Concerted amidation of activated esters: Reaction path and origins of selectivity in the kinetic resolution of cyclic amines via N-heterocyclic carbenes and hydroxamic acid cocatalyzed acyl transfer

Article abstract of DOI:10.1021/ja505784w

The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity.

Full text of DOI:10.1021/ja505784w

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Article
Concerted Amidation of Activated Esters: Reaction Path and
Origins of Selectivity in the Kinetic Resolution of Cyclic Amines
via NHC and Hydroxamic Acid Co-Catalyzed Acyl Transfer
Scott E. Allen, Sheng-Ying Hsieh, Osvaldo Gutierrez, Jeffrey W. Bode, and Marisa C Kozlowski
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja505784w • Publication Date (Web): 22 Jul 2014
Downloaded from http://pubs.acs.org on August 3, 2014
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Concerted Amidation of Activated Esters: Reaction Path and Origins of
Selectivity in the Kinetic Resolution of Cyclic Amines via NHC and
Hydroxamic Acid Co-Catalyzed Acyl Transfer
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Scott E. Allen,† Sheng-Ying Hsieh,‡ Osvaldo Gutierrez,† Jeffrey W. Bode,*, ‡ Marisa C. Kozlowski*,†
†Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104,
United States. ‡Laboratorium für Organische Chemie, ETH-Zürich, Zürich 8093, Switzerland.
Supporting Information Placeholder
N-heterocycles including piperazines, piperidines, morpholines,
ABSTRACT: The N-heterocyclic carbene and hydroxamic acid
co-catalyzed kinetic resolution of cyclic amines generates
enantioenriched amines and amides with selectivity factors up to
and isoquinolines.9
O
OH
127. In this report, a quantum mechanical study of the reaction
mechanism indicates that the selectivity-determining aminolysis
step occurs via a novel concerted pathway in which the hydroxamic
acid plays a key role in directing proton transfer from the incoming
amine. This modality was found to be general in amide bond
formation from a number of activated esters including those
generated from HOBt and HOAt, reagents that are broadly used in
peptide coupling. For the kinetic resolution, the proposed model
accurately predicts the faster reacting enantiomer. A breakdown of
the steric and electronic control elements shows that a gearing
effect in the transition state is responsible for the observed
selectivity.
O
R
10 mol% 3
10 mol% 4
Me Me
HN
N
(1)
Mes
+
1
+
20 mol% DBU
CH2Cl2
23 °C, 18 h
R
Mes
2
5
HN
O
N
R
(±)-2
O
–
ClO4
N
Mes
N
HO
N
3
4
When the resolution reaction is performed in the absence of
amine, chiral hydroxymate ester 77 is formed by the NHC-catalyzed
acylation of 44 with 1. This ester is stable and can be isolated by
column chromatography. Treatment of ester
7
with 2-
Introduction
methylpiperidine affects the kinetic resolution with the same
selectivity as the catalytic method in eq 1 (Scheme 1).10 In addition,
solid supported versions of 4 are highly effective in kinetic
Kinetic resolution is
a valuable tool for the synthesis of
enantiopure materials from racemic mixtures.1 Typically, these
reactions entail the rapid reaction of one enantiomer of a racemate
8c
resolution of amines. These observations suggest that the only
with
a chiral catalyst, which allows for the isolation of
chemical species necessary for the key resolution step are the
hydroxamic ester and the amine.
enantioenriched unreacted starting material as well as an
enantioenriched product. Many compounds that act as acyl transfer
regents for kinetic resolution have been reported, including 4-
aminopyridines, N-alkylimidazoles, amidines, and N-heterocyclic
carbenes (NHCs).2 In a typical reaction, the chiral nucleophilic
transfer reagent is acylated by a carboxylic acid derivative. This
moiety activates the acyl group for preferential nucleophilic
displacement by one enantiomer of the substrate, releasing the
chiral catalyst.
Scheme 1. Effect of ester structure on selectivity factor.
Me
Me
O
Me
CH2Cl2
(0.1 M)
O
O
HN
HN
R
N
N
23 °C, 18 h
R
O
(±)-6
1.0 equiv
O
7a-c
0.5 equiv
6
8a-c
The origins of selectivity for the kinetic resolution of secondary
alcohols involving acyl transfer as catalyzed by 4-aminopyridine
analogs,3 amidines,4 tetrapeptides,5 and yttrium salen complexes6
have been elucidated via experiment and computation. Cation-π
effects have been found to govern the acyl transfer-mediated kinetic
resolution of lactams and thiolactams with amidine catalysts.7
Despite the widespread importance of amine acylation reactions,
the precise details of the mechanism of the kinetic resolution of
unactivated amines have never been fully elucidated, reflecting a
fundamental gap in the literature.
Me
R =
Me
Me
Me
Me
7a
s = 18
7c
s = 2
7b
s = 14
In this paper, DFT calculations support a reactivity enhancement
in the amine acylation due to hydrogen bonding of the incoming
amine nucleophile by the carbonyl of the hydroxamic acid moiety.
Computations with other commonly used acyl transfer reagents
(HOBt, HOAt, and 7-Cl-HOBt) also show a strong preference for
this bimolecular mechanism via a concerted 6/7-member transition
In 2011, the Bode lab reported a kinetic resolution of 2-
substituted cyclic amines using a dual catalyst system consisting of
an achiral NHC 33 and a chiral hydroxamide 4 (eq 1).8 This process
offered the first catalytic method for resolving enantiomers of chiral
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Page 2 of 9
state. The mechanism also accounts for the results observed with minimize the conformational freedom in the transition state. Both
1
2
3
4
5
6
7
8
highly and poorly selective substrates. Implications for the rational
design of novel acyl transfer reagents are discussed.
the water-catalyzed (hydrous) and uncatalyzed (anhydrous)
pathways were examined.
Results & Discussion
Scheme 3. Aminolysis pathways with water-catalyzed
proton transfer.
Paramount to understanding the origin of the reactivity and
selectivity in a kinetic resolution proceeding through an aminolysis
mechanism (Scheme 1) is elucidation of the reaction pathway.
Although introductory organic texts propose a mechanism in which
‡
‡
‡
O
H
H
H
H
O
H
O
H
O
NR2
H
O
Me
MeO
MeO
Me
the amine adds to the ester to generate
a zwitterionic
NR2
Me
N
R2
O
9
H O
intermediate,11 theoretical studies indicate that this intermediate is
high in energy and can be located only through the inclusion of at
least five explicit water molecules.12 This arrangement is possible in
aqueous solution,13 but is unlikely in dry organic solvents. The
zwitterionic pathway can also be promoted by 2-pyridinone14 and
within enzymatic active sites.15
Me
9A-TS2water
H
10
11
12
13
14
15
16
17
18
19
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9A-TS1water
Two-step pathway
-amine addition -alcohol elimination
9A-TSwater
Concerted pathway
The differences between the solvated and gas-phase relative free
energies (Figure 1) show the importance of implicit solvation in
modeling these reaction pathways due to the large amount of
charge separation. The black lines represent the anhydrous reaction
path, while the blue lines indicate the hydrous path. The inclusion
of water as a proton transfer agent lowers the energy of activation in
the first step of the two-step pathway (Figure 1, 110A-TS1 vs 10A-
TS1water) by ca. 7 kcal/mol. The presence of water in this
transition state allows for an N–H–O angle of 153°, as opposed to
112° in the anhydrous reaction. In the anhydrous transition state,
the N–H bond must lie parallel to the carbonyl for optimum proton
transfer, inducing significant strain between the substitution on the
carbonyl and C2 and C6 of the piperidine ring. This strain is
alleviated slightly in the hydrous transition state.
The formation of amides from esters is a key reaction in
synthesis and studies to date have shown that the transformation
proceeds through a neutral transition state in which nucleophilic
addition and displacement accompanies proton transfer.16,17,18,19 In a
two-step pathway (Scheme 2), the amine undergoes nucleophilic
attack with concurrent proton transfer via 9A-TS1 to generate a
tetrahedral intermediate (9B). The alcohol nucleofuge departs in a
second, neutral step (99A-TS2). In
mechanism, addition and elimination occur simultaneously,
without explicit participation of the carbonyl via 99A-TS.
a potential concerted
Scheme 2. Uncatalyzed aminolysis pathways.
For the two-step pathways, the transition state between the two
tetrahedral intermediate rotamers (10-B and 10-Bconf) from the
first and second steps was not located; presumably, the barrier to
interconversion of these rotamers will be much smaller than the
other barriers. The second step, elimination of the hydroxamide,
does not benefit from the inclusion of an explicit water molecule
(10A-TS2 vs 10A-TS2water). Here, the entropic cost of the
trapped water molecule is not sufficiently compensated by the
enthalphic benefits of the larger angles of proton transfer.31 The
second step of the hydrous two-step mechanism lies less than 2
kcal/mol lower than the first step, suggesting that the rate-limiting
step may vary given the substitution in the system. On the other
hand, the elimination step (10A-TS2) of the anhydrous pathway
is over 10 kcal/mol lower in energy than the addition step (110A-
TS1). The anhydrous proton transfer still proceeds at an
unfavorable angle, but the steric strain between the carbonyl and
the departing hydroxamide is significantly lower compared to the
approach of the secondary amine in the first step.
O
OH
NR2
O
MeO
Me
Me
OMe
Me
NR2
HNR2
MeOH
9A
9B
9C
‡
‡
O
H
H O
MeO
Two-step
pathway
NR2
MeO
Me
NR2
Me
9A-TS2
9A-TS1
‡
Concerted
pathway
O
NR2
Me
MeO
H
9A-TS
A proton transfer catalyst, such as water, can promote both
reaction pathways (Scheme 3).17,18 The water-mediated proton
transfer alleviates the strain associated with a four-membered
proton transfer.20,21 This role can also be served by a vicinal
alcohol.22,23 A second amine molecule can also facilitate the proton
transfer via the general base pathway.24,25,26,27 Theoretical and
19
In the concerted path (Figure 1, right), the nucleophilic attack of
the piperidine occurs with simultaneous proton transfer and
departure of the hydroxamide via 10A-TS/10A-TSwater. The
amine approach necessary for this reaction alleviates much of the
steric strain observed in the first step of the two-step pathway. The
wider proton transfer angle of the hydrous transition state 10A-
TSwater lowers the energy of activation for this pathway, but only by
1.81 kcal/mol. Notably, the lowest energy conformation of the
hydrous concerted pathway is 3.09 kcal/mol lower in energy than
the rate-determining first step of the hydrous two-step pathway.
experimental28 studies have shown that 2-pyridinone, acetic acid,29
and triazabicyclodecene (TBD)30 can also act as proton conduits.
In many systems the two-step and concerted pathways are nearly
isoelectronic; greater differentiation comes from steric and
electronic interactions between the reacting partners.
Kinetic studies of the reaction in Scheme 1 indicated that the
reaction is first order in amine;31 therefore the general base
pathway, in which a second equivalent of amine facilitates the
proton transfer, was not explored. For the elementary reaction path
studies, a model system utilizing methyl acetate (Scheme 1, R =
Me) and unsubstituted piperidine were employed in order to
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H O
N
H
H
O
H
O
O
Me
N
Me
O
O
O
N
Me
N
O
O
H
H
N
O
H
O
Me
ꢀG298.15
(kcal/mol)
O
N
O
H O
O
H
N
N
O
O
N
H
N
O
Me
10A-TS1
10A-TS1water
50
O
O
H
O
43.51
(46.63)
N
Me
O
O
O
O
H
N
45
40
35
30
25
20
15
10
5
10A-TS2
10A-TSwater
10A-TS
O
O
35.28
(44.07)
34.80
(22.64)
10A-TS2water
10
11
12
13
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36.56
(30.66)
33.47
(27.53)
31.53
(32.92)
25.26
(20.42)
21.84
(18.86)
20.48
(25.73)
15.68
H
Me
O
(19.93)
O
N
N
Me
HO
O
0.00
(0.00)
0.00
(0.00)
O
N
O
N
0
-5
O
Me
O
10-A
O
N
H
–9.29
(–5.91)
–9.29
(–5.91)
O
O
Me
10-Bconf
O
O
NH
N
-10
N
O
10-C
10-C
O
O
-15
-20
10-A
10-B
Two-Step Pathway
Concerted Pathway
Figure 1. Reaction coordinate for the hydrous (blue) and anhydrous (black) two-step pathway (left) and concerted pathway (right). Relative
Gibbs free energy values calculated at IEPCM-CH2Cl2-M06-2X/6-311+G(d,p)//B3LYP/6-31G(d,p);32 parenthetical values are gas-phase
B3LYP/6-31G(d,p) free energies.
Since the barriers of all the above processes were high relative to
the experimental barrier (~22 kcal/mol based on observed reaction
rates and times,)8a a third mechanism was investigated. In this
variant of the concerted mechanism, the carbonyl of the
174°
O
hydroxamide removes the proton from the amine as the leaving
N
O
O
group departs (Figure 2). Notably, a related 6-membered transition
state was found not to be the operative pathway in ester amination
under pyridone catalysis as reported by Wang and Zipse.19 The
lowest energy conformation of the seven-membered transition
state (10A-TS7-m em ber) is 10.79 kcal/mol lower in energy than the
hydrous concerted transition state in (10A-TSwater; Figure 1). The
Me
ꢀG298.15
(kcal/mol)
2.24 Å
O
1.51 Å
H
N
30
25
20
15
10
5
10A-TS7-member
O
22.68
(22.91)
subsequent proton transfer (10A-TS7-m em ber
)
that effects
N
Me
HO
N
O
tautomerization of the nitrone to regenerate the hydroxamate co-
catalyst, calculated here as an intramolecular process, requires little
energy. Based on the much lower energy barriers for the
intramolecular proton transfer (Figure 2 vs Figure 1), this pathway
was utilized for the study of the enantioselective kinetic resolution
process (see below). In comparison to the pathways discussed
earlier (Figure 1), implicit solvation (see parenthetic values in the
figures) has little effect on the activation energies for this reaction
pathway (Figure 2).
O
H
10A-TSH-transfer
10-B1
5.83
(5.82)
10-A
2.57
(6.20)
0
-5
0.00
(0.00)
–9.29
(–5.91)
O
-10
-15
N
Me
10-C
O N
O
To probe the generality of the concerted bimolecular reaction
pathway involving C–N bond forming, C–O bond breaking, and
concomitant proton transfer, we investigated the competing
pathways for various commonly used acyl transfer reagents
including N-hydroxysuccinimide (11), HOAt (112), HOBt (113),
and 6-Cl-HOBt (114). In the reaction of the acetyl derivatives of
11-14 with piperidine, the lowest energy pathway for each (Table
HO
Hydroxamic Acid Proton Transfer Pathway
Figure 2. Reaction coordinate for the seven-membered concerted
transition state pathway at the IEPCM-CH2Cl2-M06-2X/6-
311+G(d,p)//B3LYP/6-31G(d,p); parenthetical values are gas-phase
B3LYP/6-31G(d,p) free energies.
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1) involves concerted bond breaking/forming with concomitant and 7-membered transition states (Figure 3) is possible and reveals
1
2
3
4
5
6
7
8
proton transfer either via a seven-member transition state (conc-
TS7-m em ber) or six-member transition state (conc-TS6-m em ber). For
HOAt, which can adapt either 6- or 7-member TS with nitrogen Nb
or nitrogen Nd, respectively, the 7-member transition state is
slightly favored. Previous work has shown the importance of Nd in
comparison to agents lacking this nitrogen [i.e., HOBt (113)33 and
variants of HOAt34] in the efficiency of peptide couplings but no
computational support, to date, has been reported.
that the former also facilitates a near ideal deprotonation (bond
angle 174°), but at an energetic cost of 1 kcal/mol in accord with
the slower rates observed with HOBt (113).
33
1.52
1.50
2.79
2.61
1.15
1.29
1.31
1.47
174º
9
169º
These data convincingly show that
a
concerted
1.30
1.29
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
addition/elimination mechanism involving proton transfer in a
cyclic transition state plays a key role in amide bond formation with
these broadly used reagents. This stands in contrast to mechanisms
typically invoked involving stepwise addition/elimination and a
tetrahedral intermediate. The stabilization of the concerted
transition states arises from appropriate orientations of
12-conc-TS7-member
19.1
12-conc-TS6-member
20.0
heteroatoms to facilitate
a strain-free deprotonation of the
incoming amine while forming the C-N bond (Figure 3). In
particular, near ideal trajectories can be found in the 7-membered
transition states of both hydroxamate 4 and HOAt (112) as
evidenced by the O–H–N bond angles of 174° (Figure 2) and 169°
(Figure 3), respectively. For HOAt, a direct comparison of the 6-
Figure 3. Structrures of the six- and seven-membered concerted
transition state with HOAt (12) at IEPCM-CH2Cl2-M06-2X/6-
311+G(d,p)//B3LYP/6-31G(d,p); bond distances indicated in Å,
angles in degrees.
Table 1. Relative reaction barriers (free energies in kcal/mol; IEPCM-CH2Cl2-M06-2X/6-311+G(d,p)//B3LYP/6-31G(d,p)) for the
competing pathways using representative acyl transfer agents (44, 11-14) with acetyl and piperidine.
HOAt
HOBt
6-Cl-HOBt
c
c
c
b
N
acylating
agent
b
N
b
N
N
O
N
N
O
N
a
N
a
N
a
N
N
HO
HO
HO
HO
HO
transition
state
N
d
O
O
Cl
4
11
12
13
14
O
Me
H
O
N
43.5
36.6
45.3
37.3
43.0
43.0
42.5
step-anhy-TS
N
H
O
H
Me
O
step-hyd-TS
35.4
35.2
34.7
H
O
N
N
O
Me
O
35.3
33.5
27.0
33.4
22.5
26.4
23.0
28.1
22.0
27.1
conc-anhy-TS
conc-hyd-TS
N
N
N
H
O
Me
N
H
O
H
O
N
O
H
N
N
N
O
O
O
N
O
O
Me
Me
N
O
O
O
N
conc-TS7-member
H
H
NA
O
NA
O
N
Me
O
H
N
22.7
25.0
19.1
Cl
N
O
O
N
O
N
O
Me
Me
Me
N
N
N
N
N
N
N
NA
NA
conc-TS6-member
N
N
N
H
H
H
19.2
20.4
20.0
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The calculations also show that the overall barriers for acyl
Table 2.
Relative enthalpies (kcal/mol) and Boltzman
1
2
3
4
5
6
7
8
transfer reagents 12-14 are significantly lower than that for 44
leading to the expectation of faster rates with 112-14. In accord
with the computational data, kinetic studies (eq 2), show relative
rates of 112 > 14 >> 4 in amide-forming reactions.
distribution for the acetyl and propionyl derived transition states
corresponding to Figure 5 in the solvated phase.
7 (R = Et)
7 (R = Me)
Rel ΔH‡
Rel ΔH‡
Piperidine
Config
Ar
TS
(%)
(%)
a
a
Bn
activated
ester
Bn
O
TS4
TS52
TS34
TS42
TS26
TS18
TS51
TS8
S
S
0.00
3.21
2.33
3.71
3.89
2.19
5.46
2.37
2.31
4.29
2.80
4.21
2.98
4.37
5.05
5.15
8.01
4.66
3.74
7.17
4.79
4.89
4.88
5.57
7.10
4.05
89.8
0.4
1.8
0.2
0.1
2.2
<0.1
1.7
1.8
0.1
0.8
0.1
0.6
0.1
<0.1
<0.1
<0.1
<0.1
0.00
0.07
0.50
1.20
1.65
1.71
2.08
2.27
2.45
2.57
2.65
2.68
2.89
2.89
3.01
3.16
3.21
3.39
3.43
3.50
3.51
3.59
3.76
3.77
3.85
4.01
36.7
32.6
15.7
4.8
2.3
2.1
1.1
0.8
0.6
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
<0.1
O
(2)
HN
N
CDCl3 , 23 °C
O
9
R
R
R
R
S
16
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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MeO
Ph
Ph
Br
N
N
N
N
N
N
O
O
S
O
O
N
O
O
TS1
TS38
TS6
R
R
R
R
S
N
O
Cl
6-Cl-HOBt (14) ester
k = 0.0261 M-1s-1
O
HOAt (12) ester
4-Br ester
k = 0.00026 M-1s-1
k
0.0608 M-1s-1
krel
a
231
16 s
14 s
100
38 s
17 s
1
3,813 s
6,637 s
TS33
TS12
TS56
TS60
TS54
TS41
TS22
TS2
TS30
TS40
TS27
TS19
TS46
TS53
TS7
t 1/2
t 1/2
b
S
S
aFrom k with 1 M. bFrom ꢀG‡ with 1 M.
With a likely reaction pathway in hand, our attention turned to
the factors controlling the enantioselective acylation. In the
stoichiometric resolution process the pentanoate (7b, R = n-butyl,
Scheme 1) gives very similar selectivity to the mesityl-substituted
ester 7a, suggesting that the aryl ring (and any
electronic/dispersion interactions that accompany it) is not
required for selectivity. However, the poor performance of the
acetate (7c, R = Me), confirms that the ester cannot be completely
truncated. In order to model the butyl group while minimizing the
number of rotamers, the hydroxamic propionate (77, R = Et) was
utilized. In addition, 2-methylpiperidine, which has well-defined
conformations, was employed. In order to affirm the validity of this
model, transition states and the selectivity factor were also obtained
for the corresponding acetate (7c, R = Me, Scheme 1).
R
R
R
R
R
S
S
S
R
R
S
0.2
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
0.1
aAll values calculated at 298 K using IEFPCM-CH2Cl2-M062X/6-
311+G(d,p)//B3LYP/6-31G(d,p). For structural descriptions of each
transition sate, see the supporting information.
Examination of the seven-membered transition state reveals
seven key variables that contribute to the conformational flexibility
of this system. Through a systematic study of these variables with
both enantiomers of 2-methylpiperidine, all of the 128 possible
transition states were studied. The lowest energy ethyl rotamer for
each possible combination is shown in the Supporting
The lowest energy transition state overall is depicted in the top
left of Figure 4 (TS4). The energetic consequence of each
conformational variable was assessed via comparison to this
transition state. Most of the lowest energy transition states
contained the (S)-enantiomer of 2-methylpiperidine. However,
several transition states with (R)-enantiomer (e.g., TTS18) do
contribute significantly to the reaction outcome (within 2.5
kcal/mol of the lowest energy transition state).
31
Information. For these transitions states, the enthalpies35
contributing to the Boltzmann distribution at 25 °C are tabulated in
Table 2.31 This table clearly depicts that the most stable transition
state is similar for both the acetate and propionate substrates.
Furthermore, the ten lowest energy transition states account for the
vast majority (~98%) of the product, but a significant redistribution
of energies with R = Et explains for the higher selectivity for the
propionate.
The hydroxamic ester can undergo cis-trans isomerization
(TS36rot
, Figure 4); in the absence of amine the trans
conformation is 3 kcal/mol higher in energy. In the presence of
amine, the trans conformation is even higher in energy because the
conformational changes required to avoid the strong A1,2 strain
between the hydroxamide and the ester block the approach of the
amine.
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1
Most Stable Conformer (re)
Ester Rotamer
Opposite Facial Approach - (si)
2
3
4
5
6
7
8
9
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60
8.79
2.19
0.00
TS4
TS36rot
TS18
(0.00)
(8.84)
(3.23)
Ethyl Rotamer
Morpholine Ring Inversion
Nitrogen Inversion
2.70
2.98
TS12
2.37
TS8
TS4rot
(2.69)
(3.30)
(2.61)
Figure 4. Lowest energy transition state and key steric interactions for each conformational variable. Relative enthalpies of activation (298 K,
kcal/mol) from IEFPCM-CH2Cl2-M06-2X/6-311+G(d,p)//B3LYP/6-31G(d,p). Parenthetical values are the corresponding gas phase B3LYP/6-
31G(d,p) values.
The chiral, nonracemic ester effects energetic differentiation of
the si- and re-faces of the carbonyl group. In both approaches the
indane is directed away from the amine so that the hydroxamic acid
carbonyl can remove the amine proton. In the more favored re-
approach, the indane is directed away from the ethyl group. In the
si-approach (TTS18, Figure 4, top right), the indane abuts the ethyl
group, causing an unfavorable steric interaction that renders all si-
approaches higher in energy relative to their re-face counterparts.
The lowest energy si-face transition state depicted (TS18) is also
the lowest energy transition state for the more slowly reacting (R)-
amine enantiomer.
2.70
(2.61)
kcal/mol
TS4rot
The ethyl group of the hydroxamic acid propionate (Scheme 1,
R = Et) has, in theory, three rotamers. In practice, however, one
conformation is not viable due to steric overlap and a second is
routinely higher in energy (Figure 4, TS4 vs TS4rot). In the higher
energy conformation, the pendant methyl group orients toward the
2-methylpiperidine (Figure 5, top), imparting significant steric
strain, while in the lower energy rotamer the methyl group nearly
eclipses the carbonyl (Figure 5, bottom).
0.00
(0.00)
kcal/mol
TS4
Ring inversion of the morpholine portion changes the
orientation of the indane portion of the co-catalyst. When the
morpholine oxygen lies trans to the indane (Figure 4, TTS12), a
destabilizing syn-pentane interaction is introduced between the N-
hydroxyl group and the aromatic ring of the indane.
Figure 5. Newman projections of the transition state ethyl rotamers
with relative solvated enthalpies (kcal/mol). Parenthetical values are
the corresponding gas phase values.
In the 2-methylpiperidine ring, nitrogen inversion occurs
independently of ring inversion; the barrier to nitrogen inversion in
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piperidine is 6.1 kcal/mol.36 Theoretical and experimental studies
higher barriers for thiomorpholine in accord with the very low
observed reactivity of this substrate (entry 4).
1
2
3
4
5
6
7
8
of 2-alkylpiperidine conformations have shown that the lowest
energy conformation possesses an axial lone pair and equatorial
substitution at the 2-position.37 However, the axial lone pair leads
to a higher energy transition state due to unfavorable steric
interactions between the carbonyl and the axial hydrogens on the
amine (Figure 4, TTS8). For each orientation of the nitrogen lone
pair, four piperidine conformations are available (Figure 6). In the
most stable transition state (Figure 5 and Figure 6, TTS4), the
methyl group is on C2 of the piperidine and axial. The analogous
equatorial conformation is slightly higher in energy (Figure 5,
TS1). Location of the methyl group to the C6 piperidine carbon is
significantly higher in energy due to steric interactions with the
propionate (Figure 6, TTS2 and TS3).
The structural differences between the lowest energy transition
states leading to the acylated (S)-amine and the unreacted (R)-
amine (Figure 4, TS4 and TS18, respectively), suggest that
increasing the penalty for the ethyl-indane interaction may serve to
improve the selectivity. However, completely eliminating this
pathway (Figure 4, TS18) will not give rise to a completely
selective process due to other low-lying transition states from the
enantiomeric starting material that are unaffected by this
substituent, such as the (R)-equatorial transition state (Figure 6,
TS1). Therefore, the design of improved catalysts requires taking
into account multiple reaction pathways.
9
10
11
12
13
14
15
16
17
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23
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34
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45
46
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Substitution at C2
Table 3. Comparison of experimental and calculated selectivity
factors (krel = S).
Me
Me
O
Me
CH2Cl2
23 °C
O
O
HN
HN
R
N
2
N
2
X
X
R
X
O
(±)-6
1.0 equiv
O
6
7a-c
0.5 equiv
6
8
6
(S)-axial
(R)-equatorial
2.31
TS1
0.00
kcal/mol
TS4
ꢀG‡ of Lowest
Selectivity Factor (Major
Amide Product)
Experimenta Calculatedc
(0.00)
(1.42)
Energy Transition
State (kcal/mol) d
Substitution at C6
Entry Substrate
R = Et,
14 (S)
2 (S)
11(S)
NRb
12.79 (S)
2.63 (S)
10.6 (S)
12.5 (S)
22.0
22.7
24.3
25.7
1
X = CH2
R = Me,
2
2
X = CH2
2
2
R = Et,
6
3
X = O
6
6
R = Et,
(S)-equatorial
(R)-axial
4
TS2
TS3
3.74
5.35
X = S
(3.22)
(4.36)
aExperimental value employs R = n-butyl for entries 1 and 2, R = Bn
Figure 6. The four possible piperidine variations in the transition
states with solvated relative enthalpies (kcal/mol). Parenthetical
values are the corresponding gas phase values.
c
for entries 3 and 4. bNo reaction observed. From IEFPCM-CH2Cl2-
M06-2X/6-311+G(d,p)//B3LYP/6-31G(d,p) enthalpies at 25 °C.
dIEFPCM-CH2Cl2-M06-2X/6-311+G(d,p)//B3LYP/6-31G(d,p)at
25 °C.
A theoretical selectivity factor (Table 3) was calculated using the
Boltzmann distribution from Table 2.31 For both the ethyl and
methyl substrates (entries 1 and 2), the model correctly anticipates
that the (S)-enantiomer acylates more rapidly. In addition, the
model expects that higher acyl congeners, such as the propionyl, are
more selective than the acetyl(calc krel 12.79 vs 2.63) in accord with
the experimental results (expt krel = 14 vs 2). Notably, one key
transition state (TS 34) accounts for most of the selectivity
difference between the acetyl and propionyl cases. A steric
interaction between the axial methyl group of the amine and the
propionyl in TS34 is absent in the acetyl analog due to the shorter
alkyl chain. Rotating the propionyl ethyl group to avoid this
interaction in TS34 only introduces other disfavorable steric
interaction with the arene of the indane. The computed and
experimental results are also in good agreement for the morpholine
congener of the substrate (entry 3). Finally, the model predicts
Conclusions
Our studies support a kinetic resolution of 2-alkyl cyclic amines
via a concerted, seven-membered transition state involving a
hydroxamic acid proton transfer. The energy of activation for this
concerted pathway is 10.97 kcal/mol lower in energy than the next
lowest pathway, which involves water catalysis. This study
highlights the advantages of acyl transfer catalysts that also
incorporate a group to enable proton transfer from the incoming
nucleophile. Concerted amidation of the resultant activated esters
via cyclic transition states is found to account for the relative
reactivity of different peptide bond forming reagents, including
HOAt and HOBt. This understanding can facilitate the
7
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development of further reagents for amide formation. The
Page 8 of 9
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2
3
4
5
6
7
8
developed transition state models also accurately predict the
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using the current system.
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Calculation Methods. To identify the different reaction
mechanisms, a conformational search was conducted for each
10
11
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23
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38
transition state using the OPLS_2005 force field as employed in
39
MacroModel. The lowest energy conformation was optimized at
40,41
B3LYP/6-31G(d,p),
followed by single point calculations with
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42 43
,
44
2X/6-311+G(d,p)
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frequencies) and transition states (one imaginary frequency).
Intrinsic reaction coordinate (IRC) calculations were performed to
45
confirm the identity of identified transition states. Local minima
were found by nudging transition states along the reaction
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Transition state conformations to calculate selectivity factors
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state geometry optimization was performed using B3LYP/6-
31G(d,p) followed by solvated single point energy calculations
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ASSOCIATED CONTENT
Supporting Information. Full computational and experimental
details. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
marisa@sas.upenn.edu, bode@org.chem.ethz.ch
ACKNOWLEDGMENT
We thank Michael Binanzer (ETH-Zürich) for preliminary kinetic
studies. We are grateful to the National Institutes of Health (GM-
079339 and GM-087605), the National Science Foundation (CHE-
0449587), and the (ERC Starting Grant No. 306793 – CASAA) for
financial support of this research. Computational support was
provided by XSEDE on SDSC Gordon (TG-CHE120052) and PSC
Blacklight (TG-CHE110080). Additional computational support was
provided by the NSF CRIF program, grant CHE-013112, and the ETH
High-Performance Cluster, Brutus.
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31) See supporting information for details.
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TOC Graphic:
O
O
N
N
–
ClO4
N
HO
N
Mes
O
O
R
R
R
10 mol%
10 mol%
OH
N
HN
HN
20 mol% DBU
CH2Cl2, 23 °C, 18 h
Me Me
Mes
Mes
Concerted Nucleophilic Addition/Displacement:
O
N
N
O
O
O
H
N
O
O
Me
N
O
N
Me
H
N
N
O
N
N
N
H
N
R
Me
Hydroxamic Ester
Enantiodifferentiating Step
HOAt
HOBt
9
ACS Paragon Plus Environment