Acid-facilitated debenzylation of N-Boc, N-benzyl double protected 2-aminopyridinomethyl pyrrolidine derivatives

Article abstract of DOI:10.1016/j.tet.2011.12.013

2-Aminopyridinomethyl pyrrolidines represent a class of highly potent and selective neuronal nitric oxide synthase inhibitors. Conditions for a Mitsunobu reaction of a naphthol and a hindered secondary alcohol were optimized to give good to excellent yiel

Full text of DOI:10.1016/j.tet.2011.12.013

Tetrahedron 68 (2012) 1359e1366
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Acid-facilitated debenzylation of N-Boc, N-benzyl double protected
2-aminopyridinomethyl pyrrolidine derivatives
,
b
,
,
,
b
,
,b,
*
Haitao Ji a y, Qing Jing a b, Jinwen Huang a z, Richard B. Silverman a
a Department of Chemistry, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston,
IL 60208-3113, United States
b Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road,
Evanston, IL 60208-3113, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 October 2011
Received in revised form 28 November 2011
Accepted 6 December 2011
Available online 13 December 2011
2-Aminopyridinomethyl pyrrolidines represent a class of highly potent and selective neuronal nitric
oxide synthase inhibitors. Conditions for a Mitsunobu reaction of a naphthol and a hindered secondary
alcohol were optimized to give good to excellent yields. A key step in the synthesis of these inhibitors is
the deprotection of the benzyl group from the N-Boc and N-Bn double protected 2-aminopyridine ring at
a late stage of the synthesis, which has been proven difficult in our previous syntheses. Acetic acid was
found to facilitate the N-Bn deprotection.
Keywords:
2-Aminopyridinomethyl pyrrolidines
Mitsunobu reaction
Ó 2011 Elsevier Ltd. All rights reserved.
N-Benzyl deprotection
Palladium-catalyzed hydrogenation
1. Introduction
molecule inhibitors with a 2-aminopyridinomethyl pyrrolidine
scaffold (1e3 in Fig. 1).2,3 The 2-aminopyridine group was used to
In our continued efforts to develop neuronal nitric oxide syn-
thase (nNOS)-selective inhibitors,1 we established a new approach
for fragment-based de novo design, called fragment hopping.2 The
core of this approach is the derivation of the minimal pharmaco-
phoric element for each pharmacophore. The minimal pharmaco-
phoric element can be an atom, a cluster of atoms, a virtual graph or
vectors. The new fragments that match the requirements of the
minimal pharmacophoric elements are generated and hopped onto
the corresponding position in the active site using LUDI fragment
libraries. After linking the fragments by LUDI linker library, new
inhibitors with novel scaffolds can be generated. The key features
for both ligand binding affinity and isozyme selectivity can be in-
cluded in the definition of minimal pharmacophoric elements,
which leads to the generation of new inhibitors with greater iso-
zyme selectivity. By using this new approach and starting with
dipeptide inhibitors (e.g., DIP1, DIP3, DIP9, Fig. 1), we were able to
discover a series of novel highly potent and nNOS-selective small-
mimic the amidino moiety of the nitroguanidino group of DIP1,
DIP3, and DIP9. The pKa value of 2-amino-2,4-dimethylpyridine is
7.1.4 This fragment could act as a charge bioswtich. In the small
intestine, the fragment could be in its neutral form, which is fa-
vorable for absorption; in the NOS active site, the local acidic en-
vironment would convert it into the protonated form, which is
favorable for binding. The pyrrolidino fragment of 1 was generated
as a substitute for the a-amino group of the dipeptide inhibitors
that was responsible for the nNOS/eNOS (endothelial nitric oxide
synthase) selectivity of DIP1, DIP3, and DIP9. First, the dipeptide
inhibitors adopt distinctly different conformations in nNOS and
eNOS.5 By replacing the inhibitor
a-amino group with a rigid pyr-
rolidine secondary amine, the pyrrolidine amino group is locked in
a conformation for enhanced interactions with nNOS D597 (the
corresponding position in eNOS is N368), favoring nNOS selectivity.
Second, a secondary amino group is more lipophilic and has less
polar surface area compared with a primary amino group, which is
better for membrane permeability. The introduction of halogen-
substituted phenyl group increases inhibitor lipophilicity and also
the selectivity between nNOS over iNOS (inducible nitric oxide
synthase) because the corresponding pocket is L337 in nNOS
and T121 in iNOS.6 Compounds 2 and 3 exhibit the highest
in vitro nNOS inhibitory potency and nNOS selectivity over eNOS
reported to date.7e9
* Corresponding author. Tel.: þ1 847 491 5653; fax: þ1 847 491 7713; e-mail
address: Agman@chem.northwestern.edu (R.B. Silverman).
y
Current address: Department of Chemistry, University of Utah, Salt Lake City,
UT 84112-0850, United States
z
Current address: Shanghai HotMed Sciences Co., Ltd., Shanghai Zhangjiang
Hi-Tech Park, 211-214 NO.518, Bibo Road, Shanghai, China
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.013

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H. Ji et al. / Tetrahedron 68 (2012) 1359e1366
Fig. 1. nNOS inhibitor design by fragment hopping.
One key step in the synthesis of this series of inhibitors is the
observed that the yields for deprotection of the N-Bn group at a late
stage in the synthesis were not reproducible, leading to recovery of
the starting material, generating new spots at the baseline of the
TLC, or causing reduction of the pyridine ring, thereby generating 2-
amino cyclic amidine derivatives 9 and 11 (Fig. 2).13,14
conversion of trans-alcohols 4 to cis-amines or cis-alcohols 5
(Scheme 1). It was found that mono-Boc-protected 40-[(6-
aminopyridin-2-yl)methylpyrrolidin]-30-ol (4) underwent an
intramolecular cyclization to generate 7 instead of the desired ad-
dition by an external nucleophile in our original SN2 or Mitsunobu
experiments (Scheme 1).2,3 Later, we found that double protection
of the remote 2-amino group of the pyridine ring by a Boc/Bn or
Boc/Boc combination can effectively block intramolecular cycliza-
tion.10 With dual protection, Mitsunobu reactions proceed
smoothly to generate 6 (Scheme 1).
The Boc/Boc combination was then pursued as an alternative
protection strategy for the Mitsunobu reactions.10 Although this
strategy requires two more steps (protection of the 3-hydroxyl
group in 4 with TBS, and then deprotection of TBS with TBAF af-
ter the second Boc group is added to the 2-amino group of the
pyridine ring), it was found that each step can be achieved in high
yields (>95%), and the deprotection of the Boc group is facile.10 This
approach has been used in the synthesis of derivatives in this
class.15 However, the second N-Boc group on the same amine is
labile to various bases. Our recent study demonstrated that di-Boc
deprotected 40-[(6-aminopyridin-2-yl)methylpyrrolidin]-30-ol (5b)
can cause a fast N/O Boc migration via a base-generated alkox-
ide.16 The mechanism of the migration is intramolecular, impli-
cating an unusual nine-membered cyclic transition state.
2. Results and discussion
In our ongoing search for new nNOS-selective inhibitors based
on scaffolds 1 and 2, we were interested in synthesizing more li-
pophilic derivatives (13, Scheme 2) using a Mitsunobu reaction.
Although quite a few successful examples have been reported for
the reaction between
a secondary alcohol and a phenolic
group,17e19 the reaction between a secondary alcohol and a steri-
cally hindered phenolic hydroxyl group is challenging. Reaction
times usually require 3e7 days or the reaction concentration of the
starting material has to be increased to 3 M and then subjected to
sonication.20 In our study, a model reaction using 5 (R¼Me; P¼Boc
Scheme 1.
The Boc/Bn combination was then used as a standard protection
strategy for the Mitsunobu chemistry of this class of in-
hibitors.3,8,11,12 Deprotection of the N-Bn group can be achieved by
20% Pd(OH)2/C, 1 atm of hydrogen, 60 ꢀC in EtOH for
24ꢁ48 h,3,8,11e14 or 20% Pd(OH)2/C, 2:1 EtOH/HCl (12 N), room
temperature, 575 psi of hydrogen for 48 h.11 However, it was
or SEM) and a-naphthol as the substrate was conducted to identify
optimal reaction conditions, as summarized in Supplementary
Table 1. No product was generated, as detected by TLC, by varying
the protecting group (P) from Boc to [(trimethylsilyl)ethoxy]methyl
A13
Boc
N
Boc
N
Boc
Boc
F
F
F
F
Pd(OH)2/C, , 1atm. H2
Boc
N
F
F
Boc
Boc
N
F
N
Bn
N
N
O
O
N
H
N
O
EtOH, 60°C, 48h
(55%)
8
9
Boc
N
Boc
N
B14
Boc
N
Boc
N
Pd(OH)2/C, 575 psi. H2
Boc
F
N
Bn
N
N
O
H
2:1 EtOH/HCl (12 M), rt, 40h
(quantitative)
11
10
Fig. 2. Debenzylation of Boc/Bn or Boc/Boc-diprotected analogs 7 and 9.

H. Ji et al. / Tetrahedron 68 (2012) 1359e1366
1361
Boc
N
Boc
N
OH
DIAD, Ph3P
+
R1
Boc
Boc
THF
N
P
N
OH
N
P
N
O
R1
13
5
12
Scheme 2.
(SEM). No product was generated when the concentration of the
starting material was increased to 0.06 M, DIAD was changed to
DEAD, or the reaction time was extended to 3 days. When the re-
action mixture was heated to reflux for 24 h18,21 or a base (Et3N)
was added, as suggested in the literature,22 the product was
detected by TLC, but significant amounts of impurities were gen-
erated, which made silica gel column purification extremely
difficult.
Recognizing that the base might be able to play an important
role in facilitating the reaction,23e25 different bases were tried with
another set of starting materials (enantiomer 14 with 15 in Scheme
3). One reason to use 15 is that the electron-withdrawing effect of
the 4-fluoro-3-trifluoromethylphenyl group might enhance the
pyrrolidine hydroxyl group of the other starting material, although
no definitive data were obtained to substantiate that hypothesis.
When 19 was allowed to react with
a-naphthol by the same
protocol, the yield of product was much higher (Scheme 4B);
desired product 20 was isolated in a 70% yield by silica gel column
chromatography. When 21 was subjected to the Mitsunobu re-
action with
a-naphthol by the same protocol, a 91% yield of
product 22 was generated after silica gel column chromatography
(Scheme 4C). This protocol (0.02 M of 21 allowed to react with
0.03 M of a-naphthol, 0.03 M of DIAD, and 0.03 M of Ph3P in an-
hydrous THF from 0 ꢀC to room temperature for 14 h) was used as
the standard protocol for the Mitsunobu reaction of this series of
compounds.
Boc
OH
Boc
N
N
Ph3P, DIAD
+
Boc
Boc
Base, THF
0 °C − rt
N
N
OH
N
SEM
N
O
SEM
F
CF3
F
16
14
15
CF3
Scheme 3.
acidity of the a-naphthol. However, without a base, no product was
detectable by TLC after the reaction mixture was stirred for 26 h at
room temperature (other reaction conditions remain the same as
entry 1 in Supplementary data Table 1). When 5 equiv of Et3N was
added to the reaction mixture, desired product 16 was isolated by
silica gel column chromatography in a 19% yield after 18 h of stir-
ring at room temperature. The structure of the product was con-
firmed by NMR and high-resolution mass spectrometries. Other
bases were tried to see whether or not the reaction yield could be
A
Boc
N
Boc
N
HO
N
N
Boc
Boc
N
H
O
O
O
N
H
OH
OH
OH
DIAD, Ph3P
THF, 0~25°C
(21%)
(
)-18
(
)-17
B
Boc
N
€
Boc
N
increased. Hunig’s base (N,N-diisopropylethylamine) or 4-
HO
methylmorpholine afforded better yields (25% and 23%, re-
spectively), while 2,6-lutidine offered a worse result (<10% yield).
One general problem observed in the base-promoted Mitsunobu
reaction was that more impurities were generated, which made
product purification extremely difficult.
Having experienced the difficulty with the Mitsunobu reactions
using the Boc/Boc or Boc/SEM protecting strategy, we decided to
return to the Boc/Bn protecting strategy, because the lesson we
learned was protection of the 2-amino group can affect remote
SN2 reactions. A related compound (17, Scheme 4),3 did not un-
dergo the previously observed intramolecular cyclization in the
Mitsunobu reaction because of ring strain; instead, the Mitsunobu
reaction proceeded smoothly in a 52% yield when diphenylphos-
phorylazide (DPPA) was used as the nucleophile, as reported in
our previous study.9 Compound 17 was, therefore, used in a Mit-
Boc
Boc
N
Bn
N
N
Bn
N
DIAD, Ph3P
THF, 0~25°C
(70%)
(
)-20
(
)-19
C
Boc
N
Boc
N
HO
Boc
Boc
N
Bn
N
N
Bn
N
DIAD, Ph3P
THF, 0~25°C
(91%)
(
)-22
(
)-21
Scheme 4.
Encouraged by the results from the Boc/Bn protecting group
strategy, the para-methoxybenzyl (PMB) protecting group was also
tried. Compound 23 was deprotonated with NaH in DMF and then
allowed to react with PMBCl to generate 24 in a 78%, which was
then subjected to the Mitsunobu reaction by the protocol discussed
above to successfully generate 25 in an 85% yield (Scheme 5).
However, deprotection of the N-PMB group again proved to be
difficult. Various catalytic hydrogenation reactions were tried, as
shown in Supplementary Scheme 1. When 10% palladium on acti-
vated carbon was used as the catalyst, 25 was not converted to the
sunobu reaction with
reaction was surprisingly clean. When 0.02 M of 17 was allowed to
react with 0.03 M of -naphthol in anhydrous THF at room tem-
a-naphthol. As shown in Scheme 4A, this
a
perature for 14 h, only two products were generated. Desired
product 18 was easily isolated by silica gel column chromatogra-
phy in a 21% yield. The major product (in a 66% yield) was sus-
pected to be a self-assembled oligomer via an intermolecular
attack by the pyridine nitrogen of one starting material on the

1362
H. Ji et al. / Tetrahedron 68 (2012) 1359e1366
Boc
HO
N
Boc
N
Boc
N
PMBCl
Boc
Boc
Boc
NaH, DMF
(78%)
DIAD, Ph3P
THF, 0~25°C
(85%)
N
PMB
N
OH
N
PMB
N
O
N
H
N
OH
(
)-23
( )-24
(
)-25
Boc
N
CAN
Boc
N
H
N
O
CH3CN/H2O
1h
(15%)
( )-26
Scheme 5.
deprotected product under a hydrogen atmosphere at room tem-
perature; only starting material was recovered. When 20% Pd(OH)2/C
was used as the catalyst, 25 was not converted to the product (26) at
room temperature or 40 ꢀC. Less than 10% of 26 was generated when
the reaction mixture was stirred under a hydrogen atmosphere at
60 ꢀC for 24 h. The N-PMB group of 25 also could not be removed with
the oxidative reagent 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ);
all of the starting material was recovered by silica gel column chro-
matography after the reaction mixture was stirred at room temper-
ature for 24 h. On the other hand, 25 undergoes a rapid and complete
reaction in 1 h using ceric ammonium nitrate (CAN) as the oxidant. In
all of the starting material disappeared, but the yield of 26 was only
26% after silica gel column chromatography (Scheme 6A). Other by-
products, which would not migrate even when 100% EtOAc was
used as eluent, stayed at the baseline. Another series of compounds
was subjected to debenzylation conditions, as shown in Scheme 6B.
One millimole of 27 in 60 mL of EtOH was allowed to hydrogenate
with 300 mg of 20% Pd(OH)2/C at 1 atm of hydrogen. A similar re-
sult was observed, namely, that 27 was totally consumed in the
reaction, but only 65% of 28 was obtained after silica gel column
purification. This reaction was repeated three times, and the yield
was consistently about 65%.
A
Boc
N
Boc
N
20% Pd(OH)2/C
Boc
Boc
N
H
N
O
N
Bn
N
N
O
O
H2, EtOH,
60 °C, 24h
(26%)
( )-26
( )-22
Boc
N
Boc
N
B
20% Pd(OH)2/C
Boc
Boc
H2, EtOH
60 °C, 24 h
(65%)
N
OH
N
H
N
O
OH
Bn
28
27
Scheme 6.
the CAN reaction, however, many impurities were generated, which
made the separation of the product very difficult; compound 26 was
obtained in a yield of 15% after silica gel column chromatography.
Another reason why more impurities were generated in the CAN
reaction and the yield of the product was so low is because of the
After consideration of the reaction mechanism, an acid additive,
such as acetic acid, was thought to be helpful for the reaction be-
cause hydrogenolysis of more polarized
s bonds is easier than
nonpolarized bonds.27 Protonation of the pyridine ring can polarize
the BneN bond and make the BneN bond more electrophilic for
surface hydride attack in hydrogenolysis. When variable equiva-
lents of acetic acid (0.5, 1, 1.5 or 2 equiv) was added to the reaction
mixture as an additive, and the other reaction conditions were kept
the same as those in Scheme 6, the yields of products in all re-
actions were constant and dramatically increased compared with
those without acetic acid. The yield of product for starting material
22 was increased to over 60%, while the yield of product from 27
was increased to 89%. The time to complete the reaction was
shortened to 14 h. This reaction was repeated twice for 27, and the
yields were consistently high. Compound 27 was further used to
optimize the reaction conditions. It was found that when the
quantity of 20% Pd(OH)2/C was cut in half (150 mg per 1 mmol of
27), the reaction gave the same yield. However, if the quantity of
electron-rich character of the
product.
a-naphthol ether substructure in the
DDQ oxidation can be a much cleaner reaction, as it was re-
ported that the 2,4-dimethoxybenzyl protecting group of Boc-
protected amines can be easily deprotected by DDQ.26 An alterna-
tive protection and deprotection strategy was proposed, as shown
in Supplementary Scheme 2. However, the synthesis of 2,4-
dimethoxybenzyl halides could not be achieved after several at-
tempts because of the electron-rich benzene.
Therefore, deprotection of the N-benzyl group of 22 was
attempted again. It was found that when 45 mg of 20% Pd(OH)2/C
was used with 0.15 mmol of 22 in 10 mL of EtOH, and the reaction
mixture was stirred at 60 ꢀC for 24 h under a hydrogen atmosphere,

H. Ji et al. / Tetrahedron 68 (2012) 1359e1366
1363
20% Pd(OH)2/C, was reduced to 100 mg/1 mmol of starting mate-
rial, or the reaction mixture was left at room temperature or
maintained at 40 ꢀC, the yields of product decreased. The reaction
time of ꢂ14 h also was important. Reaction times of 14 or 18 h
afforded complete conversion of the starting material with similar
yields, while reaction times of 6 or 10 h left significant amounts of
starting material, as monitored by NMR spectrometry. A possible
mechanism that explains the role of the acetic acid is shown in
Supplementary Scheme 3.
with phosphomolybdic acid or ninhydrin spray reagent or with
a UVevisible lamp. Column chromatography was performed with
silica gel 60 (230e400 mesh). Tetrahydrofuran (THF) and ethyl
ether were redistilled under nitrogen using sodium and benzo-
phenone as the indicator. Dichloromethane was redistilled from
CaH2 under nitrogen. Other dry solvents were directly purchased
from the companies.
4.2. General procedure for the Mitsunobu reaction
Additional substrates gave similarly high yields with the newly
developed protocol (1 mmol substrate in 60 mL of EtOH containing
1.5 mmol of acetic acid allowed to hydrogenate with 150 mg of 20%
Pd(OH)2/C at 1 atm hydrogen and 60 ꢀC for 14 h), as shown in
Scheme 7. Compound 29 can be smoothly converted to 30 in a yield
of 90%. The reaction was run three times, and the yield was re-
producible. Compound 31 was converted to 32 in a yield of 90%, and
8 was converted to 33 in a yield of 87%. Reactions of 8 and 31 were
repeated twice, and the yields were reproducible. By using this new
protocol, none of the 2-amino cyclic amidine products (see Fig. 2)
was observed with any of the substrates (8, 22, 27, 29, and 31)
tested so far, which had been a serious problem with molecules
subjected to this synthetic route.
To a solution of triphenylphosphine (Ph3P, 0.079 g, 0.3 mmol),
the starting alcohol (0.2 mmol), and
a-naphthol (0.043 g,
0.3 mmol) in dry THF (10 mL) was added dropwise diisopropyl
azodicarboxylate (DIAD, 0.061 g, 0.060 mL, 0.3 mmol) at 0 ꢀC. The
solution was stirred at 0 ꢀC for 1 h and then at room temperature
overnight (13 h). The reaction mixture was concentrated in vacuo,
and the crude residue was purified by silica gel column chroma-
tography to yield the product.
4.2.1. (ꢃ)-tert-Butyl 3-{{20-[(tert-butoxycarbonyl)amino]-60-methyl-
pyridin-40-yl}methyl}-4-hydroxypyrrolidine-1-carboxylate (17). 1H
NMR (CDCl3, 500 MHz):
d
7.649e7.582 (m, 2H), 6.639 (s, 1H), 4.062
A
Boc
N
Boc
N
Pd(OH)2/C
HOAc, , 1 atm H2
OH
Boc
Boc
OH
EtOH, 60 °C
(90%)
N
Bn
N
N
O
O
N
H
N
O
30
29
Boc
N
Boc
N
B
Pd(OH)2/C
Boc
N
Boc
N
Boc
F
F
Boc
F
HOAc, 1atm. H2
N
Bn
N
H
N
O
°
EtOH, 60 C, 14h
32
31
(90%)
Boc
N
C
Boc
N
Boc
N
Pd(OH)2/C
Boc
F
F
F
F
HOAc, 1atm. H2
Boc
Boc
N
F
N
Bn
N
O
N
H
N
O
°
EtOH, 60 C, 14h
8
33
(87%)
Scheme 7.
3. Conclusions
Reaction conditions for a Mitsunobu reaction of
(m, 1H), 3.684e3.497 (m, 2H), 3.286e3.234 (m, 1H), 3.100 (m, 1H),
2.769e2.730 (m, 1H), 2.518e2.378 (m, 5H), 1.496 (s, 9H), 1.448 (s,
a
-naphthol with
9H). 13C NMR (CDCl3, 125.7 MHz):
d 156.923 (1C), 154.830 (1C),
a hindered secondary alcohol have been optimized. A variety of
reaction conditions were tried for debenzylation of an N-tert-
butyloxycarbonyl (N-Boc) and N-benzyl (N-Bn) double protected 2-
aminopyridine, and it was shown that low yields of debenzylated
product were obtained unless 1.5 equiv of acetic acid is added
during hydrogenolysis.
152.644 (1C), (151.766þ151.689) (1C), 151.515 (1C), 118.711 (1C),
109.476 (1C), 80.971 (1C), (79.698þ79.629) (1C), (74.414þ73.833)
(1C), (52.682þ52.431) (1C), (49.061þ48.891) (1C), (46.957þ46.419)
(1C), 37.180 (1C), 28.619 (3C), 28.394 (3C), 23.999 (1C). MS (ESI,
CH2Cl2): [C21H33N3O5] m/z 407.9 ([MþH]þ).
4.2.2. (ꢃ)-tert-Butyl 3-{{20-[(tert-butoxycarbonyl)amino]-60-methyl-
pyridin-40-yl}methyl}-4-(naphthalen-1-yloxy)pyrrolidine-1-
carboxylate (18). Column chromatography (hexanes/EtOAc¼7:3).
4. Experimental section
4.1. General methods, reagents, and materials
1H NMR (CDCl3, 400 MHz):
d 8.300e8.271 (m, 1H), 7.965 (m, 1H),
7.828e7.802 (m, 1H), 7.677e7.667 (m, 1H), 7.548e7.499 (m, 2H),
7.475e7.434 (m, 1H), 7.365e7.307 (m, 1H), 6.712e6.660 (m, 1H),
6.583 (s, 1H), 4.848e4.800 (m, 1H), 3.811e3.485 (m, 4H),
3.123e3.056 (m, 1H), 2.973e2.907 (m, 1H), 2.773e2.692 (m, 1H),
2.244 (s, 3H), 1.471 (s, 9H), (1.453þ1.379) (m, 9H). 13C NMR (CDCl3,
All reagents were used without further purification unless
stated otherwise. 1H NMR and 13C NMR spectra were recorded in
CDCl3. Chemical shifts are reported as values in parts per million
(ppm) and the reference resonance peaks set at 0 ppm
[TMS(CDCl3)] for 1H NMR spectra and 77.23 ppm (CDCl3) for 13C
NMR spectra. Thin-layer chromatography was carried out on pre-
coated silica gel 60 F254 plates with visualization accomplished
125.7 MHz):
d
156.86 (1C), (154.40þ154.35) (1C), 152.55 (1C),
152.41 (1C), 152.34 (1C), 151.57 (1C), 151.42 (1C), 151.39 (1C),
(134.76) (1C), 134.72 (1C), (127.66þ127.56) (1C), (126.68þ126.49)

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H. Ji et al. / Tetrahedron 68 (2012) 1359e1366
(1C), (126.24þ126.18) (1C), (125.64þ125.59) (1C), 125.38 (1C),
(121.94þ121.78) (1C), 120.90 (1C), 118.85 (1C), 108.86 (1C),
(106.00þ105.86) (1C), (80.83þ80.79) (1C), (79.82þ79.61) (1C),
(76.77þ76.10) (1C), (51.49þ51.03) (1C), (49.48þ49.13) (1C),
(44.93þ42.26) (1C), (33.03þ32.92) (1C), (28.48þ28.39þ28.24) (6C),
23.77 (1C). HRMS (ESI, CH3OH) calcd for C31H40N3O5 533.2890;
found 533.2887.
117.243 (1C), 105.106 (1C), 81.382 (1C), 79.617 (1C), (70.798þ70.068)
(1C), (51.561þ51.217þ50.028) (1C), (49.731þ49.324) (1C),
(43.022þ42.466) (1C), 34.636 (1C), (28.635þ28.571) (3C), 28.296
(3C), (22.146þ22.087) (1C). HRMS (ESI, CH3OH) calcd for C38H45N3O5
623.3359; found 623.3358.
4.2.7. (ꢃ)-tert-Butyl 3-{{60-[(tert-butoxycarbonyl)amino]-40-methyl-
pyridin-20-yl}methyl}-4-hydroxypyrrolidine-1-carboxylate (23). 1H
4.2.3. (ꢃ)-tert-Butyl 3-{{6-[benzyl(tert-butoxycarbonyl)amino]pyr-
idin-2-yl}methyl}-4-hydroxypyrrolidine-1-carboxylate (19). 1H NMR
NMR (CDCl3, 500 MHz):
d
(8.032e7.994þ7.787e7.757) (m, 1H),
7.662 (s, 1H), 6.664e6.650 (m, 1H), 5.338 (br s, 1H), 4.111e4.104 (m,
1H), 3.766e3.574 (m, 2H), 3.260e3.043 (m, 2H), 2.843e2.721 (m,
2H), 2.475e2.381 (m, 1H), 2.307 (s, 3H), 1.479 (s, 9H), 1.446 (s, 9H).
(CDCl3, 500 MHz):
d 7.572e7.458 (m, 2H), 7.291e7.192 (m, 5H),
6.880e6.853 (m, 1H), 5.184e5.159 (m, 2H), 4.045 (m, 1H),
3.716e3.532 (m, 2H), 3.213e3.154 (m, 1H), 3.115e3.057 (m, 1H),
2.938e2.728 (m, 2H), 2.458e2.403 (m, 1H), 1.449e1.438 (m, 18H).
13C NMR (CDCl3, 125.7 MHz):
(154.618þ154.521) (1C),
d
(157.457þ157.395) (1C),
(152.478þ152.428) (1C),
13C NMR (CDCl3, 125.7 MHz):
d
(157.61þ157.59) (1C),
(151.573þ151.507) (1C), 150.644 (1C), 119.342 (1C), 110.734 (1C),
(80.936þ80.863) (1C), (79.377þ79.338) (1C), (74.982þ74.371) (1C),
(52.566þ52.257) (1C), (49.700þ49.189) (1C), (45.220þ44.802)
(1C), (39.161þ39.049) (1C), 28.495 (3C), 28.220 (3C), 21.349 (1C).
MS (ESI, CH2Cl2): [C21H33N3O5] m/z 407.9 ([MþH]þ).
(154.58þ154.55) (1C), (154.25þ154.21) (1C), 153.82 (1C),
(139.27þ139.20) (1C), (137.94þ137.85) (1C), 128.23 (2C), 127.94
(2C), 126.77 (1C), (119.42þ119.17) (1C), (117.77þ117.56) (1C), 81.55
(1C), 79.33 (1C), (75.06þ74.33) (1C), (52.59þ52.17þ51.61) (1C),
(50.42þ50.25þ49.59þ49.18) (1C), (45.28þ44.22) (1C), 39.29 (1C),
28.48 (3C), 28.14 (3C). HRMS (ESI, CH3OH) calcd for C27H38N3O5
483.2733; found 483.2733.
4.2.8. (ꢃ)-tert-Butyl 3-{{60-[(tert-butoxycarbonyl)(400-methoxybenzyl)
amino]-40-methylpyridin-20-yl}methyl}-4-hydroxypyrrolidine-1-
carboxylate (24). 1H NMR (CDCl3, 500 MHz):
d 7.270e7.223 (m, 1H),
4.2.4. (ꢃ)-tert-Butyl 3-{{60-[benzyl(tert-butoxycarbonyl)amino]pyr-
idin-20-yl}methyl}-4-(naphthalen-1-yloxy)pyrrolidine-1-carboxylate
(20). Column chromatography (CH2Cl2/EtOAc¼8.5:1.5). 1H NMR
7.185e7.171 (2H, m), 6.792e6.779 (m, 2H), 6.691 (m, 1H), 5.065 (s,
2H), 4.113e4.041 (m,1H), 3.720e3.710 (m, 3H), 3.694e3.551 (m, 2H),
3.224e3.179 (m, 1H), 3.110e3.100 (m, 1H), 2.846e2.834 (m, 1H),
2.684e2.603 (m, 1H), 2.480e2.441 (m, 1H), 2.254 (s, 3H),
(CDCl3, 400 MHz):
d 8.276e8.260 (m, 1H), 7.882 (m, 1H),
7.572e7.232 (m, 11H), 6.736 (m, 1H), 6.409e6.392 (m, 1H), 5.163 (s,
2H), 4.999e4.989 (m, 1H), 3.744e3.354 (m, 4H), 3.205 (m, 1H),
3.017 (m, 1H), 2.887e2.831 (m, 1H), 1.441e1.348 (m, 18H). 13C NMR
1.431e1.422 (m, 18H). 13C NMR (CDCl3, 125.7 MHz):
d 158.343 (1C),
157.290 (1C), 154.502 (1C), 154.201 (1C), 153.708 (1C),
(148.891þ148.785) (1C), (131.275þ131.173) (1C), 128.538 (2C),
(120.470þ120.309) (1C), (118.344þ118.123) (1C),113.413 (2C), 81.019
(1C), 79.088 (1C), (74.662þ73.953) (1C), 54.962 (1C),
(52.572þ52.139) (1C), (49.640þ49.504) (1C), (49.423þ49.037) (1C),
(45.417þ44.696) (1C), 39.072 (1C), 28.357 (3C), 28.081 (3C), 20.917
(1C). MS (ESI, CH3OH): [C29H41N3O6] m/z 528.4 ([MþH]þ). HRMS
(ESI, CH3OH) calcd for C29H41N3O6 527.2995; found 527.3000.
(CDCl3, 125.7 MHz):
d 157.28 (1C), 154.35 (1C), 154.29 (1C), 153.78
(1C), 152.72 (1C), 139.74 (1C), 139.65 (1C), 137.54 (1C), 131.14 (1C),
128.16 (2C), 128.13 (1C),127.23 (1C), 126.85 (2C), 126.78 (1C), 126.63
(1C),126.52 (1C),125.71 (1C),125.49 (1C),122.35 (1C), (118.63) (1C),
116.62 (1C), 81.41 (1C), 79.52 (1C), (70.80þ69.91) (1C),
(51.34þ49.85) (1C), (49.55þ49.14) (1C), (42.94þ42.23) (1C), 34.58
(1C), (28.49þ28.43þ28.15) (6C). HRMS (ESI, CH3OH) calcd for
C37H43N3O5 609.3203; found 609.3212.
4.2.9. (ꢃ)-tert-Butyl 3-{{60-[(tert-butoxycarbonyl)(400-methoxybenzyl)
amino]-40-methylpyridin-20-yl}methyl}-4-(naphthalen-1-yloxy)pyrro-
lidine-1-carboxylate (25). Column chromatography (hexanes/
4.2.5. (ꢃ)-tert-Butyl 3-{{60-[benzyl(tert-butoxycarbonyl)amino]-40-
methylpyridin-20-yl}methyl}-4-hydroxypyrrolidine-1-carboxylate
Me2CO¼7:3). 1H NMR (CDCl3, 400 MHz):
d 8.277e8.263 (m, 1H),
(21). 1H NMR (CDCl3, 500 MHz):
d
7.338e7.178 (m, 6H),
7.907 (m, 1H), 7.557e7.232 (m, 5H), 7.163e7.149 (m, 2H),
6.797e6.785 (m, 2H), 6.582 (m, 1H), 6.457e6.441 (m, 1H), 5.770 (s,
2H), 4.992 (m, 1H), 4.736 (m, 1H), 3.769 (s, 3H), 3.728e3.454 (m,
3H), 3.155 (m, 1H), 2.998e2.880 (m, 2H), 2.124 (m, 3H),
6.713e6.696 (m, 1H), 5.168e5.079 (m, 2H), (4.164þ3.869) (br s, 1H),
4.061e4.042 (m, 1H), 3.726e3.528 (m, 2H), 3.211e3.144 (m, 1H),
3.094e3.044 (m, 1H), 2.812e2.765 (m, 2H), 2.488e2.364 (m, 1H),
2.296e2.289 (m, 3H), 1.452e1.416 (m, 18H). 13C NMR (CDCl3,
1.432e1.265 (m, 18H). 13C NMR (CDCl3, 125.7 MHz):
d 158.35 (1C),
125.7 MHz):
d
157.398 (1C), (154.727þ154.666) (1C), 154.405 (1C),
158.28 (1C), 156.93 (1C), 156.13 (1C), 154.39 (1C), 153.90 (1C),
148.63 (1C), 131.80 (1C), 131.70 (1C), 131.15 (1C), (128.38þ128.29)
(2C), 127.43 (1C), 126.56 (1C), 125.71 (1C), 125.49 (1C), 122.38 (1C),
120.13 (2C), 117.50 (1C), 113.44 (2C), 104.94 (1C), 81.17 (1C), 79.55
(1C), (70.75þ69.96) (1C), 55.23 (1C), (51.42þ51.00) (1C),
(49.64þ49.30þ49.22) (1C), 43.06 (1C), 34.636 (1C), (28.48þ28.42)
(6C), 22.01 (1C). HRMS (ESI, CH3OH) calcd for C39H47N3O6
653.3465; found 653.3464.
154.016 (1C), (149.463þ149.341) (1C), (139.530þ139.445) (1C),
128.340 (2C), 127.180 (1C), 126.871 (1C), (120.914þ120.696) (1C),
(118.577þ118.358) (1C), 81.516 (1C), 79.416 (1C), (75.287þ74.577)
(1C), (52.798þ52.367) (1C), (50.619þ50.461) (1C), (49.817þ49.404)
(1C), (45.403þ44.638) (1C), 39.368 (1C), 28.634 (3C), 28.294 (3C),
21.257 (1C). MS (ESI, CH3OH): [C28H39N3O5] m/z 498.4 ([MþH]þ);
m/z 995.2 ([2MþH]þ).
4.2.6. (ꢃ)-tert-Butyl 3-{{60-[benzyl(tert-butoxycarbonyl)amino]-40-
methylpyridin-20-yl}methyl}-4-(naphthalen-1-yloxy)pyrrolidine-1-
carboxylate (22). Column chromatography (hexanes/Me2CO¼7:3).
4.3. General procedure for the debenzylation reaction
1H NMR (CDCl3, 400 MHz):
d
8.263 (m, 1H), 7.931 (m, 1H),
To a solution of the starting material (1 mmol) in EtOH (60 mL)
was added HOAc (1.5 mmol) at room temperature. The solution was
then treated with 20 wt% Pd(OH)2 on carbon (150 mg). The reaction
mixture was stirred at 60 ꢀC under an atmosphere of hydrogen for
14 h. The catalyst was filtered through Celite. The Celite pad was
washed with EtOH (30 mLꢄ2). The combined filtrate was concen-
trated in vacuo. The residue was purified by silica gel column
chromatography to afford the desired product.
7.606e7.202 (m, 10H), 6.574 (m, 1H), 6.402e6.393 (m, 1H), 5.160 (s,
2H), 4.996 (m, 1H), 4.689 (m, 1H), 3.722e3.440 (m, 3H), 3.143 (m,
1H), 2.975e2.842 (m, 2H), 2.127 (m, 3H), 1.560e1.415 (m, 18H). 13C
NMR (CDCl3, 125.7 MHz):
d 157.025 (1C), 156.376 (2C), 154.513 (1C),
153.974 (1C), 152.854 (1C), 148.771 (1C), 139.999 (1C), 131.320 (1C),
128.265 (2C), 127.501 (1C), 127.008 (1C), 126.923 (1C), 126.720 (1C),
126.622 (1C), 125.799 (1C), 125.595 (1C), 122.480 (2C), 120.214 (1C),

H. Ji et al. / Tetrahedron 68 (2012) 1359e1366
1365
4.3.1. (ꢃ)-tert-Butyl 3-{{60-[(tert-butoxycarbonyl)amino]-40-methyl-
pyridin-20-yl}methyl}-4-(naphthalen-1-yloxy)pyrrolidine-1-
carboxylate (26). Column chromatography (hexanes/EtOAc¼7:3).
127.052
(2C),
(126.649þ126.576)
(1C), 120.306
(1C),
(117.208þ117.149) (1C), (81.332þ81.288) (1C), (79.332þ79.222)
(1C), (78.212þ77.589) (1C), (69.195þ69.158) (1C), 62.617 (1C),
(51.037þ50.561) (1C), (50.107þ50.063) (1C), (49.440þ48.993)
(1C), (42.628þ41.903) (1C), 34.513 (1C), 28.587 (3C), 28.221 (3C),
21.189 (1C). MS (ESI, CH3OH): [C32H45N3O6] m/z 568.1 ([MþH]þ).
HRMS (ESI, CH3OH) calcd for C32H46N3O6 567.3308; found
567.3311.
1H NMR (CDCl3, 400 MHz):
d 8.313e8.297 (m, 1H), 7.892 (m, 1H),
7.568e7.509 (m, 4H), 7.187 (m, 2H), 6.613e6.575 (m, 2H),
5.005e4.865 (m, 2H), 3.798e3.492 (m, 3H), 3.106e2.892 (m, 3H),
2.152 (m, 3H), 1.520 (s, 9H), 1.449e1.394 (m, 9H). 13C NMR (CDCl3,
100.7 MHz): d 157.712 (1C), 156.417 (1C), 154.584 (1C), 153.061 (1C),
152.599 (1C), 151.653 (1C), 150.244 (1C), 131.438 (1C), 127.621 (2C),
126.772 (1C), 125.954 (1C), 125.727 (1C), 122.743 (2C), 119.471 (1C),
(110.519þ110.451) (1C), 105.187 (1C), 80.996 (1C), 79.776 (1C),
(70.998þ70.127) (1C), (51.632þ51.298) (1C), (49.693þ49.428) (1C),
(43.634þ43.088) (1C), 35.234 (1C), (28.683þ28.607) (3C), 28.455
(3C), 22.192 (1C). HRMS (ESI, CH3OH) calcd for C31H39N3O5
533.2890; found 533.2886.
4.3.5. (3R,4R)-tert-Butyl
3-{{60-[(tert-butoxycarbonyl)amino]-40-
methylpyridin-20-yl}methyl}-4-(40-hydroxybutoxy)pyrrolidine-1-
carboxylate (30). Column chromatography (hexanes/EtOAc¼7:3).
1H NMR (CDCl3, 500 MHz):
d 7.627e7.583 (m, 2H), 6.660e6.649 (m,
1H), 3.757e3.397 (m, 6H), 3.289e3.254 (m, 2H), 3.192e3.091 (m,
1H), 2.920e2.866 (m, 1H), 2.712e2.537 (m, 2H), 2.312e2.294 (m,
3H), 1.666 (m, 4H), 1.517 (s, 9H), 1.452 (s, 9H). 13C NMR (CDCl3,
4.3.2. (3R,4R)-tert-Butyl 3-{{60-[benzyl(tert-butoxycarbonyl)amino]-
40-methylpyridin-20-yl}methyl}-4-(30-hydroxypropoxy)pyrrolidine-1-
125.7 MHz):
d
(158.33þ158.25) (1C), (155.01þ154.76) (1C), 152.66
(1C), 151.62 (1C), 150.14 (1C), 119.32 (1C), (110.40þ110.35) (1C),
(80.92þ80.84) (1C), (79.44þ79.35) (1C), (79.35þ78.35) (1C),
(69.31þ69.14) (1C), 62.53 (1C), (50.81þ50.41) (1C), (49.34þ48.95)
(1C), (43.51þ42.82) (1C), (34.68þ34.55) (1C), 29.79 (1C), 28.63 (3C),
28.37 (3C), (26.55þ26.53) (1C), (21.44þ21.42) (1C). MS (ESI,
CH3OH): [C25H41N3O6] m/z 502.3 ([MþNa]þ). HRMS (ESI, CH3OH)
calcd for C25H41N3O5 479.2995; found 479.2998.
carboxylate (27). 1H NMR (CDCl3, 400 MHz):
d 7.389e7.353 (m, 1H),
7.303e7.174 (m, 5H), 6.710 (s, 1H), 5.161 (s, 2H), 3.696e3.536 (m,
5H), 3.444e3.370 (m, 1H), 3.334e3.260 (m, 1H), 3.217e3.047 (m,
2H), 2.924e2.870 (m, 1H), 2.728e2.676 (m, 1H), 2.595e2.532 (m,
1H), 2.298e2.284 (m, 3H), 1.760e1.751 (m, 2H), 1.459e1.442 (m,
9H), 1.413 (s, 9H). 13C NMR (CDCl3, 100.7 MHz):
d
(157.850þ157.755)
(1C), (155.023þ154.620) (1C), 154.429 (1C), 153.895 (1C), 148.658
(1C), (139.781þ139.751) (1C), 128.113 (2C), (127.065þ126.977) (2C),
(126.619þ126.553) (1C), 120.239 (1C), (117.441þ117.360) (1C),
(81.214þ81.163) (1C), 79.347 (1C), (79.222þ78.519) (1C),
(67.445þ67.254) (1C), 60.677 (1C), (50.833þ50.305) (1C), 50.086
(1C), (49.361þ48.884) (1C), (42.908þ42.227) (1C), 34.551 (1C),
(32.397þ32.295) (1C), 28.537 (3C), 28.200 (3C), 21.147 (1C). MS
(ESI, CH3OH): [C31H45N3O6] m/z 556.0 ([MþH]þ), 578.1 ([MþNa]þ).
HRMS (ESI, CH3OH) calcd for C31H46N3O6 555.3308; found
555.3313.
4.3.6. (3R,4R)-tert-Butyl 3-{{60-[benzyl(tert-butoxycarbonyl)amino]-
40-methylpyridin-20-yl}methyl}-4-{20-[(tert-butoxycarbonyl)(300-fluo-
rophenethyl)amino]ethoxy}pyrrolidine-1-carboxylate (31). The NMR
spectra are the same as those reported in the previous study.8 1H NMR
(CDCl3, 500 MHz):
d 7.426e7.395 (m, 1H), 7.237e7.178 (m, 6H),
6.986e6.857 (m, 3H), 6.634e6.609 (m, 1H), 5.163 (s, 2H), 3.646e3.165
(m, 10H), 3.086e3.022 (m, 1H), 2.893e2.779 (m, 3H), 2.692e2.649
(m, 1H), 2.558 (m, 1H), 2.291e2.273(m, 3H), 1.445e1.409 (m, 27H).
13C NMR (CDCl3, 125.7 MHz):
d
(163.967þ162.012) (1C), (157.756þ
157.665) (1C), (155.419þ155.279) (1C), (154.812þ154.623) (1C),
(154.514þ154.447) (1C), 153.974 (1C), 148.655 (1C), 142.013 (1C),
139.973 (1C), 129.997 (1C), 128.176 (2C), (127.120þ127.035) (2C),
(126.670þ126.591) (1C), (124.685þ124.667) (1C), 120.058 (1C),
(117.174þ117.126) (1C), (115.875þ115.711) (1C), (113.337þ113.246þ
113.173þ113.076) (1C), (81.298þ81.243) (1C), (79.725þ79.203þ
78.881) (3C), (68.232þ68.056) (1C), (50.934þ50.430) (1C),
(50.273þ50.194) (1C), 50.024 (1C), (49.386þ48.937) (1C), (47.971þ
47.468) (1C), (42.890þ42.762þ42.282) (1C), (35.003þ34.711þ34.341)
(2C), 28.591 (3C), 28.488 (3C), 28.275 (3C), 21.239 (1C). MS (ESI,
CH3OH): [C43H59FN4O7] m/z 763.5 ([MþH]þ), 785.5 ([MþNa]þ),1546.8
([2MþNa]þ).
4.3.3. (3R,4R)-tert-Butyl
methylpyridin-20-yl}methyl}-4-(30-hydroxypropoxy)pyrrolidine-1-
3-{{60-[(tert-butoxycarbonyl)amino]-40-
carboxylate
(28). Column
chromatography
(cylcohexanes/
EtOAc¼6:4). 1H NMR (CDCl3, 400 MHz):
d
7.907 (s, 1H), 7.663e7.653
(m, 1H), 6.674 (s, 1H), 4.335 (br s, 1H), 3.889e3.879 (m, 1H),
3.745e3.707 (m, 1H), 3.649e3.605 (m, 2H), 3.560e3.369 (m, 3H),
3.258e3.101 (m, 2H), 2.907e2.852 (m, 1H), 2.719e2.657 (m, 1H),
2.496e2.457 (m, 1H), 2.310e2.300 (m, 3H), 1.822 (m, 2H), 1.511 (s,
9H), 1.458
(s,
9H). 13C
NMR
(CDCl3, 100.7 MHz):
d
(158.055þ157.945) (1C), (154.722þ154.466) (1C), 152.496 (1C),
151.566 (1C), 150.035 (1C), 118.833 (1C), (110.292þ110.241) (1C),
(80.533þ80.497) (1C), (79.149þ79.061) (1C), (78.724þ77.691) (1C),
(66.456þ66.361) (1C), (59.417þ59.344) (1C), (50.664þ50.196) (1C),
(49.185þ48.767) (1C), (44.255þ43.508) (1C), (34.551þ34.287) (1C),
(32.177þ32.075) (1C), 28.376 (3C), 28.120 (3C), 21.184 (1C). MS (ESI,
CH3OH): [C24H39N3O6] m/z 466.3 ([MþH]þ), 488.2 ([MþNa]þ),
952.8 ([2MþNa]þ). HRMS (ESI, CH3OH) calcd for C24H40N3O6
465.2839; found 465.2839.
4.3.7. (3R,4R)-tert-Butyl 3-{20-[(tert-butoxycarbonyl)(300-fluorophen-
ethyl)amino]ethoxy}-4-{{60-[(tert-butoxycarbonyl)amino]-40-methyl-
pyridin-20-yl}methyl}pyrrolidine-1-carboxylate (32). The NMR spectra
are the same as those reported in the previousstudy.8 1H NMR (CDCl3,
500 MHz):
d 7.618e7.600 (m, 1H), 7.471e7.457 (m, 1H), 7.254e7.242
(m, 1H), 7.002e6.874 (m, 3H), 6.620e6.591 (m, 1H), 3.781e3.737 (m,
1H), 3.602e3.261 (m, 9H), 3.160e3.062 (m,1H), 2.859e2.819 (m, 3H),
2.703e2.541 (m, 2H), 2.301e2.279 (m, 3H), 1.512 (s, 9H), 1.442 (m,
4.3.4. (3R,4R)-tert-Butyl 3-{{60-[benzyl(tert-butoxycarbonyl)amino]-
40-methylpyridin-20-yl}methyl}-4-[((Z)-40-hydroxybut-20-en-10-yl)
oxy]pyrrolidine-1-carboxylate (29). 1H NMR (CDCl3, 500 MHz):
18H). 13C NMR (CDCl3, 125.7 MHz):
d
(163.870þ161.915) (1C),
(158.218þ158.169)
(1C),
(155.382þ155.334þ155.170) (1C),
d
7.401e7.368 (m, 1H), 7.292e7.163 (m, 5H), 6.699 (s, 1H),
(154.696þ154.544) (1C), 152.492 (1C), (151.527þ151.515) (1C),
149.894 (1C), (141.958þ141.898) (1C), (129.979þ129.906) (1C),
(124.600þ124.582) (1C), (119.117þ119.063) (1C), (115.790þ115.626)
(1C), (113.240þ113.149þ113.070þ112.979) (1C), (110.235þ110.168)
(1C), (80.721þ80.660) (1C), (79.616þ79.586) (1C), (79.750þ79.221þ
79.149þ78.651) (2C), (68.250þ68.159þ67.977) (1C), (50.922þ
50.485) (1C), (50.212þ50.072þ49.981) (1C), (49.216þ48.864) (1C),
(47.941þ47.449) (1C), (43.333þ43.175þ42.707þ42.556) (1C),
(34.936þ34.736þ34.547þ34.432þ34.268) (2C), 28.482 (3C), 28.385
5.799e5.699 (m, 1H) 5.640e5.573 (m, 1H), 5.158 (s, 2H),
4.139e4.061 (m, 2H), 4.011e3.929 (m, 1H), 3.809e3.532 (m, 2H),
3.456e3.368 (m, 2H), 3.209e3.063 (m, 2H), 2.941e2.876 (m, 1H),
2.751e2.588 (m, 2H), 2.303e2.289 (m, 3H), 1.454e1.435 (m, 9H),
1.406 (s, 9H). 13C NMR (CDCl3, 125.7 MHz):
d
(157.860þ157.809)
(1C), (154.923þ154.630) (1C), (154.600þ154.564) (1C), 153.868
(1C), (1C), (139.878þ139.841) (1C),
(148.594þ148.536)
(132.260þ132.143) (1C), 128.136 (2C), (127.419þ127.213) (1C),

1366
H. Ji et al. / Tetrahedron 68 (2012) 1359e1366
ꢀ
5. Flinspach, M. L.; Li, H.; Jamal, J.; Yang, W.; Huang, H.; Hah, J.-M.; Gomez-Vidal,
J. A.; Litzinger, E. A.; Silverman, R. B.; Poulos, T. L. Nat. Struct. Mol. Biol. 2004, 11,
54e59.
(3C), 28.263 (3C), 21.281 (1C). MS (ESI, CH3OH): [C36H53FN4O7] m/z
673.8 ([MþH]þ), 695.6 ([MþNa]þ), 1367.5([2MþNa]þ).
6. Ji, H.; Li, H.; Flinspach, M.; Poulos, T. L.; Silverman, R. B. J. Med. Chem. 2003, 46,
5700e5711.
7. Delker, S. L.; Ji, H.; Li, H.; Jamal, J.; Fang, J.; Xue, F.; Silverman, R. B.; Poulos, T. L. J.
4.3.8. (3R,4R)-tert-butyl 3-{{60-[benzyl(tert-butoxycarbonyl)amino]-
40-methylpyridin-20-yl}methyl}-4-{20-{(tert-butoxycarbonyl)[200,200-
difluoro-200-(3000-fluorophenyl)ethyl]amino}ethoxy}pyrrolidine-1-
carboxylate (8). The NMR spectra are the same as those reported in
the earlier study.11
Am. Chem. Soc. 2010, 132, 5437e5442.
8. Ji, H.; Delker, S. L.; Li, H.; Mart$sek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B.
J. Med. Chem. 2010, 53, 7804e7824.
9. Ji, H.; Tan, S.; Igarashi, J.; Li, H.; Derrick, M.; Martasek, P.; Roman, L. J.; Vasquez-
ꢀ
ꢀ
Vivar, J.; Poulos, T. L.; Silverman, R. B. Ann. Neurol. 2009, 65, 209e217.
10. Lawton, G. R.; Ji, H.; Silverman, R. B. Tetrahedron Lett. 2006, 47, 6113e6115.
11. Lawton, G. R.; Ralay Ranaivo, H.; Chico, L. K.; Ji, H.; Xue, F.; Martasek, P.;
4.3.9. (3R,4R)-tert-Butyl 3-{20-{(tert-butoxycarbonyl)[200,200-difluoro-
200-(3000-fluorophenyl)ethyl]amino}ethoxy}-4-{{60-[(tert-butox-
ycarbonyl)amino]-40-methylpyridin-20-yl}methyl}pyrrolidine-1-car-
boxylate (33). The NMR spectra are the same as those reported in
the previous study.11
ꢀ
Roman, L. J.; Watterson, D. M.; Silverman, R. B. Bioorg. Med. Chem. 2009, 17,
2371e2380.
12. Silverman, R. B.; Lawton, G. R.; Ralay Ranaivo, H.; Chico, L. K.; Seo, J.; Watterson,
D. M. Bioorg. Med. Chem. 2009, 17, 7593e7605.
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13. Xue, F.; Li, H.; Delker, S. L.; Fang, J.; Martasek, P.; Roman, L. J.; Poulos, T. L.;
Silverman, R. B. J. Am. Chem. Soc. 2010, 132, 14229e14238.
ꢀ
14. Xue, F.; Li, H.; Fang, J.; Roman, L. J.; Martasek, P.; Poulos, T. L.; Silverman, R. B.
Acknowledgements
Bioorg. Med. Chem. Lett. 2010, 20, 6258e6261.
15. Xue, F.; Huang, J.; Ji, H.; Fang, J.; Li, H.; Mart$sek, P.; Roman, L. J.; Poulos, T. L.;
Silverman, R. B. Bioorg. Med. Chem. 2010, 18, 6526e6537.
16. Xue, F.; Silverman, R. B. Tetrahedron Lett. 2010, 51, 2536e2538.
17. Furuta, K.; Wang, G. X.; Minami, T.; Nishizawa, M.; Ito, S.; Suzuki, M. Tetrahedron
Lett. 2004, 45, 3933e3936.
The authors are grateful to the National Institutes of Health
(GM049725) for financial support of this research.
18. Chao, J.; Israiel, M.; Zheng, J.; Aki, C. Tetrahedron Lett. 2007, 48, 791e794.
19. Chappie, T. A.; Humphrey, J. M.; Allen, M. P.; Estep, K. G.; Fox, C. B.; Lebel, L. A.;
Liras, S.; Marr, E. S.; Menniti, F. S.; Pandit, J.; Schmidt, C. J.; Tu, M.; Williams,
R. D.; Yang, F. V. J. Med. Chem. 2007, 50, 182e185.
20. Lepore, S. D.; He, Y. J. Org. Chem. 2003, 68, 8261e8263.
21. Zong, K.; Groenendaal, L.; Reynolds, J. R. Tetrahedron Lett. 2006, 47,
3521e3523.
Supplementary data
Supplementary Table 1, Supplementary Schemes 1e3, and 1H
NMR, and 13C NMR spectra for 17e32. Supplementary data related
to this article can be found online at doi:10.1016/j.tet.2011.12.013.
22. Manivel, P.; Rai, N. P.; Jayashankara, P. V.; Arunachalam, P. N. Tetrahedron Lett.
2007, 48, 2701e2705.
References and notes
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25. Lizaraburu, M. E.; Shuttleworth, S. J. Tetrahedron Lett. 2002, 43, 2157e2159.
1. Silverman, R. B. Acc. Chem. Res. 2009, 42, 439e451.
2. Ji, H.; Stanton, B. Z.; Igarashi, J.; Li, H.; Martasek, P.; Roman, L. J.; Poulos, T. L.;
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26. Dagoneau, C.; Denis, J.-N.; Vallee, Y. Synthesis 1999, 5, 602e604.
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G. V., Notheisz, F., Eds.; Academic: San Diego, CA, 1999; Chapter 4,
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