilizing isopropanol as solvent, with no detection of nitrile
reduction, to provide diamine 1 as a clear oil. The overall yield
of target diamine 1 from benzyloxyacetyl chloride was 24% over
10 steps. The final step involved coupling diamine 1 with
difluoroquinolone 20 via an aromatic nucleophilic substitution
Table 2. p-Nosylate Displacement: Reaction of 13 with
Methylamine
a
b
entry
solvent
temp (°C)
time (h)
14/15
1
2
MeOH
DMF
80
80
23
80
80
80
80
70
60
40
15
15
15
15
15
15
15
15
15
15
2/1
0.9/1
13/1
2.2/1
3.7/1
3.7/1
4/1
cd
,
3
4
5
6
7
8
9
neat
THF
MTBE
toluene
toluene/heptane (1:1)
toluene/heptane (1:1)
toluene/heptane (1:1)
toluene/heptane (1:1)
7/1
8/1
e
10
3/1
a
According to the procedure detailed in the Experimental Section, 1
equiv of 13 as a 0.1 M solution in solvent(s) at 0 °C was treated with
b
c
10% wt methylamine. Ratio determined by 1H NMR. p-Nosylate 13
d
treated with 300 equiv of methylamine at 0 °C. N-Methyl-p-
nitrobenzenesulfonamide and alcohol 12 side products observed.
Reaction did not go to completion.
e
encountered with neat methylamine was the formation of
unwanted additional side-products, such as N-methyl-p-nitro-
benzenesulfonamide and alcohol 12 from sulfur−oxygen bond
scission (the result of methylamine attack on the sulfur atom in
13).16 All attempts to minimize the side-products associated with
running the reaction in neat methylamine (e.g., lowering reaction
temperature, increasing reaction time) were unsuccessful. From
entries 5 and 6 (Table 2), we found that running the reaction in
nonpolar solvents favored the desired amine 14 over olefin 15.
Furthermore, introducing a nonpolar cosolvent such as heptane
improved the ratio of desired amine to olefin (Table 2, entry 7).
Under these nonpolar conditions, the ratio of 14/15 was highly
dependent on reaction temperature, and lowering this parameter
favored 14 (Table 2, entries 8, 9).
An attempt was made to execute the substitution reaction in
the presence of Lewis acid additives (e.g., BF3·OEt2, InCl3,
MgCl2, MgOTf2, ZnCl2); however, no improvement in 14/15
ratio or yield was observed. The isolation of 14 was most
conveniently accomplished by employing a standard acid (HCl)/
Scheme 6
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(m, 10H), 4.80 (dd, 1H, J = 18, 18 Hz), 4.62 (dd, 2H, J = 12, 21 Hz),
4.39 (dd, 2H, J = 15, 26 Hz), 4.30 (dd, 1H, J = 18, 18 Hz), 3.69 (dd,
1H, J = 6, 9 Hz), 3.31 (ddd, 1H, J = 5, 9, 14 Hz), 3.19 (ddd, 1H, J = 5,
9, 14 Hz), 2.48 (ddd, 1H, J = 5, 9, 13 Hz), 1.99 (ddd, 1H, J = 5, 9, 13
Hz); 13C NMR (100 MHz, CDCl3) δ 203.1, 169.6, 137.4, 135.8, 128.8,
128.5, 128.1, 128.0, 127.9, 127.7, 74.9, 73.4, 51.8, 46.9, 45.2, 19.4;
HRMS (ESI) Calcd for C20H22NO3 [M + H]+ 324.1594, found
324.1594; HPLC %(AUC) = 93.1 (Symmetry C-18, gradient elution
over 15 min of acetonitrile and water, from 0 to 30%, tR = 8.5 min).
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.63; H, 6.70; N, 4.70.
reaction, to afford the fluoroquinolone antibiotic PF-00951966
in 63% yield.
CONCLUSION
■
An efficient and stereoselective synthesis of diamine 1 was
developed in 10 steps from benzyloxyacetyl chloride in 24%
overall yield. The synthesis employs a catalytic asymmetric
hydrogenation reaction using a chiral DM-SEGPHOS-Ru(II)
complex to set the stereochemistry at the 3- and 1′-positions in
β-hydroxy amide 11b in good yield (73%) and high stereo-
selectivity (de 98%, ee >99%) after recrystallization. The
stereochemistry at the 1′-position was then inverted utilizing a
SN2 substitution reaction with methylamine to provide diamine
14 in high yield (80%), after efficient purification using a simple
acid/base extractive workup.
(S)-1-Benzyl-3-((S)-2-(benzyloxy)-1-hydroxyethyl)pyrrolidin-
2-one (11b). A mixture of 10 (15 g, 46.4 mmol) and [RuCl-
(cymene)((R)-DM-SEGPHOS)]Cl (0.48 g, 1 mol %, 0.48 mmol) in
MeOH (150 mL) was loaded into an Endeavor autoclave. Hydrogen
was introduced (100 psi), and the mixture was stirred at 60 °C for 20
h. After the hydrogen pressure was released, the solvent was removed
to afford crude product. The material was purified by recrystallization
from acetone−H2O (1:1), to give 11b (11.2 g, 73%, de 98%, ee >99%)
as white needles. The enantiomeric and diastereomeric excess was
assessed directly by chiral phase HPLC separation using an analytical
CHIRALCEL OJ-H column (0.46 × 25 cm, 15% i-PrOH-hexane,
0.8 mL/min). The four stereoisomers eluted with retention times of
13.3, 17.2, 20.8, and 24.3 min; compound 11b coeluted with a
retention time of 17.2 min. Note: chiral phase HPLC conditions
modified for developmental work to CHIRALCEL OJ-H column (0.46
× 25 cm, 20% i-PrOH-hexane, 1.0 mL/min), the desired stereoisomers
11b eluted with a retention time of 14.6 min: [α]23 −12 (c 5.0,
CHCl3); IR (ZnSe) 3370, 3090, 2870, 1660, 1480, 1290, 1105, 750,
EXPERIMENTAL SECTION
■
All commercially available materials and solvents were used as
received. Reaction temperatures were measured internally, unless
indicated otherwise (rt = 20−23 °C).
2-(Benzyloxy)-1-morpholinoethanone (9). A solution of
morpholine (62 mL, 707 mmol) in toluene (300 mL) was treated
with acid chloride 8 (52.2 g, 282 mmol) dissolved in toluene (100 mL)
dropwise over 30 min. The temperature rose to 70 °C. The reaction
was allowed to stir overnight. Water (100 mL) was added to the
reaction, and the solids dissolved. The layers were separated, and the
toluene layer was washed with water (100 mL), 1 N HCl (100 mL),
aqueous K2CO3 (10 g in 100 mL), and water (100 mL). The organic
layer was concentrated to give 9 (60 g, 95%) as a clear oil. The
material was used in the next step without further purification: IR
(ZnSe) 3020, 2950, 1650, 1490, 1260, 1120, 750, 702 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.21−7.28 (m, 5H), 4.52 (s, 2H), 4.09 (s, 2H),
3.51−3.57 (m, 6H), 3.38 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
167.6, 137.0, 128.3, 127.9, 127.8, 73.0, 69.1, 45.4, 41.9; HRMS (ESI)
Calcd for C13H17NO3Na [M + Na]+ 258.1101, found 258.1097;
HPLC %(AUC) = 95.23 (Symmetry C-18, gradient elution over
15 min of acetonitrile and water, from 0 to 30%, tR = 7.1 min).
1
690 cm−1; H NMR (400 MHz, CDCl3) δ 7.36−7.20 (m, 10H), 4.56
(dd, 2H, J = 12, 15 Hz), 4.44 (dd, 2H, J = 14, 19 Hz), 4.37 (ddd, 1H,
J = 4, 7, 8 Hz), 3.57 (dddd, 2H, J = 4, 10, 14, 23 Hz), 3.19 (m, 2H),
2.65 (ddd, 1H, J = 4, 9, 13 Hz), 2.50 (br s, 1H), 2.11 (m, 1H), 1.95
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.9, 138.2, 136.5, 128.9,
128.6, 128.2, 127.9, 127.8, 127.7, 73.5, 72.6, 69.2, 46.9, 45.4, 45.0, 18.9;
HRMS (ESI) Calcd for C20H24NO3 [M + H]+ 326.1751, found
326.1750; HPLC %(AUC) = 98.8 (Symmetry C-18, gradient elution
over 15 min of acetonitrile and water, from 0 to 30%, tR = 5.6 min).
Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C,
73.62; H, 7.08; N, 4.16.
(S)-2-(Benzyloxy)-1-((R)-1-benzylpyrrolidin-3-yl)ethanol (12).
A solution of 11b (17.8 g, 54 mmol) dissolved in THF (34 mL) at
23 °C was treated dropwise with lithium aluminum (1 M in THF,
109 mL, 109 mmol). The mixture was refluxed under nitrogen for 2 h.
The solution was cooled with an ice bath and quenched sequentially
with H2O (16 mL), 15% aqueous NaOH (16 mL), H2O (16 mL); the
mixture was stirred at 0 °C for 30 min and then treated with MgSO4
(10 g). The suspension was filtered under vacuum and washed with
THF (150 mL), and the filtrate was concentrated in vacuo to afford 12
(17.0 g, 97%) as a brown oil: [α]23 −4 (c 5.0, CHCl3); IR (ZnSe)
1-Benzyl-3-(2-(benzyloxy)acetyl)pyrrolidin-2-one (10). A sol-
ution of diisopropylamine (24 mL, 171 mmol) in THF (200 mL) was
cooled to −10 °C and treated with n-BuLi (1.6 M in hexane, 98 mL,
157 mmol) dropwise over 15 min. The prepared solution was treated
with 1-benzylpyrrolidin-2-one (25 g, 143 mL) to give a red solution.
After 30 min of stirring, 9 (38.6 g, 164 mL) was added over 10 min
while keeping the temperature below −5 °C. The reaction slowly lost
the red color to become a pale yellow at completion. The reaction was
allowed to warm to 10 °C and then quenched by the addition of
aqueous NaHCO3 (60 g, in 200 mL). The reaction was diluted with
toluene (300 mL), and the aqueous phase separated. The aqueous
phase was extracted with toluene (3 × 100 mL), and the combined
organic layers were washed with brine (500 mL), dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash
chromatograph (SiO2, hexane/EtOAc 10−50%) to afford 10 (26 g,
75%) as a yellow oil: IR (ZnSe) 3030, 2940, 1720, 1670, 1480, 1270,
1110, 770, 680 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.39−7.17
1
3430, 3100, 2850, 1580, 1490, 1140, 780, 690 cm−1; H NMR (400
MHz, CDCl3) δ 7.34−7.19 (m, 10H), 4.50 (dd, 2H, J = 12, 17 Hz),
3.82 (ddd, 1H, J = 5, 7, 10 Hz), 3.76 (br s, 1H), 3.57 (s, 2H), 3.37
(dddd, 2H, J = 5, 10, 13, 15 Hz), 2.69 (ddd, 1H, J = 7, 9, 13 Hz), 2.52
(m, 2H), 2.34 (m, 2H), 1.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
138.7, 138.3, 128.8, 128.5, 128.4, 128.2, 127.8, 127.2, 73.8, 73.4, 72.8,
60.2, 58.3, 53.7, 39.4, 24.3; HRMS (ESI) Calcd for C20H26NO2 [M + H]+
312.1958, found 312.1957. Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09;
N, 4.50. Found: C, 76.92; H, 8.26; N, 4.38.
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96.06 (Symmetry C-18, gradient elution over 15 min of acetonitrile
and water, from 0 to 30%, tR = 7.3 min).
(S)-2-(Benzyloxy)-1-((R)-1-benzylpyrrolidin-3-yl)ethyl 4-Ni-
trobenzenesulfonate (13). A solution of 12 (9.21 g, 30 mmol)
dissolved in DCM (45 mL) at 0 °C was treated with triethylamine
(5 mL, 35 mmol) followed by 4-nitrobenzenesulfonyl chloride (7.9 g,
35 mmol). The mixture was stirred at 0 °C for 1 h and then warmed to
room temperature, where stirring was continued for 15 h. The reaction
was quenched with 5% aqueous NaHCO3 (100 mL), the organic layer
was separated, and the aqueous layer was extracted with DCM (3 ×
50 mL). The combined organic phases were washed with brine (100 mL)
and dried over MgSO4, and the solvent removed in vacuo. The residue
was purified by flash chromatograph (SiO2, hexane/EtOAc 10−80%),
to afford 13 (12 g, 82%) as a yellow solid: [α]23 8 (c 5.0, CHCl3); IR
(ZnSe) 3120, 2870, 1520, 1390, 1180, 1090, 920, 880, 730, 690 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.07 (d, 2H, J = 9 Hz), 7.98 (d, 2H,
J = 9 Hz), 7.31−7.26 (m, 8H), 7.05 (m, 2H), 4.84 (ddd, 1H, J = 3, 7,
10 Hz), 4.30 (dd, 1H, J = 11 Hz), 4.17 (dd, 1H, J = 11 Hz), 3.65 (br s,
2H), 3.49 (m, 2H), 2.67 (m, 4H), 2.39 (m, 1H), 2.01 (m, 1H), 1.78
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 151.9, 144.7, 139.1, 138.3,
129.2, 129.1, 128.6, 128.5, 128.3, 127.9, 127.1, 124.0, 73.5, 70.7, 60.7,
60.3, 56.4, 53.6, 39.8, 26.6; HRMS (ESI) Calcd for C26H29N2O6S
[M + H]+ 497.1741, found 497.1734; HPLC %(AUC) = 99.7
(Symmetry C-18, gradient elution over 15 min of acetonitrile and
water, from 0 to 30%, tR = 7.1 min).
(R)-2-(Methylamino)-2-((R)-pyrrolidin-3-yl)ethanol Bishydro-
chloride (16). A solution of 14 (3.18 g, 9.8 mmol) in methanol (100
mL) and hydrochloric acid (12.4 M, 1.6 mL, 19.6 mmol) under argon
was treated with 20% palladium on carbon (2 g) at 23 °C. The mixture
was hydrogenated in a Parr shaker under 50 psi of hydrogen at 23 °C
for 24 h. The solution was filtered through a pad of Celite (MeOH,
100 mL), the solvent was removed via rotary evaporation, and the
product was dried under vacuum to afford 16 (2.3 g, quantitative) as a
clear viscous oil: [α]23 6 (c 5.0, H2O); IR (ZnSe) 3380, 2950, 1630,
1
1590, 1470, 1210, 1040, 910 cm−1; H NMR (400 MHz, DMSO) δ
9.66 (br s, 1H), 9.15 (br s, 1H), 5.49 (s, 1H), 3.72 (m, 1H), 3.54 (m,
1H), 3.17 (m, 2H), 3.02 (m, 2H), 2.47 (m, 3H), 2.07 (m, 2H), 1.65
(m, 2H); 13C NMR (100 MHz, D2O) δ 61.1, 57.04, 47.7, 45.3, 36.9,
30.4, 27.1; HRMS (ESI) Calcd for C7H16N2O [M + H]+ 145.1335,
found 145.1339. ELSD %(AUC) = 99.59 (Symmetry C-18, elution
over 15 min, acetonitrile/ammonium acetate buffer, tR = 1.5 min).
(R)-Benzyl 3-((R)-1-(((Benzyloxy)carbonyl)(methyl)amino)-2-
hydroxyethyl)pyrrolidine-1-carboxylate (17). A solution of 16
(2.1 g, 9.8 mmol) in THF (50 mL) and NaOH (1 M, 44 mL, 44
mmol) at 0 °C was treated with benzyl chloroformate (2.8 mL, 19.6
mmol) dropwise over 10 min. The mixture was stirred at 0 °C for 3 h,
diluted with EtOAc (50 mL), and washed sequentially with saturated
NaHCO3 (50 mL), H2O (50 mL), and brine (50 mL). The organic
layer was dried over MgSO4 and concentrated in vacuo. The residue
was purified by flash chromatograph (SiO2, hexane/EtOAc 10−80%),
to afford 17 (3.2 g, 80%) as a clear viscous oil: [α]23 9.6 (c 5.0,
CHCl3); IR (ZnSe) 3430, 3250, 2920, 2870, 1690, 1670, 1440, 1130,
(R)-2-(Benzyloxy)-1-((R)-1-benzylpyrrolidin-3-yl)-N-methyle-
thanamine (14). A 200 mL pressure vessel was charged with 13 (5 g,
10 mmol) and toluene/heptane 1:1 (100 mL) and treated with
methylamine (10% wt, 10 g, 322 mmol). The mixture was heated at
60 °C for 15 h. The vessel was cooled to room temperature, and the
solvent was removed via rotary evaporation. The residue was taken up
in DCM (100 mL) and H2O (100 mL), and the aqueous layer was
adjusted to pH 2 with 1 M HCl; the organic layer was separated, and
the aqueous layer was extracted with DCM (3 × 75 mL). The
combined DCM layers were concentrated in vacuo to give 15 (see
below). The aqueous layer was adjusted to pH 13 with 1 M NaOH
and extracted with DCM (3 × 75 mL), and the combined organic
extracts were concentrated in vacuo to afford 14 (2.5 g, 80%) as a
brown oil: [α]23 4 (c 5.0, CHCl3); IR (ZnSe) 3210, 2830, 1540, 1170,
1
810, 720, 690 cm−1; H NMR (400 MHz, CDCl3) δ 7.38−7.31 (m,
10H), 5.13 (s, 4H), 3.91 (m, 1H), 3.79 (dd, 1H, J = 4, 12 Hz), 3.71−
3.49 (m, 3H), 3.36 (ddd, 1H, J = 6, 10, 17 Hz), 3.11 (m, 1H), 2.89 (s,
3H), 2.55 (m, 2H), 1.97 (m, 1H), 1.62 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 157.6, 154.9, 137.1, 136.6, 128.7, 128.6, 128.4, 128.2, 128.1,
127.9, 67.6, 66.9, 62.5, 50.9, 46.8, 38.2, 37.7, 29.8, 28.2; HRMS (ESI)
Calcd for C23H28N2O5 [M + H]+ 413.2071, found 413.2078; HPLC
%(AUC) = 94.3 (Symmetry C-18, gradient elution over 15 min of
acetonitrile and water, from 0 to 30%, tR = 10.5 min).
1
920, 720, 680 cm−1; H NMR (400 MHz, CDCl3) δ 7.36−7.22 (m,
10H), 4.51 (dd, 2H, J = 12, 14 Hz), 3.59 (dd, 2H, J = 13, 17 Hz), 3.55
(dd, 1H, J = 4, 10 Hz), 3.38 (dd, 1H, J = 4, 10 Hz), 2.73 (m, 1H), 2.57
(m, 1H), 2.49 (m, 2H), 2.42 (m, 2H), 2.38 (s, 3H), 2.08 (br s, 1H),
1.88 (m, 1H), 1.51 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 139.2,
138.5, 128.9, 128.5, 128.3, 127.7, 127.6, 126.9, 73.3, 69.7, 63.3, 60.7,
57.8, 54.1, 39.2, 34.3, 27.9; HRMS (ESI) Calcd for C21H29N2O [M + H]+
325.2274, found 325.2272; HPLC %(AUC) = 97.7 (Symmetry C-18,
gradient elution over 15 min of acetonitrile and water, from 0 to 30%,
tR = 4.7 min).
(R)-Benzyl 3-((S)-1-(((Benzyloxy)carbonyl)(methyl)amino)-2-
cyanoethyl)pyrrolidine-1-carboxylate (18). A solution of 17
(2.1 g, 5.1 mmol) in dichloromethane (30 mL) at 0 °C was treated
with triethylamine (0.9 mL, 6.7 mmol), followed by methanesulfonyl
chloride (0.44 mL, 5.7 mmol) dropwise over 10 min. The mixture was
stirred at 0 °C for 30 min and then quenched with saturated NaHCO3
(20 mL). The organic layer was separated and washed with H2O
(20 mL) and then brine (20 mL). The organic phase was dried over
MgSO4 and concentrated in vacuo to afford the mesylate ester as a
1-Benzyl-3-(2-(benzyloxy)ethylidene)pyrrolidine (15). A yel-
1
low oil: IR (ZnSe) 3180, 2850, 1510, 1120, 920, 740, 690 cm−1; H
NMR (400 MHz, CDCl3) δ 7.36−7.23 (m, 10H), 5.51 (m, 1H), 4.49
(s, 2H), 4.00 (dd, 2H, J = 1, 7 Hz), 3.63 (s, 2H), 3.18 (dd, 2H, J = 2, 3
Hz), 2.68 (t, 2H, J = 7 Hz), 2.43 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 143.5, 138.6, 138.5, 128.9, 128.4, 128.3, 127.8, 127.6, 127.2,
116.9, 72.1, 67.7, 60.6, 59.4, 54.1, 28.4; HRMS (ESI) Calcd for
C20H23NO [M + H]+ 294.1852, found 294.1854; HPLC %(AUC) =
1
thick oil, which was used immediately in the next reaction: H NMR
(400 MHz, CDCl3) δ 7.22−7.36 (m, 10H), 5.08 (m, 4H), 4.39
(m 1H), 4.22 (dd, 2H), 3.62 (m, 2H), 3.37 (m, 1H), 3.09 (m, 1H),
2.83 (s, 3H), 2.82 (s, 3H), 2.57 (m, 1H), 2.00 (m, 1H), 1.62 (m, 1H);
MS-APCI (m/z+) 491.1 (M + H).
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The crude mesylate was dissolved in methyl t-butyl ether (25 mL)
and treated with tetrabutylammonium cyanide (2.77 g, 10.3 mmol),
and the mixture was stirred at 50 °C for 3 h. The reaction mixture was
diluted with EtOAc (50 mL) and washed with saturated NaHCO3
(30 mL). The organic layer was separated and washed with H2O (30 mL)
and then with brine (30 mL). The organic phase was dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash
chromatograph (SiO2, hexane/EtOAc 10−80%), to afford 18 (2.03 g,
93%) as a clear viscous oil: [α]23 30.4 (c 5.0, CHCl3); IR (ZnSe) 3170,
bright yellow solid was dried under vacuum to give PF-00951966 (0.46
mg, 92%) as the hydrochloride salt: [α]23 −233.6 (c 5.0, H2O); IR
(ZnSe) 3450, 3170, 2940, 2210, 1650, 1430, 1380, 1120, 810, 710
1
cm−1; H NMR (400 MHz, D2O) δ 8.50 (s, 1H), 6.41 (d, 1H, J = 13
Hz), 4.07 (m, 1H), 3.83−3.71 (m, 3H), 3.51 (m, 3H), 3.30 (m, 2H),
2.93 (s, 3H), 2.81 (m, 2H), 2.34 (m, 2H), 1.89 (m, 1H), 1.32 (m, 1H),
1.14 (m, 1H), 1.02 (m, 1H), 0.89 (m, 1H); 13C NMR (100 MHz,
D2O) δ 174.8, 168.9, 153.3 (d, JC−F = 250 Hz), 150.0, 140.9, 137.2,
137.1, 134.3, 116.9, 116.2, 105.7, 104.8, 61.2, 57.0, 53.9, 41.4, 40.2,
30.9, 28.3, 18.1, 9.9, 8.3; HRMS (ESI) Calcd for C22H25FN4O4 [M + H]+
429.1933, found 429.1942; LCMS %(AUC) = 97.3 (Phenomenex
Develosil Combi RP3 50 × 4.6 mm column, gradient elution over 4 min
of acetonitrile and water, from 2 to 50%, tR = 0.83 min). Anal. Calcd for
C22H26ClFN4O4: C, 56.83; H, 5.64; N, 12.05. Found: C, 56.45; H, 5.78;
N, 11.87.
1
2950, 2820, 2230, 1680, 1460, 1320, 1150, 790, 740, 710 cm−1; H
NMR (400 MHz, CDCl3) δ 7.27−7.21 (m, 10H), 5.06 (s, 2H), 5.04
(s, 2H), 4.03 (br s, 1H), 3.57−3.42 (m, 2H), 3.31 (m, 1H), 3.03 (m,
1H), 2.88 (br s, 3H), 2.69−2.42 (m, 3H), 1.92 (m, 1H), 1.53 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 155.8, 154.6, 136.9, 136.3, 128.7,
128.6, 128.3, 128.1, 127.9, 127.8, 117.2, 68.1, 66.9, 49.7, 49.1, 45.9,
40.0, 29.8, 28.9, 20.4; HRMS (ESI) Calcd for C24H27N3O4 [M + Na]+
444.1894, found 444.1899; HPLC %(AUC) = 98.6 (Symmetry C-18,
gradient elution over 15 min of acetonitrile and water, from 0 to 30%,
tR = 11.5 min). Anal. Calcd for C24H27N3O4: C, 68.39; H, 6.46; N,
9.97. Found: C, 68.05; H, 6.57; N, 9.99.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of proton and carbon NMR spectra and single crystal X-
ray data. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: manjinder.lall@pfizer.com.
(S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1).
A solution of 18 (9.7 g, 23 mmol) in isopropanol (150 mL) under
argon was treated with 10% palladium on carbon (2 g) at 23 °C. The
mixture was hydrogenated in a Parr shaker under 50 psi of hydrogen at
23 °C for 4 h. The solution was filtered through a pad of Celite and
rinsed with acetonitrile (100 mL), followed by methanol (100 mL).
The solvent was removed via rotary evaporation, and the product was
dried under vacuum to afford 1 (3.39 g, 95%) as a clear oil, which was
used without further purification: [α]23 2.4 (c 5.0, CH3OH); IR
(ZnSe) 3370, 2950, 2820, 2150, 1630, 1530, 1450, 1380, 1350 cm−1;
1H NMR (400 MHz, CD3OD) δ 3.23 (m, 1H), 3.07 (m, 1H), 2.98
(m, 1H), 2.77 (m, 2H), 2.65 (m, 2H), 2.43 (m, 1H), 2.41 (s, 3H), 2.29
(m, 1H), 2.04 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 119.3, 60.7,
50.7, 47.2, 44.9, 33.7, 30.5, 21.2; HRMS (ESI) Calcd for C8H15N3
[M + H]+ 154.1339, found 154.1335.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Dr. Mike Melnick and Susan Hagen
for collaborative efforts and helpful discussions. For their
technical expertise, we extend our gratitude to Norman Colbry,
Mark Lovdahl, and Mark Marlatt. The staff in spectral and
analytical services at Pfizer is recognized for their assistance in
compound characterization. Finally, we thank Takasago Int.
Corp. for kindly donating a sample of [RuCl(p-cymene)((R)-
DM-SEGPHOS)]Cl.
REFERENCES
■
(1) (a) Ellsworth, E. L.; Taylor, C. B.; Murphy, S. T.; Rauckhorst, M.
R.; Starr, J. T.; Hutchings, K. M.; Limberakis, C.; Hoyer, D. W.
Preparation of quinolone antibacterial agents. WO 2005049602 A1,
June 2, 2005. (b) Murphy, S. T.; Case, H. L.; Ellsworth, E.; Hagen, S.;
Huband, M.; Joannides, T.; Limberakis, C.; Marotti, K. R.; Ottolini, A.
M; Rauckhorst, M.; Starr, J.; Stier, M.; Taylor, C.; Zhu, T.; Blaser, A.;
Denny, W. A.; Lu, G.-L.; Smaill, J. B.; Rivault, F. Bioorg. Med. Chem.
Lett. 2007, 17, 2150−2155.
7-((R)-3-((S)-2-Cyano-1-(methylamino)ethyl)pyrrolidin-1-yl)-
1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquino-
line-3-carboxylic Acid Hydrochloride (PF-00951966). A solution
of 1 (0.4 g, 2.6 mmol) in a mixture of isopropanol/methanol/
acetonitrile (1:1:1, 15 mL) under nitrogen was treated with crushed
molecular sieves (activated type 3A, 8−12 mesh, 0.4 g), followed by
difluoroquinone 20 (0.85 g, 2.5 mmol) and Ca(OH)2 (0.55 g, 7.5
mmol) at 23 °C. The mixture was heated to 30 °C for 6 h and then
cooled to room temperature, where stirring was continued for an
additional 22 h. The reaction mixture was treated with ethanol (5 mL)
and heated to 80 °C for 5 h. The mixture was then treated with
triethylamine (0.7 mL, 5 mmol) and heated at 80 °C for 7 h. The
solution was filtered through a pad of Celite and rinsed with
acetonitrile (25 mL), and the solvent was removed via rotary
evaporation. The product was dried under vacuum to afford the free
amine as a yellow solid (0.66 g, 63%). The yellow solid (0.46 g, 0.87
mmol) was suspended in dichloromethane (20 mL) and treated with
4 M HCI in dioxane (2.2 mL). The mixture was stirred at room
temperature for 18 h, and then the solvent was removed in vacuo. The
yellow solid was slurried in ethyl acetate and dichloromethane,
collected by vacuum filtration, and rinsed with ethyl acetate. The
(2) (a) Theuretzbacher, U. Curr. Opin. Pharmacol. 2011, 11, 433−
438. (b) Andersson, D. I.; Hughes, D. Nat. Rev. Microbiol. 2010, 8,
260−271. (c) Alekshun, M. N. Expert Opin. Invest. Drugs 2005, 14,
117−134. (d) Norrby, S. R.; Nord, C. E.; Finch, R. Lancet Infect. Dis.
2005, 5, 115−119. (e) Bad Bugs, No Drugs: As Antibiotic Discovery
Stagnates ... A Public Health Crisis Brews; Infectious Diseases Society of
America: Alexandria, VA, 2004. (f) Boggs, A. F. Expert Opin. Ther. Pat.
2003, 13, 1107−1112. (g) Walsh, C. In Antibiotics: Actions, Origins,
Resistance; American Society for Microbiology (ASM) Press:
Washington, D.C., 2003; pp 89−155. (h) Wright, G. D. Chem. Biol.
2000, 7, R127−R132.
(3) (a) O’Donnell, E. P.; Hurt, K. M.; Scheetz, M. H.; Postelnick, M.
J.; Scarsi, K. K. Drugs Today 2009, 45, 379−393. (b) Zetola, N.;
Francis, J. S.; Nuermberger, E. L.; Bishai, W. Lancet Infect. Dis. 2005, 5,
275−286. (c) Huang, V.; Zervos, M. J. Infect. Dis. Clin. Pract. 2005, 13,
93−95. (d) Kaplan, S. L. Pediatr. Infect. Dis. J. 2005, 24, 457−458.
(e) Pfaller, M. A.; Jones, R. N.; Doem, G. V.; Kugler, K. Antimicrob.
Agents Chemother. 1998, 42, 1762−1770.
4738
dx.doi.org/10.1021/jo3004716 | J. Org. Chem. 2012, 77, 4732−4739

The Journal of Organic Chemistry
Article
(4) (a) Won, S. Y.; Munoz-Price, L. S.; Lolans, K.; Hota, B.;
Weinstein, R. A.; Hayden, M. K. Clin. Infect. Dis. 2011, 53, 532−540.
(b) Butler, M. S.; Cooper, M. A. J. Antibiot. 2011, 64, 413−425.
(c) Dougherty, T. J.; Magee, T. V. Exp. Opini. Ther. Pat. 2005, 15,
1409−1421. (d) Levy, S. B.; Marshall, B. Nat. Med. 2004, 10
(12,Suppl.), S122−S129. (e) Baquero, F. J. Antimicrob. Chemother.
1998, 39, 1−6. (f) Swartz, M. N. Proc. Natl. Acad. Sci. U. S. A. 1994,
91, 2420−2427.
separation using an analytical CHIRALCEL OJ-H column (0.46 × 25
cm, 15% isopropanol-hexane, 0.8 mL/min). The four stereoisomers
eluted with retention times of 13.3, 17.2, 20.8, and 24.3 min.
(14) See the Supporting Information for details.
(15) The syn (11a/b) and anti-stereoisomer (11c/d) products are
not interconvertible under the prescribed reactions conditions.
(16) Netscher, T.; Bohrer, P. Molecules 2002, 7, 601−617.
(17) Sulfonate esters were prepared in a similar manner as p-nosylate
13; see the Experimental Section for details.
(18) (a) Beak, P.; Basha, A.; Kokko, B.; Loo, D. J. Am. Chem. Soc.
1986, 108, 6016−6023. (b) Nordlander, J. E.; Catalane, D. B.;
Eberlein, T. H.; Farkas, L. V.; Howe, R. S.; Stevens, R. M.; Tripoulas,
N. A. Tetrahedron 1978, 4987−4990.
(19) The SN2 substitution reactions were run in a similar manner as
the conditions used to prepare diamine 14; see the Experimental
Section for details.
(5) Domagala, J. M., Hagen, S. E. In Quinolone Antimicrobial Agents;
Hooper, D. C., Rubinstein, E., Eds.; American Society for Micro-
biology (ASM) Press: Washington, D.C., 2003; pp 3−17.
(6) (a) Fleck, T. J.; McWhorter, W. W., Jr.; DeKam, R. N.; Pearlman,
B. A. J. Org. Chem. 2003, 68, 9612−9617. (b) Cohen, M. A.; Huband,
M. D.; Gage, J. W.; Yoder, S. L.; Roland, G. E.; Gracheck, S. J. J.
Antimicrob. Chemother. 1997, 40, 205−211.
(7) For examples on catalytic asymmetric hydrogenation of β-keto
amides and leading references, see: (a) Limanto, J.; Krska, S. W.;
Dorner, B. T.; Vazquez, E.; Yoshikawa, N.; Tan, L. Org. Lett. 2010, 12,
512−515. (b) Touati, R.; Gmiza, T.; Jeulin, S.; Deport, C.;
Ratovelomanana-Vidal, V.; Ben Hassine, B.; Genet, J.-P. Synlett
2005, 2478−2482. (c) Yuwasa, Y.; Sotoguchi, T.; Seido, N. A Process
for Producing Optically Active Derivatives. Eur. Pat. Appl. 855 390 B1,
April 10, 2001. (d) Le Gendre, P.; Offenbecher, M.; Bruneau, C.;
Dixneuf, P. H. Tetrahedron: Asymmetry 1998, 9, 2279−2284.
(e) Huang, H.-L.; Liu, L. T.; Chen, S.-F.; Ku, H. Tetrahedron:
Asymmetry 1998, 9, 1637−1640. (f) Noyori, R.; Takaya, H. Acc. Chem.
Res. 1990, 23, 345−350. (g) Kitamura, M.; Ohkuma, T.; Inoue, S.;
Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.;
Noyori, R. J. Am. Chem. Soc. 1988, 110, 629−631.
(20) The exception was NaN3 (5 equiv of NaN3, DMF, 0−23 °C, 15
h), which gave the desired azide substituted product with no detection
of olefin by LCMS.
(21) Methylamine has a dielectric constant (ε) of 9.4 at 25 °C.
Methanol has a dielectric constant (ε) of 32.63 at 25 °C. CRC
Handbook of Chemistry and Physics, 63rd ed.; Weast, R. C., Astle, M. J,
Eds.; CRC Press: Boca Raton, FL, 1982: pp E−51.
(22)
(8) For reviews on chiral ruthenium-phosphine complexes, see:
(a) Kacer, P.; Kuzma, M.; Leitmannova, E.; Cerveny, L. Organomet.
Compd. 2010, 373−401. (b) Mezzetti, A. Dalton Trans. 2010, 39,
7851−7869. (c) Sumi, K.; Kumobayashi, H. Topics Organomet. Chem.
2004, 6, 63−95. (d) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029−
3069. (e) Ager, D. J.; Lanemam, S. A. Tetrahedron: Asymmetry 1997, 8,
3327−3355. (f) For a discussion on reactions and leading references,
see: Wan, X.; Sun, Y.; Luo, Y.; Li, D.; Zhang, Z. J. Org. Chem. 2005, 70,
1070−1072. (g) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo,
N.; Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264−
267.
(23) Nitrile 18 and authentic sample1 coeluted by chiral HPLC using
an analytical CHIRALCEL OJ-H column (0.46 × 25 cm, 15%
isopropanol-hexane, 0.8 mL/min) with a retention time of 37.4 min.
1H NMR (CDCl3, 400 MHz) of 18 and authentic sample1 were in
good agreement.
(24) Methylamine substitution with inversion of configuration is the
desired and expected mode of nucleophilic attack; however, a number
of alternative reaction pathways are feasible, which would lead to
alternative products (i.e., anchimeric assistance from O-2′ or N-1 could
give intermediates A or B, respectively, leading to 14 with retention of
configuration at the 1′-position or structural isomer products of 14.
(9) (a) Holub, N.; Neidhofer, J.; Blechert, S. Org. Lett. 2005, 7,
̈
1227−1229. (b) Uenishi, J.; Hamada, M.; Aburatani, S.; Matsui, K.;
Yonemitsu, O.; Tsukube, H. J. Org. Chem. 2004, 69, 6781−6789.
(c) Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron 1997,
53, 13633−13640. (d) Sato, T.; Otera, J. Synlett 1995, 336−338.
(e) Cowdrey, W. A.; Hughes, E. D.; Ingold, C. K; Masterman, S.;
Scott, A. D. J. Chem. Soc. 1937, 1252−1271.
(10) On the basis of LCMS and 1H NMR, side-products appear to be
1-benzyl-2-pyrrolidinone homocondensation products and γ-lactam
ring-opened product.
(11) (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn.
1995, 68, 36−55. (b) Akutagawa, S. Appl. Catal., A 1995, 128, 171−
207. (c) Takaya, H.; Ohta, T.; Noyari, R. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers, Inc.: New York, 1993; pp 1−
39. (d) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura,
M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.;
Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134−9135.
(12)
(13) Stereoisomer ratio (1:1:1:1) of sample 11a/b/c/d, prepared
from the Raney Ni reduction, was assessed directly by chiral HPLC
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