Hydrophobic substituent effects on proline catalysis of aldol reactions in water

Article abstract of DOI:10.1021/jo300569c

Derivatives of 4-hydroxyproline with a series of hydrophobic groups in well-defined orientations have been tested as catalysts for the aldol reactions. All of the modified proline catalysts carry out the intermolecular aldol reaction in water and provide

Full text of DOI:10.1021/jo300569c

Article
pubs.acs.org/joc
Hydrophobic Substituent Effects on Proline Catalysis of Aldol
Reactions in Water
Qingquan Zhao,† Yu-hong Lam,‡ Mahboubeh Kheirabadi,† Chongsong Xu,† K. N. Houk,‡
and Christian E. Schafmeister*,†
†Department of Chemistry, Temple University, 1901 N. 13th Street, Philadelphia, Pennsylvania 19122, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: Derivatives of 4-hydroxyproline with a series of
hydrophobic groups in well-defined orientations have been
tested as catalysts for the aldol reactions. All of the modified
proline catalysts carry out the intermolecular aldol reaction in
water and provide high diastereoselectivity and enantioselec-
tivity. Modified prolines with aromatic groups syn to the
carboxylic acid are better catalysts than those with small
hydrophobic groups (1a is 43.5 times faster than 1f). Quantum
mechanical calculations provide transition structures, TS-
1awater and TS-1fwater, that support the hypothesis that a
stabilizing hydrophobic interaction occurs with 1a.
hydroxyproline and cyclic ketones were combined with
aldehydes and catalyst in an aqueous, biphasic environment
formed by the mixture of water and the organic ketone. The
organic ketone and the modified proline catalyst have been
proposed to assemble into micelles in water due to hydro-
phobic interactions, excluding water and driving the formation
of the enamine.8 The enamine is then more soluble in the
organic phase, where it reacts with the aldehyde to form the
carbon−carbon bond, and then hydrolysis of the resulting
iminium ion takes place. In contrast to this phase-transfer type
of mechanism, we explore here the idea that precisely placed
hydrophobic groups on modified prolines could create specific
hydrophobic interactions with the aldol substrates in water to
create organocatalysts that have high activity as well as high
diastereo- and enantioselectivity.
Recently, we have begun exploring the creation of catalytic
sites through the rational organization of functional groups on
bis-peptide scaffolds. Bis-amino acids are cyclic, stereochemi-
cally pure building blocks derived from (2S,4R)-4-hydroxypro-
line that are combined with other bis-amino acids and α-amino
acids through functionalized diketopiperazines to create spiro-
ladder oligomers with programmable shape and functionality.10
Our experience in synthesizing richly functionalized prolines
led to the idea of positioning hydrophobic groups that could
interact with the substrates of proline aldol catalysis in order to
improve diastereoselectivity, enantioselectivity, and turnover
rate. Herein, we report a series of modified prolines that exhibit
excellent diastereoselectivity and enantioselectivity with very
low loading (0.5 mol %) in an aldol reaction in water.
INTRODUCTION
■
In the past decades, small, metal-free organic molecules have
attracted considerable attention as asymmetric organocatalysts.1
Despite considerable effort, the vast majority of organocatalysts
carry out relatively few turnovers; typically more than 10 mol %
of catalyst is necessary to achieve reasonable reaction rates and
yields. X-ray structures of highly active enzymes show intricate
active sites that have shape and chemical complementarity to
their substrates and suggest the hypothesis that the activity of
organocatalysts might be improved by creating specific
interactions between the organocatalyst and their substrates.
In nonaqueous solvents, organocatalysts must utilize specific
hydrogen bonding, charge−charge, and dipole−charge inter-
actions to drive the association of the organocatalyst with their
substrates.2 In water, on the other hand, organocatalysts need
to make use of the hydrophobic interaction because the high
dielectric constant of water screens charge−charge interactions
and water competes for hydrogen bonds. The development of
organocatalytic asymmetric reactions in aqueous media is an
attractive goal because water is an inexhaustable and environ-
mentally friendly solvent.3,4
Proline was found, in the 1970s, by Hajos and Parrish5 and
Eder, Sauer, and Wiechert6 to be an organocatalyst for the
intramolecular aldol reaction and, in 2000, by List, Lerner, and
Barbas to be an organocatalyst for the intermolecular aldol
reaction.7 In organic solvents, proline requires high loadings
(∼30 mol %), and it is well-known that proline does not
catalyze the aldol reaction in water.8 Since the initial reports of
the proline-catalyzed aldol reaction, derivatives of 4-hydrox-
yproline have attracted considerable interest as catalysts of the
asymmetric aldol reaction in water.9 In these previous reports,
hydrophobic substituents were attached to the alcohol of 4-
Received: March 27, 2012
Published: April 13, 2012
© 2012 American Chemical Society
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Article
a
Scheme 1. Catalyst Synthesis
a
See ref 10.
Moreover, by placing appropriate hydrophobic groups either
syn or anti to the carboxylic acid of proline, we demonstrate a
structure/catalytic activity relationship together with computa-
tional modeling that suggests that a specific hydrophobic
interaction between the catalyst and the aldehyde substrate is
responsible for an observed rate enhancement of 43.5-fold
when compared to a catalyst that cannot form a hydrophobic
interaction.
2c were synthesized using procedures similar to those for 1a−
1e, 2a, and 2b, but no intermediates were isolated. Finally, the
organocatalyst 3 was prepared by converting the amino acid 7
to the 1-hydroxy-7-azabenzotriazole (HOAt) ester (not
isolated) and combining it with the N-functionalized amino-
isobutyric acid 22 to form the hexa-substituted diketopiperazine
17 using a new reaction that we have previously described
called “acyl-transfer coupling”.10b The carboxylbenzyl amine
and tert-butyl ester of 17 were deblocked using HBr/AcOH,
and the salt was then converted to the trifluoroacetate salt 3.
To probe the catalytic activity of 1a in the aldol reaction, 1a
(10 mol %) was combined with 1 equiv of 4-nitrobenzaldehyde
and 10 equiv of cyclohexanone at room temperature in a variety
of solvents (Table 1). Solvent screening indicated that water
and methanol afford the highest diastereomeric ratios and
enantioselectivities (entries 1 and 2, the values are capped at
98% given the practical limits of quantitation by NMR).12 The
reaction catalyzed by 1a was found to be considerably faster in
water than in methanol, as the consumption of the starting p-
nitrobenzaldehyde remained incomplete in the latter solvent
after 12 h.
The scope of aldol catalysis using 1a in water against a variety
of aldehydes and ketones as substrates is shown in Table 2.
Generally, the reaction between cyclohexanone and aldehydes
with an electron-withdrawing substituent was found to proceed
to completion with high yield and excellent diastereoselectivity
and enantioselectivity (entries 1, 4, 5, 6, and 10). The reaction
of cyclohexanone and p-nitrobenzaldehyde catalyzed by 1a (0.5
mol %) provided the aldol product in 96% yield within 78 h
(entry 11). Substituted benzaldehydes containing less electron-
withdrawing groups required longer reaction times to achieve
RESULTS AND DISCUSSION
■
Modified proline 1a was synthesized starting from (2S,4R)-4-
hydroxyproline 4 in eight steps with an overall yield of 44%
(Scheme 1). Our group previously described the first five steps
in the synthesis of 5 and 6 and their enantiomers.10 The free
amine of 5 was reductively alkylated overnight using
benzaldehyde and sodium cyanoborohydride in methanol at
room temperature. The resulting N-carboxybenzyl amino acid 7
was combined with 1.05 equiv of phenylisocyanate and 3 equiv
of Et3N at room temperature and stirred overnight. The
hydantoin 12 formed cleanly with spontaneous dehydration;
the formation of these tetrasubstituted hydantoins is facile
under these mild conditions due to assistance by the Thorpe−
Ingold effect and the presence of N-alkyl substitution on the
amino acid.11 The carboxybenzyl and tert-butyl protecting
groups were then removed with 33% HBr in acetic acid, and the
HBr salt was converted to the TFA salt 1a. Using this reaction
sequence starting from 5 and a variety of aldehydes in place of
benzaldehyde afforded organocatalysts 1b−1e. Catalysts 2a and
2b, which are epimeric to 1a and 1b at the spiro carbon on the
pyrrolidine ring, were prepared analogously starting from 6 (the
C4 epimer of 5) and the appropriate aldehyde. Catalysts 1f and
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Table 1. Solvent Screening
Table 3. Catalyst Recycling
a,b
a,b
dr
c
a
b
c
entry
solvent
II2O
product:SM ratio
ee (%)
cycle
first
time (h)
yield (%)
dr
ee (%)
1
>98:2
76:24
>98:2
>98:2
60:40
41:59
97:3
>98:2
>98:2
91:9
>98
>98
94
94
89
87
96
92
96
93
93
97
95
12
15
25
88
91
80
>98:2
>98:2
98:2
>98
>98
2
MeOH
IPA
second
third
3
>98
a
b
1
4
t-BuOH
DMSO
DMF
90:10
78:22
79:21
86:14
88:12
96:4
Isolated yield. The diastereomeric ratios were determined by H
NMR of the crude product. The ee values were determined by HPLC
c
5
6
using a Chiralpak AD column.
7
DCM
8
MeCN
toluene
Et2O
79:21
98:2
with hexanes and then adding fresh substrate to the aqueous
layer. The high diastereoselectivity and enantioselectivity were
maintained through three cycles with an approximately 50%
decrease in activity, possibly due to the loss of some catalyst as
it partitioned into the organic phase.
To probe the relationship between catalyst structure and
activity, a series of derivatives 1a−1f, 2a−2c, and 3 (Scheme 1),
which bear different aromatic groups varying stereochemistry
and ring structures at the quaternary carbon, was synthesized.
To a first approximation, the activities and selectivities of
catalysts 1b−1e are indistinguishable from those of 1a.
Switching from the 1a, 1b catalysts to the corresponding 2a,
2b catalysts involves inverting the C-4 stereocenter, which flips
the aromatic side arm to the opposite side of the proline ring
(anti to the carboxylic acid) and leads to a large drop in catalyst
rate, requiring over 7 times longer to achieve yields comparable
to those of 1a, 1b (Table 4). When the benzyl substituent on
9
10
11
12
13
14
>98:2
>98:2
>98:2
>98:2
>98:2
95:5
EtOAc
hexane
THF
94:6
95:5
94:6
cyclohexanone
92:8
1
93
c
a,b
The diastereomeric ratios were determined by 1D H NMR. The
ee values were determined by HPLC using a Chiralpak AD column.
Table 2. Substrate Screening
a
b
c
entry
n
R1
time (h) yield (%)
dr
ee (%)
1
2
2
1
3
2
2
2
2
2
2
2
2
2
p-NO2
p-NO2
p-NO2
o-NO2
m-NO2
p-CN
12
9
96
98
77
92
98
94
80
64
18
97
96
74
>98:2
95:5
>98
>98
94
Table 4. Screening Catalysts
d
3
48
80:20
>98:2
>98:2
>98:2
97:3
4
19
>98
>98
>98
>98
>98
>98
>98
>98
5
13
6
12
7
p-Br
100
100
120
13
a
b
c
entry
X
solvent
time (h) yield (%)
dr
ee (%)
8
p-Cl
97:3
1
1a
1b
1c
1d
1e
2a
2b
3
H2O
12
12
13
12
12
90
90
13
90
90
16
16
16
96
98
99
98
97
87
71
93
79
43
98
94
90
>98:2
>98:2
>98:2
>98:2
>98:2
95:5
>98
>98
>98
>98
>98
>98
98
9
p-OMe
CO2Me
p-NO2
92:8
2
H2O
10
98:2
e
3
H2O
11
78
>98:2
95:5
4
H2O
12
H
100
98
1
a
b
5
H2O
Isolated yield. The diastereomeric ratios were determined by H
NMR of the crude mixture. The ee values were determined by HPLC
using a Chiralpak AD column. 10 mol % catalyst. 0.5 mol % catalyst.
c
6
H2O
d
e
7
H2O
94:6
8
H2O
98:2
>98
>98
98
9
1f
H2O
97:3
good isolated yields, but the diastereo- and enantioselectivities
remain excellent (entries 7 and 8). The methoxy-substituted
aldehyde (electron-donating) showed poor conversion and
slightly lower diastereoselectivity, but excellent enantioselectiv-
ity was maintained (>98%, entry 9). The reactivity of 1a with
cyclopentanone is good (entry 2; 9 h, 98% yield) with a slight
reduction in diastereoselectivity but excellent enantioselectivity.
This is noteworthy, considering that there are few reports of
catalyzed aldol reactions of cyclopentanone with high levels of
diastereo- and enantioselectivity.9c,i,h,13 Cycloheptanone re-
quired 10 mol % loading of 1a to achieve a yield of 77% in
48 h (entry 3). The diastereoselectivity was modest (anti/syn =
1: 4), but the enantioselectivity of the major, anti product was
good (94% ee).
10
11
12
13
2c
H2O
93:7
d
1a
toluene
toluene
toluene
95:5
97
d
1f
95:5
96
d
2a
95:5
89
a
b
Isolated yield. dr values were determined by crude product 1H
NMR. ee values were determined by HPLC using a Chiralpak AD
c
d
column. 10 mol % catalyst.
the hydantoin of 1a was changed to an ethyl group (catalyst
1f), the activity of the catalyst drops to that of 2a and 2b
coupled with a slight decrease in diastereoselectivity. Expanding
the hydantoin on the quaternary center of 1a to the
diketopiperazine 3 (entry 8) demonstrates activity comparable
to that of 1a with a slight reduction in diastereoselectivity.
These observations are consistent with the formation of an
Catalyst 1a can be recycled, due to its good solubility in
water (Table 3), by extracting the completed reaction mixture
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additional hydrophobic interaction between the benzyl group
on the hydantoin of 1a or the similarly placed aromatic group
on the hydantoin of 1b−1e and 3 and the aldehyde substrate in
the transition state. In toluene, the activity of 1a is almost
identical to that of 1f and 2a, which would be expected when
the hydrophobic effect is eliminated.
To gain more precise measurements of the relative catalytic
rates we selected three catalysts, 1a, 2a, and 1f, and measured
the reaction kinetics of the catalyzed aldol reactions using the
procedure described in the Experimental Section. The relative
amounts of product and starting material at a series of time-
points were measured using 1H NMR. and the data were fit to
a first-order kinetic model using nonlinear optimization. The
results demonstrated that catalyst 1a reacts 43.5 times faster
than 1f, which has the same stereochemistry as 1a but presents
only an ethyl group, and that 1a is 9 times faster than catalyst
2a, which is the C4-epimer of 1a (Figure 1).
Figure 2. Optimized transition structures for the aldol addition step
catalyzed by 1a and 1f in water.
stabilization of TS-1awater relative to TS-1fwater. This is in
excellent agreement with the experimentally observed 43.5-fold
acceleration with the use of 1a in water when compared with 1f.
Using transition state theory, the value of ΔΔG⧧ associated
with a krel of 43.5 is −2.3 kcal/mol at 300 K. The SMD model
treats solvent as a dielectric medium with a surface tension term
calculated at the solute−solvent boundary that models the
hydrophobic effect.14 These results are consistent with the
hypothesis that the observed acceleration is due to a
hydrophobic interaction in 1a that is not present in 1f.15
In summary, we present a series of proline-based catalysts
1a−1e and 3 that catalyze the aldol reaction in water with high
activity and excellent diastereo- and enantioselectivity. Both
enantiomers of these catalysts are synthetically accessible
starting from (2S,4R)-4-hydroxyproline,10 making them
practical catalysts for the synthesis of stereochemically pure
aldol products. Catalysts that present an aromatic group that
can interact with the aromatic ring of the aldehyde acceptor
through a specific hydrophobic interaction are significantly
faster than those that do not. Quantum chemical calculations
point to a hydrophobic edge-to-face interaction that stabilizes
the transition state of 1a relative to 1f by 2.6 kcal/mol, in
excellent agreement with the experimentally observed ΔΔG⧧ of
2.3 kcal/mol. These results suggest that the rational positioning
of hydrophobic functional groups can significantly stabilize
transition states through hydrophobic interactions in water and
that stepwise incorporation of more groups could lead to
proline aldol catalysts with even greater activity.
Figure 1. Linearized kinetic data for the aldol reactions of
cyclohexanone and p-nitrobenzaldehyde catalyzed by 1a, 2a, and 1f
in water.
To better understand the nature of the reaction transition
states, quantum chemical computations were performed on the
aldol reactions of cyclohexanone and benzaldehyde using 1a
and 1f (Table 5). The geometries were optimized by M06-2X/
Table 5. Gibbs Free Energies of Transition Structures for the
Aldol Addition Step Relative to Isolated Reactants and
a
Organocatalyst (kcal/mol)
ΔG⧧
ΔΔG⧧ (1a−1f)
TS-1avacuum
TS-1fvacuum
TS-1awater
TS-1fwater
34.6
34.4
24.7
27.3
0.2
−2.6
EXPERIMENTAL SECTION
■
General Procedure for Synthesis of Catalyst 1a−1e, 2a, and
2b. Step 1. To a solution of (3S,5S)-1-((benzyloxy)carbonyl)-5-(tert-
butoxycarbonyl)-3-aminopyrrolidine-3-carboxylic acid 5 (2.0 g, 5.5
mmol, 1.0 equiv) in methanol (60 mL) was added benzaldehyde (670
μL, 6.6 mmol, 1.2 equiv), and the mixture was stirred for 30 min at
room temperature. Sodium cyanoborohydride (518 mg, 8.3 mmol, 1.5
equiv) was then added and stirred for 20 h at room temperature until
the reaction was complete, as monitored by LC−MS. The reaction
mixture was concentrated under vacuum and the resulting residue was
dissolved in 50 mL H2O. The pH was adjusted to 7 by dropwise
addition of 2 N HCl and the white precipitate (2.2 g, 4.8 mmol, 88%
yield) was obtained by vacuum filtration. This product was used
without further purification in the next step. For characterization, the
compound was purified by reverse phase C18 high performance liquid
chromatography using a 5−95% H2O/acetonitrile gradient.
a
The geometries were fully optimized by M06-2X/6-31G(d) in
vacuum or using the SMD model to account for the solvation effect of
water.
6-31G(d) in the gas phase and using the SMD model with
water as solvent.14 In vacuum, the difference in free energy of
TS-1a and TS-1f is very small (0.2 kcal/mol) (Table 5). This is
consistent with the very similar rates of 1a and 1f in toluene
(entries 11 and 12 in Table 4). On the other hand, in water, the
free energy of activation associated with 1a is more stabilizing
than 1f by 2.6 kcal/mol (Table 5). The optimized transition
states taking into account the solvation effect of water are
illustrated in Figure 2. The benzyl side arm of 1a comes into
edge-to-face contact with the aromatic ring of the acceptor
aldehyde in the List−Houk transition state, affording
(3S,5S)-3-(Benzylamino)-1-[(benzyloxy)carbonyl]-5-[(tert-
butoxy)carbonyl]pyrrolidine-3-carboxylic Acid, 7. 1H NMR
(500 MHz, DMSO-d6, 350 K, δ) 1.38 (9H, s), 2.36 (1H, dd, J =
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8.5, 13.3), 2.93 (1H, dd, J = 8.4, 13.3), 3.70 (1H, d, J = 11.4), 4.19
(3H, m), 4.34 (1H, t, J = 8.2), 5.11 (2H, s), 7.30−7.50 (10H, m); 13C
NMR (125 MHz, DMSO-d6, 350 K, δ) 28.0, 28.2, 30.9, 49.0, 55.0,
59.4, 66.7, 81.2, 127.2, 127.8, 128.1, 128.5, 128.7, 137.3, 140.4, 154.2,
170.9, 174.4, 206.2; HPLC analysis (C18 reverse phase, 40 min, 5−
100% H2O/ACN with 0.1% formic acid) tR = 17.3 min; HRMS-ESI:
m/z calcd for C25H31N2O6 (M + H)+ 455.2177, found 455.2182.
Step 2. To a solution of 7 (2.2 g, 4.8 mmol, 1.0 equiv),
triethylamine (1.4 mL, 10.2 mmol, 2.1 equiv) in 130 mL of anhydrous
THF, phenyl isocyanate (1.1 mL, 9.7 mmol, 2.0 equiv) was added in
one portion. The reaction mixture was stirred at room temperature for
20 h until completion, as determined by LC−MS. The reaction was
quenched with saturated NH4Cl (aq) (40 mL) and extracted with
EtOAc (100 mL + 2 × 50 mL). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. The yellow,
solid product was obtained by removal of the solvent in vacuum. The
crude product 12 was used directly in the next step without further
purification. For characterization, the compound was purified by
reverse phase column using 5−95% H2O/acetonitrile gradient. Note:
diphenyl urea was found in the crude product mixture (detected by
LC−MS) but did not interfere with the next step.
128.3, 129.0, 129.1, 129.7, 130.8, 131.8, 133.9, 137.0, 154.1, 170.6,
171.7; HPLC analysis (C18 reverse phase, 40 min, 5−100% H2O/ACN
with 0.1% formic acid) tR = 19.7 min; HRMS-ESI: m/z calcd for
C29H33N2O6 (M + H)+ 505.2333, found 505.2343.
7-Benzyl-8-tert-butyl(5S,8S)-1-(naphthalen-1-ylmethyl)-2,4-
dioxo-3-phenyl-1,3,7-triazaspiro[4,4]nonane-7,8-dicarboxy-
late, 13. 1H NMR (500 MHz, DMSO-d6, 350 K, δ) 1.20 (9H, s), 2.19
(1H, dd, J = 8.4, 13.7), 2.72 (1H, dd, J = 8.5, 13.7), 3.61 (1H, d, J =
11.8), 4.03 (1H, d, J = 11.8), 4.35 (1H, t, J = 8.4), 5.06 (2H, s), 5.18
(2H, s), 7.28−7.33 (5H, m), 7.42−7.45 (1H, m), 7.47−7.63 (8H, m),
7.88 (1H, d), 7.98 (1H, d), 8.21 (1H, d); 13C NMR (125 MHz,
CDCl3, 298 K, δ) 27.6, 35.4, 42.0, 49.6, 58.2, 66.1, 67.5, 81.9, 123.1,
125.3, 125.9, 126.1, 126.3, 127.0, 127.8, 128.0, 128.4, 129.0, 129.1,
129.3, 131.0, 131.3, 134.0, 136.0, 154.1, 154.7, 170.5, 173.2. IR (neat)
1694, 1403, 1349, 1149, 1124 cm−1; [α]18 = −3.6 (MeOH); HPLC
D
analysis (C18 reverse phase, 40 min, 5−100% H2O/ACN with 0.1%
formic acid) tR = 27.6 min; HRMS-ESI: m/z calcd for C36H35N3NaO6
(M + Na)+ 628.2418, found 628.2422.
(5S,8S)-1-(Naphthanlen-1-ylmethyl)-2,4-dioxo-3-phenyl-
1,3,7-triazaspiro[4,4]nonane-8-carboxylic Acid·TFA, 1b. Yield
592 mg, 70% yield from 13; 1H NMR (500 MHz, DMSO-d6, 350 K, δ)
2.54 (1H, m), 2.98 (1H, dd, J = 6.7, 13.7), 3.66 (1H, d, J = 13.4), 3.83
(1H, d, J = 13.4), 4.57 (1H, dd, J = 6.7, 12.5), 5.23 (2H, s), 7.42−7.87
(9H, m), 7.88(1H, d, J = 7.8), 7.98 (1H, d, J = 7.5), 8.17 (1H, d, J =
8.5); 13C NMR (125 MHz, DMSO-d6, 350 K, δ) 34.6, 41.3, 48.4, 59.2,
68.0, 122.8, 123.5, 126.0, 126.5, 126.8, 127.3, 127.8, 128.6, 129.1,
129.2, 130.4, 132.2, 132.8, 133.6, 154.8, 169.0, 174.2; IR (neat) 1775,
7-Benzyl-8-tert-butyl(5S,8S)-1-benzyl-2,4-dioxo-3-phenyl-
1,3,7-triazaspiro[4,4]nonane-7,8-dicarboxylate, 12. 1H NMR
(500 MHz, DMSO-d6, 350 K, δ) 1.34 (9H, s), 2.21 (1H, dd, J =
8.3, 13.8), 2.72 (1H, dd, J = 8.6, 13.7), 3.60 (1H, d, J = 11.8), 4.00
(1H, d, J = 11.8), 4.39 (1H, t, J = 8.4), 4.69 (2H, s), 5.10 (2H, s),
7.29−7.43 (11H, m), 7.50 (4H, m); 13C NMR (125 MHz, CDCl3,
298K, δ) 27.8, 36.3, 43.4, 50.3, 58.3, 66.3, 67.6, 82.1, 125.8, 127.7,
127.8, 128.0, 128.1, 128.3, 128.4, 129.0, 129.1, 131.3, 136.0, 136.8,
154.1, 154.8, 170.8, 173.2; IR (neat) 1692, 1402, 1348, 1149, 1124
1721, 1502, 1415, 1385, 1185, 1138 cm−1; [α]18 = +13.1 (MeOH);
D
HPLC analysis (C18 reverse phase, 40 min, 5−100% H2O/ACN with
0.1% formic acid) tR = 14.3 min; HRMS-ESI: m/z calcd for
C24H22N3O4 (M + H)+ 416.1605, found 416.1611.
cm−1; [α]18 = −5.0 (MeOH); HPLC analysis (C18 reverse phase, 40
D
Synthetic Procedure for Catalyst 1c. Starting from Cbz,tert-
butyl Pro4(SS) amino acid 5 (364 mg, 1.0 mmol), the synthesis of
catalyst 1c follows the same procedure as that of catalyst 1a with the
following changes: (1) 1-pyrenealdehyde substituted for benzaldehyde
in step 1; (2) after the methanol was removed by concentration under
vacuum, 10 mL of H2O was added to the residue, and 2 drops of 2 N
KOH (aq) was added to assist the dissolution of the amino acid before
adjusting the pH to 7 in step 1.
(3S,5S)-1-[(Benzyloxy)carbonyl]-5-[(tert-butoxy)carbonyl]-3-
[(pyren-1-ylmethyl)amino]pyrrolidine-3-carboxylic Acid, 9.
Yield 462 mg, 80% crude yield in step 1; 1H NMR (500HMz,
DMSO-d6, 350 K, δ) 1.41 (9H, s), 2.74 (1H, dd, J = 8.9, 13.1), 3.06
(1H, dd, J = 8.3, 12.8), 4.03 (1H, d, J = 11.4), 4.33 (1H, d, J = 11.4),
4.42 (1H, t, J = 8.2), 4.97 (2H, dd, J = 13.5, 23.9), 5.15 (2H, s), 7.31−
7.40 (5H, m), 8.12 (1H, t, J = 7.7), 8.21 (2H, m), 8.31−8.39 (5H, m),
8.58 (1H, d, J = 9.3); 13C NMR (125 MHz, DMSO-d6, 350 K, δ) 28.0,
28.1, 36.2, 46.5, 52.8, 59.4, 67.1, 80.0, 123.6, 124.3, 124.6, 126.1, 126.0,
126.2, 126.5, 126.9, 127.7, 127.8, 128.3, 128.6, 128.8, 129.9, 130.8,
131.3, 132.1, 137.0, 154.1, 170.2, 170.8; HPLC analysis (C18 reverse
phase, 30 min, 5−95% H2O/ACN with 0.1% formic acid) tR = 22.5
min; HRMS-ESI: m/z calcd for C35H35N2O6 (M + H)+ 579.2490,
found 579.2500.
min, 5−100% H2O/ACN with 0.1% formic acid) tR= 26.3 min;
HRMS-ESI: m/z calcd for C32H33N3NaO6 (M + Na)+ 578.2262, found
578.2267.
Step 3. Ph-[Cbz, t-Bu] Pro4 (SS) hydantoin 12 (4.8 mmol) was
dissolved in CH2Cl2 (20 mL) followed by the addition of 33% HBr/
AcOH (40 mL). The reaction mixture was stirred at room temperature
for 2 h. Removal of solvents by vacuum evaporation produced a dark
red liquid that was purified by reverse phase using 5−95% H2O/
acetonitrile gradient to afford the product as a white powder. The
amino acid was mixed with 50% TFA/CH2Cl2 for 30 min with stirring.
After concentration under vacuum, the remaining solution (1 to 2 mL
volume) was added dropwise to 200 mL diethyl ether/hexane (1:1),
and a white precipitate 1a formed (2.0 g, 85% yield from 7). The
precipitate was filtered and dried under high vacuum.
(5S,8S)-1-Benzyl-2,4-dioxo-3-phenyl-1,3,7-triazaspiro[4,4]-
1
nonane-8-carboxylic Acid·TFA, 1a. H NMR (500 MHz, DMSO-
d6, 350 K, δ) 2.48 (1H, m), 2.85 (1H, dd, J = 6.8, 13.7), 3.58 (1H, d, J
= 13.4), 3.74 (1H, d, J = 13.4), 4.55 (1H, dd, J = 6.8, 12.3), 4.71 (2H,
s), 7.29−7.53 (10H, m); 13C NMR (125 MHz, DMSO-d6, 350 K, δ)
35.3, 42.8, 49.0, 59.7, 68.4, 127.2, 127.3, 127.6, 128.6, 128.9, 129.1,
132.2, 138.0, 154.9, 169.6, 174.2; IR (neat) 1775, 1718, 1495, 1414,
1181, 1134 cm−1; [α]18 = +10.9 (MeOH); HPLC analysis (C18
D
7-Benzyl-8-tert-butyl(5S,8S)-2,4-dioxo-3-phenyl-1-(pyren-1-
ylmethyl)-1,3,7-triazaspiro[4,4]nonane-7,8-dicarboxylate, 14.
1H NMR (500 MHz, DMSO-d6, 350 K, δ) 1.08 (9H, s), 2.13 (1H,
reverse phase, 40 min, 5−100% H2O/ACN with 0.1% formic acid) tR
= 11.9 min; HRMS-ESI: m/z calcd for C20H20N3O4 (M + H)+
366.1448, found 366.1450.
dd, J = 8.5, 13.6), 2.69 (1H, dd, J = 8.5, 13.5), 3.66 (1H, d, J = 11.8),
4.05 (1H, d, J = 11.8), 4.33 (1H, t, J = 8.5), 5.03 (2H, s), 5.49 (2H, dd,
J = 16.9, 29.6), 7.26−7.30 (5H, m), 7.43−7.46 (1H, m), 7.52−7.59
(4H, m), 8.10 (1H, m), 8.15−8.20 (3H, m), 8.28−8.34 (4H, m), 8.52
(1H, d, J = 9.3); 13C NMR (125 MHz, CDCl3, 298K., δ) 27.5, 35.4,
42.1, 49.4, 58.1, 66.1, 67.5, 81.8, 122.3, 124.6, 125.0, 125.1, 125.6,
125.7, 125.9, 126.3, 126.6, 127.3, 127.7, 127.9, 128.4, 128.7, 128.8,
129.1, 130.7, 131.3, 131.6, 136.0, 154.1, 154.9, 170.3, 173.2; IR (neat)
Synthetic Procedure for Catalyst 1b. Starting from Cbz,tert-
Butyl Pro4(SS) amino acid 5 (728 mg, 2.0 mmol), catalyst 1b was
synthesized following the same synthetic procedure of 1a with the
exception of substituting 1-naphthylaldehyde for benzaldehyde in step
1.
(3S,5S)-1-[(Benzyloxy)carbonyl]-5-[(tert-butoxy)carbonyl]-3-
[(naphthanlen-1-ylmethyl)amino]pyrrolidine-3-carboxylic
Acid, 8. Yield 807 mg, 80% crude yield in step 1; 1H NMR (500 MHz,
DMSO-d6, 350 K, δ) 1.38 (9H, s), 2.40 (1H, dd, J = 8.1, 13.2), 3.00
(1H, dd, J = 8.5, 13.1), 3.75 (1H, d= 11.3), 4.24 (1H, d, J = 11.3), 4.37
(1H, t, J = 7.9), 4.57 (2H, dd, J = 13.2, 22.5), 5.13(2H, s), 7.32−7.39
(5H, m), 7.53−7.64 (3H, m), 7.70 (1H, d), 7.98 (2H, t, J = 9.3), 8.24
(1H, d, J = 8.5); 13C NMR (125 MHz, DMSO-d6, 350 K, δ) 28.0, 28.1,
37.1, 46.5, 53.4, 59.4, 67.1, 81.8, 124.1, 125.7, 126.5, 127.0, 127.8,
1839, 1620, 1486, 1387, 1332, 1116 cm−1; [α]18 = −11.2 (MeOH);
D
HPLC analysis (C18 reverse phase, 40 min, 5−100% H2O/ACN with
0.1% formic acid) tR = 29.9 min; HRMS-ESI: m/z calcd for
C42H37N3NaO6 (M + Na)+ 702.2575, found 702.2569.
(5S,8S)-2,4-Dioxo-3-phenyl-1-(pyren-1-ylmethyl)-1,3,7-
triazaspiro[4,4]nonane-8-carboxylic Acid·TFA, 1c. Yield 352 mg,
4788
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The Journal of Organic Chemistry
Article
1
73% yield from 14. H NMR (500 MHz, DMSO-d6, 350 K, δ) 2.56
(1H, d, J = 12.6), 4.17 (2H,m), 4.35 (1H, t, J = 8.3), 5.12 (2H, s), 6.99
(2H, d, J = 8.7), 7.32−7.42 (7H, m); 13C NMR (125 MHz, DMSO-d6,
350 K, δ) 28.0, 28.1, 39.1, 48.5, 55.0, 55.7, 59.5, 66.6, 81.1, 114.2,
127.7, 128.1, 128.7, 129.8, 132.3, 137.3, 154.2, 159.0, 171.0, 174.4;
HPLC analysis (C18 reverse phase, 30 min, 5−95% H2O/ACN with
0.1% formic acid) tR = 17.4 min; HRMS-ESI: m/z calcd for
C26H33N2O7 (M + H)+ 485.2282, found 485.2292.
(1H, t, J = 13.2), 3.09 (1H, dd, J = 6.6, 13.5), 3.64 (1H, d, J = 13.6),
3.87 (1H, d, J = 13.6), 4.57 (1H, dd, J = 6.7, 12.8), 5.53 (2H, s), 7.40−
7.65 (5H, m), 8.10−8.48 (10H, m); 13C NMR (125 MHz, DMSO-d6,
350 K, δ) 34.1, 41.7, 48.2, 58.8, 67.8, 123.1, 123.7, 124.3, 124.4, 125.4,
125.8, 125.9, 126.9, 127.3, 127.4, 127.5, 127.9, 128.1, 128.7, 129.2,
130.4, 130.7, 130.9, 131.4, 132.2, 155.0, 168.8, 174.2; IR (neat) 1777,
1719, 1502, 1415, 1186, 1139 cm−1; [α]18 = +3.5 (MeOH); HPLC
7-Benzyl-8-tert-butyl(5S,8S)-1-[(4-methoxyphenyl)methyl)-
D
analysis (C18 reverse phase, 40 min, 5−100% H2O/ACN with 0.1%
formic acid) tR = 17.4 min; HRMS-ESI: m/z calcd for C30H24N3O4 (M
+ H)+ 490.1761, found 490.1768.
2,4-dioxo-3-phenyl-1,3,7-triazaspiro[4,4]nonane-7,8-dicarbox-
1
ylate, 16. H NMR (500 MHz, DMSO-d6, 350 K, δ) 1.36 (9H, s),
2.20 (1H, dd, J = 8.3, 13.8), 2.69 (1H, dd, J = 8.6, 13.7), 3.61 (1H, d, J
= 11.8), 3.76 (3H, s), 3.97 (1H, d, J = 11.8), 4.38 (1H, t, J = 8.4), 4.62
(2H, s), 5.09 (2H, s), 6.91 (2H, d, J = 8.7), 7.28−7.38 (7H, m), 7.42
(1H, m), 7.47−7.53 (4H, m); 13C NMR (125 MHz, CDCl3, 298K, δ)
27.8, 36.2, 42.9, 50.2, 55.3, 58.3, 66.2, 67.6, 82.1, 114.4, 125.8, 127.8,
128.1, 128.3, 128.5, 128.9, 129.1, 129.2, 129.4, 131.3, 136.1, 154.1,
154.7, 159.4, 170.8, 173.3; IR (neat) 1682, 1607, 1493, 1399, 1344,
Synthetic Procedure for Catalyst 1d. Starting from Cbz,tert-
butyl Pro4(SS) amino acid 5 (364 mg, 1.0 mmol), the synthesis of
catalyst 1d follows the same procedure as that of catalyst 1a with the
following exceptions: (1) 4-nitrobenzaldehyde substituted for
benzaldehyde in step 1; (2) after the methanol was removed by
concentration under vacuum, 10 mL of H2O was added to the residue,
and 2 drops of 2 N KOH (aq) was added to assist the dissolution of
the amino acid before adjusting the pH to 7 in step 1.
1239, 1121 cm−1; [α]18 = −4.0 (MeOH); HPLC analysis (C18
D
reverse phase, 40 min, 5−100% H2O/ACN with 0.1% formic acid) tR
= 25.9 min; HRMS-ESI: m/z calcd for C33H35N3NaO7 (M + Na)+
608.2367, found 608.2377.
(3S,5S)-1-[(Benzyloxy)carbonyl]-5-[(tert-butoxy)carbonyl]-3-
([(4-nitrophenyl)methyl]amino)pyrrolidine-3-carboxylic Acid,
1
10. Yield 439 mg, 88% crude yield in step 1; H NMR (500 MHz,
(5S,8S)-1-[(4-Methoxyphenyl)methyl]-2,4-dioxo-3-phenyl-
1,3,7-triazaspiro[4,4]nonane-8-carboxylic Acid·TFA, 1e. Yield
207 mg, 48% yield from 16; 1H NMR(500 MHz, DMSO-d6, 350 K, δ)
2.46 (1H, m), 2.80 (1H, dd, J = 6.7, 13.6), 3.57 (1H, d, J = 13.3), 3.70
(1H, d, J = 13.4), 3.76 (3H, s), 4.54 (1H, dd, J = 6.8, 12.1), 4.62 (2H,
s), 6.91 (2H, d, J = 8.7), 7.34 (2H, d, J = 8.7), 7.39−7.43 (1H, m),
7.49−7.51 (4H, d, J = 4.3); 13C NMR (125 MHz, DMSO-d6, 350 K, δ)
34.5, 42.6, 48.3, 55.6, 58.9, 67.9, 114.6, 127.1, 128.5, 129.0, 129.1,
129.8, 132.3, 154.8, 159.3, 168.6, 173.9; IR (neat) 1775, 1719, 1513,
1414, 1247, 1179, 1135 cm−1; [α]18D = +7.8 (MeOH); HPLC analysis
(C18 reverse phase, 40 min, 5−100% H2O/ACN with 0.1% formic
acid) tR = 12.2 min; HRMS-ESI: m/z calcd for C21H22N3O5 (M + H)+
396.1554, found 396.1562.
DMSO-d6, 350 K, δ) 1.37 (9H, s), 2.22 (1H, dd, J = 6.8, 13.1), 2.82
(1H, dd, J = 8.8, 13.0), 3.56 (1H, d= 11.2), 4.00−4.08 (3H, m), 4.32
(1H, t, J = 7.6), 5.10 (2H, s), 7.30−7.38 (5H, m), 7.68 (2H, d, J = 8.7),
8.19 (2H, d, J = 8.7); 13C NMR (125 MHz, DMSO-d6, 350 K, δ) 28.0,
28.1, 38.1, 48.3, 54.1, 59.3, 66.9, 81.6, 123.6, 127.8, 128.2, 128.7, 130.2,
137.1, 145.7, 147.7, 154.1, 170.6, 172.9; HPLC analysis (C18 reverse
phase, 30 min, 5−95% H2O/ACN with 0.1% formic acid) tR = 18.7
min; HRMS-ESI: m/z calcd for C25H30N3O8 (M + H)+ 500.2027,
found 500.2032.
7-Benzyl-8-tert-butyl(5S,8S)-1-[(4-nitrophenyl)methyl)-2,4-
dioxo-3-phenyl-1,3,7-triazaspiro[4,4]nonane-7,8-dicarboxy-
late, 15. 1H NMR (500 MHz, DMSO-d6, 350 K, δ) 1.34 (9H, s), 2.21
(1H, dd, J = 8.0, 13.8), 2.83 (1H, dd, J = 8.7, 13.8), 3.61 (1H, d, J =
11.9), 4.07 (1H, d, J = 11.9), 4.42 (1H, t, J = 8.3), 4.82 (2H, dd, J =
17.3, 25.4), 5.09 (2H, s), 7.30−7.34 (5H, m), 7.42 (1H, m), 7.48−7.56
(4H, m), 7.68 (2H, d, J = 8.8), 8.19 (2H, d, J = 8.8); 13C NMR (125
MHz, CDCl3, 298K, δ) 27.8, 37.3, 42.8, 51.6, 58.4, 66.8, 67.8, 82.6,
124.1, 125.7, 128.0, 128.3, 128.5, 129.2, 131.1, 135.8, 144.3, 147.6,
154.1, 154.9, 171.0, 172.7; IR (neat) 1704, 1596, 1516, 1493, 1402,
Synthetic Procedure for Catalyst 2a. The synthesis of catalyst
2a follows the same procedure as that of catalyst 1a with the change of
beginning with Cbz,tert-butyl Pro4(SR) amino acid 6 (364 mg, 1.0
mmol) rather than Cbz,tert-butyl Pro4(SS) amino acid 5.
(3R,5S)-3-(Benzylamino)-1-[(benzyloxy)carbonyl]-5-[(tert-
butoxy)carbonyl]pyrrolidine-3-carboxylic Acid, 18. Yield 341
mg, 75% crude yield in step 1; 1H NMR (500 MHz, DMSO-d6, 350 K,
δ) 1.38 (9H, s), 2.58 (1H, dd, J = 5.6, 14.1), 2.88 (1H, t, J = 9.0), 3.84
(1H, d, J = 12.5), 4.07−4.16 (3H, m), 4.51 (1H, t, J = 6.7), 5.11 (2H,
s), 7.30−7.48 (10H, m); 13C NMR (125 MHz, DMSO-d6, 350 K, δ)
28.1, 28.2, 39.0, 48.4, 54.7, 59.5, 66.7, 81.2, 127.1, 127.8, 128.1, 128.3,
128.5, 128.7, 137.3, 140.8, 154.5, 171.2, 173.5; HPLC analysis (C18
reverse phase, 40 min, 5−100% H2O/ACN with 0.1% formic acid) tR
= 16.5 min; HRMS-ESI: m/z calcd for C25H31N2O6 (M + H)+
455.2177, found 455.2181.
7-Benzyl-8-tert-butyl(5R,8S)-1-benzyl-2,4-dioxo-3-phenyl-
1,3,7-triazaspiro[4,4]nonane-7,8-dicarboxylate, 20. 1H NMR
(500 MHz, DMSO-d6, 350 K, δ) 1.37 (9H, s), 2.40 (1H, dd, J =
6.9, 14.6), 2.77 (1H, dd, J = 9.4, 14.3), 3.63 (1H, d, J = 12.1), 3.86
(1H, d, J = 11.0), 4.35 (1H, broad), 4.60 (2H, broad), 5.05 (1H, d, J =
12,1), 7.28−7.35 (11H, m), 7.50 (4H, d, J = 4.4); 1H NMR(500 MHz,
CDCl3, 298K, δ, rotamersobserved): 1.37−1.45 (9H, d), 2.41−2.62
(2H, m), 3.76 (0.5H, d, J = 11.8), 3.87 (0.5H, dd, J = 11.8), 3.91
(0.5H, d, J = 12.1), 3.99 (0.5H, d, J = 12.1), 4.14 (0.5H, dd, J = 6.8,
9.3), 4.43−4.51 (1.5H, m), 4.76 (0.5H, d, J = 15.8), 4.84 (0.5H, d, J =
15.8), 4.92 (0.5H, d, J = 12.2), 5.11 (0.5H, d, J = 12.2), 5.17 (1H, tt, J
= 12.5), 7.23−7.53 (15H, m); 13C NMR (125 MHz, CDCl3, 298K, δ)
27.8, 27.9, 38.6, (29.9, 44.5, 54.6, 58.9, 59.5, 67.5, 68.4, 69.3, 82.5,
125.8, 127.5, 127.6, 128.0, 128.1, 128.2, 128.3, 128.5, 128.6, 128.9,
129.1, 131.5, 135.9, 136.0, 136.6, 136.7, 153.4, 153.7, 154.7, 154.8,
169.6, 169.8, 171.0, 171.3; IR (neat) 1702, 1492, 1406, 1353, 1139
cm−1; [α]18D = −88.1 (MeOH); HPLC analysis (C18 reverse phase, 40
min, 5−100% H2O/ACN with 0.1% formic acid) tR = 25.9 min;
HRMS-ESI: m/z calcd for C32H33N3NaO6 (M + Na)+ 578.2262, found
578.2267.
1340, 1125 cm−1; [α]18 = +0.75 (MeOH); HPLC analysis (C18
reverse phase, 40 min, 5−100% H2O/ACN with 0.1% formic acid) tR
= 25.8 min; HRMS-ESI: m/z calcd for C32H32N4NaO8 (M + Na)+
623.2112, found 623.2111.
D
(5S,8S)-1-[(4-Nitrophenyl)methyl]-2,4-dioxo-3-phenyl-1,3,7-
triazaspiro[4,4]nonane-8-carboxylic Acid·TFA, 1d. Yield 290 mg,
1
63% yield from 15; H NMR (500 MHz, DMSO-d6, 350 K, δ) 2.43
(1H, t, J = 13.2), 2.95 (1H, dd, J = 6.6, 13.5), 3.51 (1H, d, J = 13.6),
3.74 (1H, d, J = 13.5), 4.53 (1H, dd, J = 6.6, 12.8), 4.87 (2H, s), 7.41−
7.54 (5H, m), 7.72 (2H, d, J = 8.8), 8.24 (2H, d, J = 8.8); 13C NMR
(125 MHz, DMSO, 350 K, δ) 34.1, 42.6, 48.3, 58.7, 67.5, 124.0, 127.2,
128.3, 128.7, 129.2, 132.0, 145.9, 147.2, 154.9, 168.7, 173.9; IR (neat)
1777, 1718, 1517, 1413, 1345 cm−1; [α]18 = +1.1 (MeOH); HPLC
D
analysis (C18 reverse phase, 40 min, 5−100% H2O/ACN with 0.1%
formic acid) tR = 12.7 min; HR-MS (M + H)+ Calculated for
+
C20H19N4O6 : 411.1299; found: 411.1303.
Synthetic Procedure for Catalyst 1e. Starting from Cbz,tert-
butyl Pro4(SS) amino acid 5 (364 mg, 1.0 mmol), the synthesis of
catalyst 1e follows the same procedure as that of catalyst 1a with the
following changes: (1) 4-methoxybenzaldehyde substituted for
benzaldehyde in step 1; (2) after the methanol was removed by
concentration under vacuum, 10 mL of H2O was added to the residue,
and 2 drops of 2 N KOH (aq) was added to assist the dissolution of
the amino acid before adjusting the pH to 7 in step 1.
(3S,5S)-1-[(Benzyloxy)carbonyl]-5-[(tert-butoxy)carbonyl]-3-
([(4-methoxyphenyl)methyl]amino)pyrrolidine-3-carboxylic
1
Acid, 11. Yield 411 mg, 85% crude yield in step 1; H NMR (500
MHz, DMSO-d6, 350 K, δ) 1.40 (9H, s), 2.38 (1H, dd, J = 8.6, 13.3),
2.92 (1H, dd, J = 8.4, 13.2), 3.72 (1H, d, J = 11.4), 3.79 (3H, s), 4.10
4789
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Article
(5R,8S)-1-Benzyl-2,4-dioxo-3-phenyl-1,3,7-triazaspiro[4,4]-
nonane-8-carboxylic Acid·TFA, 2a. Yield 227 mg, 63% yield from
equiv) was added, and the reaction mixture was stirred at room
temperature for 40 h until completion, as indicated by LC−MS. The
solvent was removed under vacuum, and the residue was dissolved in
CH2Cl2 (5 mL). To this solution was added 33% HBr/AcOH (7 mL),
and the reaction mixture was stirred for 2 h at room temperature until
the Cbz- and tert-butyl- groups were removed completely, as indicated
by LC−MS. After the removal of solvent under vacuum, the residue
was purified by reverse phase. The purified compound was added to
50% TFA/CH2Cl2 (20 mL) and stirred at room temperature for 30
min. After concentration under vacuum, the remaining solution (1−2
mL volume) was added dropwise to 100 mL diethyl ether/hexane
(1:1), and a white precipitate 1f formed (97 mg, 15% overall yield
from 5). The precipitate was filtered and dried under high vacuum.
(5S,8S)-1-Ethyl-2,4-dioxo-3-phenyl-1,3,7-triazaspiro[4,4]-
1
20; H NMR (500 MHz, DMSO-d6, 350 K, δ) 2.61 (1H, dd, J = 9.7,
14.5), 2.71 (1H, dd, J = 5.9, 14.5), 3.54 (1H, d, J = 13.2), 3.80 (1H, d, J
= 13.2), 4.62 (1H, t, J = 6.0), 4.71 (2H, dd, J = 16.9, 51.8), 7.25−7.55
(10H, m); 13C NMR (125 MHz, DMSO-d6, 350 K, δ) 35.1, 43.1, 49.7,
58.8, 68.0, 127.2, 127.3, 127.7, 128.6, 129.0, 129.1, 132.2, 137.9, 155.0,
169.3, 173.3; IR (neat) 1776, 1714, 1494, 1415, 1185, 1135 cm−1;
[α]18 = +13.1 (MeOH); HPLC analysis (C18 reverse phase, 30 min,
D
5−95% H2O/ACN with 0.1% formic acid) tR = 11.6 min; HRMS-ESI:
m/z calcd for C20H20N3O4 (M + H)+ 366.1448, found 366.1454.
Synthetic Procedure for Catalyst 2b. The synthesis of catalyst
2b follows the same procedure as that of catalyst 1b with the exception
of Cbz,tert-butyl Pro4(SR) amino acid 6 (364 mg, 1.0 mmol),
substituted for Cbz,tert-butyl Pro4(SS) amino acid 5.
1
nonane-8-carboxylic Acid·TFA, 1f. H NMR (500 MHz, DMSO-
d6, 350 K, δ) 1.27 (3H, t, J = 7.0), 2.55 (1H, m), 2.86 (1H, dd, J = 6.8,
13.7), 3.48 (2H, dd, J = 7.2, 14.4), 3.61 (1H, d, J = 13.4), 3.72 (1H, d, J
= 13.4), 4.57 (1H, dd, J = 6.9, 12.2), 7.39−7.52 (5H, m); 13C NMR
(125 MHz, DMSO-d6, 350 K, δ) 14.7, 35.1, 35.6, 49.9, 59.5, 68.3,
127.0, 128.4, 129.0, 132.4, 154.1, 169.7, 174.2; IR (neat) 1774, 1718,
(3R,5S)-1-[(Benzyloxy)carbonyl]-5-[(tert-butoxy)carbonyl]-3-
[(naphthanlen-1-ylmethyl)amino]pyrrolidine-3-carboxylic
1
acid, 19. Yield 439 mg, 87% crude yield in step 1; H NMR (500
MHz, DMSO-d6, 350 K, δ) 1.41 (9H, s), 2.63 (1H, d, J = 13.5), 2.94
(1H, t, J = 9.9), 3.89 (1H, d, J = 12.4), 4.14 (1H, d, J = 12.5), 4.50−
4.61 (3H, m), 5.12 (2H, s), 7.30−8.30 (12H, m); 13C NMR (125
MHz, DMSO-d6, 350 K, δ) 28.0, 28.1, 45.6, 53.8, 59.1, 67.1, 81.9,
124.0, 124.1, 125.7, 126.6, 127.2, 128.0, 128.3, 128.7, 129.1, 129.2,
129.4, 129.6, 130.0, 130.1, 131.8. 134.0. 136.9, 153.9, 170.2; HPLC
analysis (C18 reverse phase, 40 min, 5−100% H2O/ACN with 0.1%
formic acid) tR = 19.2 min; HRMS-ESI: m/z calcd for C29H33N2O6 (M
1502, 1421, 1186, 1138 cm-1; [α]18 = +11.1 (MeOH); HPLC
D
analysis (C18 reverse phase, 30 min, 5−95% H2O/ACN with 0.1%
formic acid) tR = 7.7 min; HRMS-ESI: m/z calcd for C15H18N3O4 (M
+ H)+ 304.1292, found 304.1296.
Synthetic procedure for catalyst 2c. The synthesis of catalyst
2c follows the same procedure as that of catalyst 1f with the exception
of Cbz,tert-butyl Pro4(SR) amino acid 6 (364 mg, 1.0 mmol)
substituted for Cbz,tert-butyl Pro4(SS) amino acid 5.
+
+ H) 505.2333, found 505.2342.
7-Benzyl-8-tert-butyl(5R,8S)-1-(naphthalen-1-ylmethyl)-2,4-
dioxo-3-phenyl-1,3,7-triazaspiro[4,4]nonane-7,8-dicarboxy-
late, 21. 1H NMR (500 MHz, DMSO-d6, 350 K, δ) 1.33 (9H, s), 2.41
(1H, dd, J = 6.1, 14.6), 2.78 (1H, s), 3.63 (1H, d, J = 12.1), 3.87 (1H,
broad), 4.18 (1H, broad), 4.72 (1H, broad), 4.88 (1H, broad), 5.13
(1H, s), 7.19 (2H, d, J = 6.8), 7.31 (3H, m), 7.39−7.57 (9H, m), 7.86
(5R,8S)-1-Ethyl-2,4-dioxo-3-phenyl-1,3,7-triazaspiro[4,4]-
nonane-8-carboxylic Acid·TFA, 2c. Yield 60 mg, 14% overall yield
from 6; 1H NMR (500 MHz, DMSO-d6, 350 K, δ) 1.28 (3H, t, J =
7.0), 2.70−2.82 (2H, m), 3.49 (2H, m), 3.63 (1H, d, J = 13.2), 3.82
(1H, d, J = 13.2), 4.76 (1H, dd, J = 6.4, 9.5), 7.39−7.51 (5H, m); 13C
NMR (125 MHz, DMSO-d6, 350 K, δ) 15.0, 35.6, 37.3, 52.6, 59.7,
69.2, 126.9, 128.3, 129.0, 132.6, 154.2, 171.4, 173.9; IR (neat) 1775,
1
(1H, d, J = 8.2), 7.96 (1H, d, J = 7.2), 8.19 (1H, d, J = 7.9); H
NMR(500 MHz, CDCl3, 298 K, δ, rotamers observed): 1.31−1.41
(9H, d), 2.14 (0.5H, dd, J = 9.7, 14.6), 2.33 (0.5H, dd, J = 10.5, 14.7),
2.38−2.49 (1H, m), 3.67 (0.5H, d, J = 11.8), 3.81−3.85 (1H, m), 3.91
(0.5H, d, J = 12.2), 4.09 (0.5H, d, J = 12.2), 4.24 (0.5H, dd, J = 5.8,
9.6), 4.87 (1H, dd, J = 15.9, 29.5), 5.03 (1H, dd, J = 12.3, 15.2), 5.09−
5.59 (2H, m), 7.22−7.60 (14H, m), 7.78−7.92 (2H, m), 8.16−8.20
(1H, t, J = 6.7); 13C NMR (125 MHz, CDCl3, 298 K, δ) 27.7, 27.8,
38.0, 39.5, 42.7, 43.0, 54.0, 58.9, 59.5, 67.4, 68.6, 69.6, 82.4, 123.0,
123.2, 125.1, 125.2, 125.8, 125.9, 126.2, 126.2, 126.9, 127.1, 127.2,
127.5, 128.0, 128.1, 128.3, 128.4, 128.5, 128.5, 129.1, 129.4, 131.0,
131.1, 131.2, 131.2, 131.5, 131.5, 133.9, 133.9, 136.0, 136.0, 153.5,
154.5, 154.7, 169.5, 169.7, 171.7, 171.8; IR (neat) 1720, 1704, 1647,
1719, 1502, 1423, 1187, 1137 cm-1; [α]18 = +9.6 (MeOH); HPLC
D
analysis (C18 reverse phase, 30 min, 5−95% H2O/ACN with 0.1%
formic acid) tR = 7.4 min; HRMS-ESI: m/z calcd for C15H18N3O4 (M
+ H)+ 304.1292; found: 304.1297.
Synthetic Procedure for 17. In a flame-dried 50 mL round-
bottom flask under argon, 1-((benzyloxy)carbonyl)-5-(tert-butoxycar-
bonyl)-3-(benzylamino)pyrrolidine-3-carboxylic acid 7 (454 mg, 1.0
mmol, 1 equiv) and HOAt (1.36 g, 10.0 mmol, 10.0 equiv) were
dissolved in 18 mL of CH2Cl2/DMF (2:1) for 10 min followed by
addition of DIC (188 μL, 1.2 mmol, 1.2 equiv). The reaction mixture
was stirred at room temperature for 2 h. To the reaction was added a
suspension of 1-naphthyl-Aib-OH 22 (292 mg, 1.2 mmol, 1.2 equiv)
and DIPEA (416 μL, 2.4 mmol, 2.4 equiv) in 6 mL of DMF in one
portion. The reaction mixture was stirred at room temperature for 12
h. To the reaction mixture was added DIC (188 μL, 1.2 mmol, 1.2
equiv) in one portion, and the reaction mixture was stirred at room
temperature for an additional 12 h until completion, as determined by
LC−MS. The reaction was quenched by the addition of saturated
NH4Cl (aq) (20 mL), and the product was then extracted with EtOAc
(100 mL followed by 2 × 50 mL). The combined organic EtOAc
layers were washed sequentially with saturated NaHCO3 (aq) and
brine and dried over anhydrous Na2SO4. The Na2SO4was removed by
filtration, and the filtrate was concentrated under vacuum to produce a
yellow, solid crude product. The pure white powder product 17 (440
mg, 67% yield) was obtained after purification by C18 reverse phase
chromatography (5−100% water/acetonitrile).
1417, 1270 cm−1; [α]18 = −31.4 (MeOH); HPLC analysis (C18
D
reverse phase, 40 min, 5−100% H2O/ACN with 0.1% formic acid) tR
= 27.5 min; HRMS-ESI: m/z calcd for C36H35N3NaO6 (M + Na)+
628.2418, found 628.2423.
(5R,8S)-1-(Naphthanlen-1-ylmethyl)-2,4-dioxo-3-phenyl-
1,3,7-triazaspiro[4,4]nonane-8-carboxylic Acid·TFA, 2b. Yield
244 mg, 53% yield from 21; 1H NMR (500 MHz, DMSO-d6, 350 K, δ)
2.71 (1H, dd, J = 10.0, 14.6), 2.87 (1H, dd, J = 4.8, 14.6), 3.62 (1H, d,
J = 13.2), 3.88 (1H, d, J = 13.2), 4.63 (1H, dd, J = 4.9, 10.1), 5.20 (2H,
s), 7.35−7.70 (9H, m), 7.89 (1H, d, J = 8.2), 8.00 (1H, d, J = 7.5), 8.13
(1H, d, J = 8.3); 13C NMR (125 MHz, DMSO-d6, 350 K, δ) 34.8, 41.7,
49.6, 58.7, 68.0, 123.2, 123.6, 126.0, 126.5, 126.7, 127.3, 127.9, 128.6,
129.0, 129.1, 130.5, 132.2, 132.7, 133.6, 154.9, 169.4, 173.7; IR (neat)
1777, 1719, 1502, 1418, 1187, 1137 cm-1; [α]18 = +2.6 (MeOH);
D
HPLC analysis (C18 reverse phase, 30 min, 5−95% H2O/ACN with
0.1% formic acid) tR= 14.2 min; HRMS-ESI: m/z calcd for
C24H22N3O4 (M + H)+ 416.1605; found: 416.1608.
Synthetic Procedure for Catalyst 1f. To a solution of Cbz,tert-
butyl Pro4(SS) amino acid 5 (547 mg, 1.5 mmol, 1.0 equiv) in
methanol was added acetaldehyde (102 μL, 1.8 mmol, 1.2 equiv) in
one portion at room temperature, and the mixture was stirred for 30
min, followed by addition of sodium cyanoborohydride (142 mg, 2.3
mmol, 1.5 equiv). After the reaction was complete after 20 h, as
monitored by LC−MS, phenyl isocyanate (327 μL, 3.0 mmol, 3.0
2-Benzyl-3-tert-butyl(3S,5S)-6-benzyl-8,8-dimethyl-9-(naph-
thalen-1-ylmethyl)-7,10-dioxo-2,6,9-triazaspiro[4,5]decane-
1
2,3-dicarboxylate, 17. H NMR (500 MHz, DMSO-d6, 350 K, δ)
1.35 (9H, s), 1.55 (3H, s), 1.59 (3H, s), 2.35 (1H, dd, J = 7.6, 14.1),
2.84 (1H, dd, J = 9.2, 14.0), 3.77 (1H, d, J = 12.0), 4.08 (1H, d, J =
12.0), 4.36 (1H, t, J = 7.7), 4.67 (1H, d, J = 16.4), 4.85 (1H, d, J =
16.4), 5.07 (2H, s), 5.19 (2H., d, J = 11.9), 7.20−7.65 (14H, m), 7.81
(1H, d, J = 8.3), 7.96 (1H, d, J = 8.4). 8.17 (1H, d, J = 8.4); 13C NMR
(125 MHz, CDCl3, 298K, δ) 26.6, 27.3, 27.7, 39.8, 43.7, 46.9, 55.0,
4790
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The Journal of Organic Chemistry
Article
60.1, 61.8, 66.9, 67.4, 81.9, 122.2, 122.7, 125.4, 125.9, 126.2, 126.5,
127.4, 127.7, 127.8, 127.9, 128.4, 128.9, 129.1, 130.5, 131.8, 133.8,
136.1, 137.4, 154.0, 168.8, 170.6, 171.7; IR (neat) 1698, 1644, 1395,
1.32 mmol, 1.0 equiv). The reaction mixture was stirred vigorously at
room temperature. At specific time points (shown in Supporting
Information), 200 μL of the reaction mixture was taken out by pipet
and added to a vial containing 1 mL of saturated NH4Cl (aq), followed
by 600 μL of CDCl3. After shaking the vial and the formation of two
layers, the CDCl3 layer was taken out by pipet carefully for analysis by
1345, 1121 cm−1; [α]18 = −2.3 (MeOH); HPLC analysis (C18
D
reverse phase, 40 min, 5−100% H2O/ACN with 0.1% formic acid) tR
= 28.7 min; HRMS-ESI: m/z calcd for C40H44N3O6 (M + H)+
662.3225, found 662.3234.
1
1D H NMR. The starting material/product ratio was determined by
the integration of the aldehyde proton peak (10.11 ppm) versus the
proton peak of the α position of the hydroxyl group (5.42 ppm for syn
products, 4.86 ppm for anti products).
Synthetic Procedure for Catalyst 3. 33% HBr/AcOH (7 mL)
was added to the solution of compound 17 (440 mg, 0.67 mmol) in
CH2Cl2 (5 mL) in one portion, and the reaction mixture was stirred at
room temperature for 2 h. Removal of solvent under vacuum resulted
in a dark red liquid that was reverse phase purified with 5−95% water/
acetonitrile gradient. After lyophilization, the white powder was
dissolved in 50% TFA/CH2Cl2 (50 mL) and stirred for 30 min at
room temperature. After concentration under vacuum, the remaining
solution (1 to 2 mL volume) was added dropwise to 100 mL of diethyl
ether/hexane (1:1), and a white precipitate 3 formed (250 mg, 64%
yield). The precipitate was filtered and dried under high vacuum.
(3S,5S)-6-Benzyl-8,8-dimethyl-9-(naphthalen-1-ylmethyl)-
7,10-dioxo-2,6,9-triazaspiro[4,5]decane-3-carboxylic Acid·TFA,
3. 1H NMR (500 MHz, DMSO-d6, 350 K, δ) 1.57 (3H, s), 1.59 (3H,
s), 2.58 (1H, t, J = 13.6), 2.85 (1H, dd, J = 7.4, 13.9), 3.64 (1H, d, J =
13.1), 3.80 (1H, d, J = 13.1), 4.59 (1H, dd, J = 7.5, 11.4), 4.74 (1H, d, J
= 16.6), 4.90 (1H, d, J = 16.6), 5.22 (2H, d, J = 3.4), 7.23−7.63 (9H,
m), 7.82 (1H, d, J = 8.2), 7.95 (1H, d, J = 7.1), 8.17 (1H, d, J = 8.4);
13C NMR (125 MHz, DMSO-d6, 350 K, δ) 26.4, 26.9, 39.2, 44.3, 46.5,
Quantum Mechanical Calculations. All of the computations
were performed in Gaussian 09.16 The geometries were fully optimized
by M06-2X/6-31G(d) either in the gas phase or using the SMD model
to account for the solvation effects of water. The computations in
water as solvent were performed using the SMD model parameters14
along with the IEF-PCM algorithm17 for bulk electrostatics as
implemented in Gaussian 09.14,16 The reported free energies were
computed from partition functions evaluated using a quasiharmonic
approximation in both the gas phase and the solution.14c This
approximation is the same as the usual harmonic approximation,
except that the vibrational frequencies lower than 100 cm−1 are raised
to 100 cm−1.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of catalysts, aldol
reactions and catalyst recycling, full citation for ref 16, energies
and Cartesian coordinates for all computed structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
52.2, 60.3, 61.8, 68.6, 122.8, 123.4, 126.0, 126.1, 126.3, 126.6, 127.2,
127.4, 129.1, 130.5, 133.0, 133.7, 138.2, 168.6, 169.5, 169.8; IR (neat)
1654, 1403, 1363, 1303, 1199 cm−1; [α]18 = +8.8 (MeOH); HPLC
D
analysis (C18 reverse phase, 30 min, 5−95% H2O/ACN with 0.1%
formic acid) tR = 16.1 min; HRMS-ESI: m/z calcd for C28H30N3O4 (M
+ H)+ 472.2231, found 472.2236.
AUTHOR INFORMATION
Corresponding Author
*E-mail: meister@temple.edu.
Typical Procedure for Aldol Reaction Catalyzed by 1a−1f,
2a, 2b, and 3. To a vial containing 1a (6.3 mg, 0.0132 mmol, 0.01
equiv) and 3 mL of H2O was added a mixture of cyclohexanone (1.37
mL, 13.2 mmol, 10.0 equiv) and 4-nitrobenzaldehyde (200 mg, 1.32
mmol, 1.0 equiv). The reaction mixture was stirred at room
temperature until completion as determined by TLC. The reaction
was quenched by addition of 6 mL of saturated NH4Cl (aq) and
extracted with CHCl3 (10 mL + 2 × 5 mL). The combined organic
layers were concentrated to afford the crude product. The
diastereoselectivity was determined by proton NMR of the crude
product. Purification by silica gel chromatography using 10−30%
EtOAc/hexanes afforded the pure aldol reaction product (316 mg,
96% yields). The enantioselectivity was determined by chiral HPLC
with a Chiralpak AD column (UV detection set at 254 nm, flow rate of
0.5 mL/min, 20% i-PrOH/hexane as the eluting solvent).
Procedure for Catalyst Recycling. To a vial containing 1a (6.3
mg, 0.0132 mmol, 0.01 equiv) and 3 mL of H2O was added a mixture
of cyclohexanone (1.37 mL, 13.2 mmol, 10.0 equiv) and 4-
nitrobenzaldehyde (200 mg, 1.32 mmol, 1.0 equiv). The reaction
mixture was stirred at room temperature until completion, as
determined by TLC. Hexanes (6 mL) was added to the reaction
mixture and mixed for 5 min. The hexanes layer was removed carefully
by pipet. To the aqueous layer was added a fresh aliquot of
cyclohexanone (1.37 mL, 13.2 mmol, 10.0 equiv) and 4-nitro-
benzaldehyde (200 mg, 1.32 mmol, 1.0 equiv) for the second
recycling round. The recycling procedure was then repeated for a third
time. The combined organic layers were evaporated under vacuum,
and the residue was analyzed by proton NMR with CDCl3 as solvent
to determine the diastereoselectivity. The yield was determined after
purification of the crude products by silica gel using 20% EtOAc/
hexanes. The enantioselectvity was determined by injection of the
purified products into an HPLC with a Chiralpak AD column (UV
detection set at 254 nm, flow rate of 0.5 mL/min, 20% i-PrOH/hexane
as the eluting solvent).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Defense Threat Reduction
Agency (DOD-DTRA) (HDTRA1-09-1-0009) and the Na-
tional Institute of General Medical Sciences, National Institute
of Health (GM36700). We thank UCLA Institute of Digital
Research and Education and the Shared Research Computing
Services Pilot Project for the UC systems. This research was
supported by an allocation of advanced computing resources
provided by the National Science Foundation (TG-
CHE100059). The computations were performed on Kraken
at the National Institute for Computational Sciences (http://
www.nics.tennessee.edu/) We also thank Dr. Arne Dieckmann
for helpful discussions.
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(15) Interestingly, Gallardo and Fernandez-Mayoralas reported that a
linear, 1:1 copolymer of proline methacrylate and styrene, when used
in conjunction with MgCl2 (0.5 M), afforded the highest anti/syn
(>20:1) and enantioselectivity (96% ee) in the aldol reaction of
cyclohexanone and p-nitrobenzaldehyde in water. Use of proline
methacrylate homopolymers, or the copolymer without the added salt,
gave inferior conversions and stereoselectivities. They suggested that
the styrene-containing copolymer provides hydrophobic interactions
between the ketone substrate and the phenyl ring of the catalyst. This
interaction might be akin to the type of interaction shown in TS-1awater
in our study. (a) Doyaguez, E. G.; Corrales, G.; Garrido, L.;
̈
Rodríguez-Hernan
́ ́
dez, J.; Gallardo, A.; Fernandez-Mayoralas, A.
Macromolecules 2011, 44, 6268−6276. (b) Doyaguez, E. G.; Parra,
F.; Corrales, G.; Fernandez-Mayoralas, A.; Gallardo, A. Polymer 2009,
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50, 4438−4446.
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