In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non-proteinogenic α-Amino Esters

Article abstract of DOI:10.1021/acs.joc.7b01274

An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected α-amino esters. These reactions proceeded rapidly to afford the pivotal α-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. To better understand this one-pot transformation and the orchestration of the components' condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our findings suggest that the halogenation step toward the formation of α-chloroglycine is the rate-determining step likely proceeding through the formation of N-carbamoyl iminium. Also, the initial kinetic profiling for the nucleophilic substitution supports an S_N1-like (S_N2C+) mechanism in which nucleophiles add to the iminium-chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophiles to be efficiently exploited to synthesize novel non-proteinogenic α-amino esters.

Full text of DOI:10.1021/acs.joc.7b01274

Subscriber access provided by BOSTON UNIV
Article
In Situ-Generated Glycinyl Chloroaminals for a One-
Pot Synthesis of Non-Proteinogenic #-Amino Esters
Shyam S. Samanta, and Stephane P. Roche
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01274 • Publication Date (Web): 24 Jul 2017
Downloaded from http://pubs.acs.org on July 28, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 23
The Journal of Organic Chemistry
In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of
1
2
3
Non-Proteinogenic α-Amino Esters
4
5
6
Shyam S. Samanta, Stéphane P. Roche*
7
8
9
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
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431.
*sroche2@fau.edu.
TOC/Abstract Graphic
ABSTRACT:
An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate and various
types of nucleophiles is reported for the synthesis of orthogonally protected -amino esters. These reactions
proceeded rapidly to afford the pivotal -chloroglycine intermediate in excellent yields which can be directly
functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found
to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic
-amino esters. To better understand this one pot transformation, and the orchestration of the components
condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our
findings suggest that halogenation step towards the formation of the -chloroglycine is the rate determining step
likely proceeding through the formation of an N-carbamoyl iminium. Also, the initial kinetic profiling for the
nucleophilic substitution support an SN1-like (SN2C+) mechanism in which nucleophiles add to the iminium–
chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen-
bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophile to be
efficiently exploited to synthesize novel non-proteinogenic -amino esters.
.
INTRODUCTION:
Non-proteinogenic -amino acids (Xaas) represent an important class of organic compounds. They are prevalent
foundational building blocks in many biologically active small-molecules, non-ribosomal peptides (NRPs) and
pharmaceuticals (Figure 1).1 For example, NRPS containing -aryl glycine units prove to typically have important
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 23
antibacterial properties (e.g. amoxicillin, ampicillin, vancomycin, teicoplanin, ramoplanin) or anti-HIV properties
(e.g. neuroprotectins A and B, feglymycin).2 Due to their extraordinary diversity (structural and functional), non-
1
2
3
4
5
proteinogenic Xaas are also widely used
Figure 1. Chemicals derived from non-proteinogenic Xaa structural motifs
6
7
as chiral building blocks in the synthesis
8
9
chiral auxiliaries, organocatalysts and
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
ligand backbone for metal catalysis thus
imparting them with a crucial role in
modern organic synthesis. As a result,
scalable and asymmetric synthesis of
non-proteinogenic -amino acids has
attracted significant attention in the past decades.3 For example, asymmetric alkylations of glycine-derived Schiff
base4 or azlactone5 and NH-insertion6 of -diazo esters are well-documented and useful methods for the
catalytic asymmetric synthesis of -amino esters. Of importance, numerous asymmetric functionalizing methods
of -iminoglycinates 1 have also been reported (Strecker, 7 Mannich, 8 Petasis, 9 hydrogenation10 or aza-
11
Friedel−Crafts
reactions)
Scheme 1. Multicomponent assembly of non-proteinogenic α-amino esters 7
demonstrating the prodigious versatility
of this substrate for the synthesis of non-
proteinogenic Xaas (Scheme 1).
However,
the
instability
of
-
iminoglycinates 1, which require
cumbersome preparation and some
typical protecting groups manipulations are an inherent limitation leading overall to multi-pot operations to
produce marketable -amino esters 8.12 To overcome some of these issues, -haloglycine esters13 5 and -
amido sulfones14 have been exploited as surrogates of -iminoglycinates 1 (Scheme 1) in multi-pot operations.
On the other hand, only sparse examples of cascade reactivity or multicomponent reactions (MCRs) to
synthesize chiral -amino esters in a single step have been reported.15 The most practical asymmetric MCRs for
the synthesis of non-proteinogenic Xaas are certainly the Strecker-3CR (requiring one hydrolysis extra-step) and
ACS Paragon Plus Environment

Page 3 of 23
The Journal of Organic Chemistry
the Petasis-3CR which can accommodate several
Scheme 2. One-pot Synthesis of -chloroglycine ester 6a a
1
2
3
4
5
6
7
8
9
type of functionalizations. However, the vast majority
of MCRs reported to date, using iminoglycinate 1 as
pivotal intermediate are achiral and present a narrow
scope of nucleophiles.16 Thus we were drawn to
establish a scalable and more versatile one-pot
synthesis of -amino esters which could also be
amenable to enantioselective catalysis17 to prepare
Xaas bearing marketable carbamate protecting
groups (e.g. N-protecting groups such as
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
benzyloxycarbamate
(Cbz)
or
fluorenylmethyloxycarbamate (Fmoc) 18 . We now
wish to expand the scope of this work and fully exploit
our recently reported autocatalytic-like synthesis of
-chloroglycinate 6a to take advantages of the high
reactivity of glycinate iminium 7 (Scheme 2). While -
halogenoglycine synthons have been extensively
exploited in the 80’s, no kinetic studies have been
previously reported and the mode of reactivity was
not well understood. 13,19 We hope to demonstrate
a Reaction mixture aliquots were taken during the course of the reaction and solvent
was evaporated under vacuum. Mesitylene was added as an internal standard and
conversions were calculated from 1H NMR using a quantitative protocol with the
appropriate acquisition parameters (see experimental section).
that this novel method is truly amenable to the practical synthesis of numerous classes of -amino esters and
offers a great opportunity for some chiral variant to be developed.
.
RESULTS AND DISCUSSION:
Summary of Previous Results. Recently, our group established a suitable system for a practical racemic route
to α-aryl -amino esters bearing carbamate protecting groups.18 We have previously shown that primary
carbamates 2, ethyl glyoxylate (hydrate) 3 and arene nucleophiles 4 have been condensed to achieve a stepwise
3-component synthesis of numerous -aryl -amino esters 8 in a single pot transformation (Scheme 2A). The
reaction advances through a pathway involving three main steps: 1) the condensation between 2 and 3, followed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 23
by 2) the activation of the -hydroxyglycine 5 to -chloroglycine 6 and the final 3) nucleophile addition. As
proposed in Scheme 2A, a system of AcOH(cat.)/AcCl was previously found to assist both steps (1 & 2) while
enhancing the overall reaction’ rate, leading us to propose a new mechanism for this transformation. We have
previously suggested that the condensation between 2 and 3 catalyzed by acetic acid (10 mol%) afforded modest
conversion to -hydroxyglycine 5a (72% conversion) due to the reversibility of the initial condensation step.20 In
the other end, catalyzed reaction with acid and excess of acetyl chloride proceeded more rapidly to a full
conversion in 5a and further afforded the desired -chloroglycine 6a in quantitative yields (Scheme 2B). To
rationalize these results, we propose that catalytic amount of acid facilitates the condensation between benzyl
carbamate 2a and ethyl glyoxylate 3a to rapidly form the first intermediate -hydroxyglycine 5a (less than 2
hours) which further irreversibly evolve by reaction with acetyl chloride (catalyzed by AcOH and/or HCl) to deliver
-chloroglycine ester 6a in an autocatalytic-like manner.21 The preliminary kinetic experiments support that the
halogenation is the rate determining step (persistent hemiaminal 5a >80% formation in 2 h) and that acetyl
chloride not only promotes the condensation step between 2a and 3a, but also trap the water formed during the
reaction, producing more acetic acid by-product which autocatalyzes and accelerates the overall cascade (slope
characteristic of a rate acceleration in -chloroglycine 6a formation; Scheme 2B).
1
2
3
4
5
6
7
8
9
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
Optimization of Reaction Conditions. From an extensive screening of hemiaminal 5a activatation (previous
publication18) to chloro-, bromo-, or acetoxy-aminals, acetyl chloride was found the most efficient reagent in the
Table 1. Optimizations to synthesize the pivotal α-chloroglycin ester 6a
prospect of a tandem process. During the
investigation, we faced the expected problem of full
entry
solvent, temp. a
CHCl3, RT
activator
time (h)
12
conversion (%) b
conversion to the desired -chloroglycine 6a and
1
2
3
-
AcCl
-
5a (62) c
proposed that the modest yields observed for the
condensation between carbamate 2a and ethyl
glyoxylate 3a, 62% and 82% yield in chloroform and
ethyl acetate respectively are due to the
reversibility of the condensation (Table 1, entries 1
& 3).20 Upon activation with acetyl chloride the
reactions proceeded to full conversion and further
afforded the desired -chloroglycine 6a with a
CHCl3, RT
18
5a (76); 6a (4)
5a (82) c
CH3CO2Et, RT
12
4
CH3CO2Et, RT
AcCl
18
5a (59); 6a (19)
5
6
7
8
9
CH3CO2Et, 60 oC
CHCl3, 60 oC
THF, 60 oC
Toluene, 60 oC
CH3CN, 60 oC
AcCl
AcCl
AcCl
AcCl
AcCl
9
6a (100)
6a (100)
5a (61); 6a (25)d
5a (44); 6a (56)
6a (100)
12
12
12
24
a Reactions were performed with 2a (1.0 mmol), 3a (1.3 mmol), acetyl chloride
b
(2.5 mmol), and acetic acid (10 mol%); Conversions are reported due to the
innate instability of chloroaminal 6a, using a quantitative 1H NMR technique [ref
21] with mesitylene as internal standard; c Isolated yields of pure hemiaminal 5a
d
were 60% and 81% for entries 1 and 3 respectively; Decomposition and
possible polymerization were observed.
ACS Paragon Plus Environment

Page 5 of 23
The Journal of Organic Chemistry
conversion of 4% and 19% respectively (Table 1, entries 2 & 4).22 Under strict anhydrous conditions at 60 oC, -
chloroglycine 6a was obtained in a quantitative manner in ethyl acetate and chloroform (Table 1, entries 5 & 6).23
Several other solvents were tested (Table 1, entries 7-9), and -chloroglycine 6a was also synthesized
quantitatively in CH3CN in 24 hours. After optimizations, two sets of conditions in CHCl3 and CH3CN were
established for the quantitative preparation of -chloroglycine ester 6a in a single step, which represents an
advancement from the previous literature (2 steps).24
1
2
3
4
5
6
7
8
9
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
Scope and Limitation of the Methods A/B. We then turn our attention to the aza-Friedel−Crafts alkylation of
the in situ generated -chloroglycine ester 6a with a series of arene nucleophiles (Table 2). Experiments were
conducted with reduced amount of ethyl glyoxylate 3a (1.05 equiv.) to avoid the formation of direct aza-
Friedel−Crafts by-products.25 According to the empirical nucleophilicity scale established by Mayr,26 the reactivity
of carbocations can be predicted using the correlation equation log k(20 C) = sN (E + N), in which the strength of
o
the N-carbamoyliminium electrophile 9 would be characterized by the parameter E and the various -nucleophile
arenes tested would be characterized by two parameters N and sN. For each substrate tested in the arylation
(Table 2), both solvent conditions were compared CHCl3 (Method A) and CH3CN (Method B) and the reactivity
parameters were used to rationalize the scope of the iminium arylations depending on solvent polarity. The
experiments summarized in Table 2 revealed that the most reactive arenes (electron rich; N > 3.0) reacted in
CHCl3 at low temperatures (Method A) while less reactive arenes (electron poor; N < 1.5) reacted more cleanly
in CH3CN and at higher temperatures (Method B). Several phenolic derivatives were selected to compare their
innate reactivity (electronic and steric factors) while heteroaromatic substrates also showed a broad scope of
reactivity as demonstrated by the range of temperature utilized (entries 1-5). For example, anisole (N = -1.2,
CH2Cl2)27, furan (N = 1.4, CH2Cl2)28, anthracene (N = 2.0, CH2Cl2)29 as well as bromoresorcinol and a chalcone
substrate shown very modest reactivity in CHCl3 as anticipated from the corresponding nucleophilic factor (N),
therefore these substrates were subjected to more efficient reaction conditions in CH3CN (Method B). We then
observe a complete switch of reactivity for the most electronically rich arenes, for which the mildest reaction
conditions in CHCl3 (Method A) afford the best results in terms of yield and regioselectivity (entries 6-12). Pyrrole
(N = 4.6, CH3CN), N-methylpyrrole (N = 5.8, CH3CN)30, indole (N = 5.6, CH2Cl2) and N-methylindole (N = 5.7,
CH2Cl2)31 are extremely powerful -nucleophiles which facilitate the synthesis of the corresponding indolyl 8k-l
and pyrrolyl 8i, 8m -amino esters in high yields (62-79% yields) as single regioisomers. Finally, several MCRs
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 23
were examined using dimethoxybenzene as nucleophile (N = 2.5, CH2Cl2)32 (entry 6) in CH3CN and CHCl3 and
it was found that particular carbamate protecting group also affect reactions’ rate. While the Cbz-protected amino
ester 8f was obtained in 9 hours (82% yield) the corresponding Fmoc-protected product 8g was produced more
slowly over 36 hours in 61% yield. Some other limitation for both methods (A/B) are the over-reaction of
electronically rich arenes (indole and pyrrole) which tend to competently polymerize while electron deficient
heteroarenes (oxazole and thiazole) are unreactive even at elevated temperatures.
1
2
3
4
5
6
7
8
9
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
Mechanism Investigation. Taken altogether, the results shown above demonstrate that the empirical Mayr’s
scale of nucleophilicity seems extremely useful to predict the nucleophile reactivity with the N-carbamoyl iminium
Table 2. Scope for the synthesis of racemic α-aryl α-amino esters 8a-l a
a Method A: reaction performed in CHCl3, steps 1/2 for 12 h, Method B: reaction performed in CH3CN, steps 1/2 for 24 h; both methods are followed by
the addition of arenes (step 3) for the specified time and temperature; isolated yields are reported. b factors of nucleophilicity have been previously reported
c
d
in CH3CN or CH2Cl2. Using excess of arenes (3.0 equiv.), the isolated yields for 8a and 8b are 60% and 71% respectively. Ratio of regioisomers
(para/ortho) are reported (rr) based on 1H NMR integration values. e Synthesis of these compounds was previously reported, see ref. [18]. f Nucleophile
employed is the aniline hydrochloric salt.
ACS Paragon Plus Environment

Page 7 of 23
The Journal of Organic Chemistry
electrophile 9 (Table 2). Therefore, by using the approximate equation of reactivity that dictates the reaction
advancement in which electrophiles and nucleophiles have to fulfil the conditions N + E ≥ -5, we were able to
estimate the electrophilic parameter of iminium 9. To this aim, several arene nucleophiles previously reported
and characterized by Mayr were tested in the reaction with the N-Cbz -chloroglycine ester 6a (precursor of the
1
2
3
4
5
6
7
8
Figure 2. Comparison of iminium and imine
9
proposed N-carbamoyl iminium electrophile 9) at room temperature in
electrophilic reactivities E
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
CH2Cl2 for two days.21,33 Reactions using anisole (N = -1.2, CH2Cl2) and
thiofuran (N = -1.0, CH2Cl2) as nucleophiles only faintly proceeded
while the reaction with a furan nucleophile (N = 1.4, CH2Cl2) delivered
the corresponding -amino esters under the same conditions (11% isolated yield).21 Thus, it is reasonable to
Scheme 3. Kinetic profiling to assess the Friedel-Crafts reaction mechanism
consider that an electrophilic value E can be
estimated for the N-carbamoyl iminium electrophile
9, in a tight ionic pair as E ≈ -5 -1.4 = -6.4 (Figure
2). In comparison, the most reactive iminium
characterized by Mayr to date (N,N-dimethyl-
substituted iminium 10; E = -9.3) is likely in the
range of 4 orders of magnitude less reactive than
the present N-carbamoyl iminium 9. Eventhough
iminiums such as 9 have been previously proposed
as the highly reactive intermediate for the formation
of C-C bonds, 34 no concrete spectroscopic or
kinetic evidence have been reported to support this
hypothesis. Therefore we undertook a preliminary
kinetic profiling of the aza-Friedel-Crafts reactions
to assess the different mechanistic possibilities
(Scheme 3). Observation of characteristic spectral
features of both -chloroglycine ester 6a, N-methyl
indole and product 8l by in situ 1H NMR
spectroscopy enabled kinetic analysis of the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 23
reaction progress under synthetically relevant conditions (CDCl3–benzene-d6 solvent mixture at room
temperature). The kinetic order of each of the reagents was determined via “different-excess” experiments in
which the initial concentration of N-methyl indole was varied while the concentration of 6a was kept constant.
Four distinct experiments were performed and plotted with the N-methyl indole concentration varying from [0.75
M] to [0.3 M] to measure the formation of product 8l and determine the kinetic order in -chloroglycine ester 6a
(overlay shown Scheme 3A). As shown in Scheme 3B, the plots of reciprocal concentration in [6a]t versus time
exhibit slightly offset straight lines with different slopes which fit well with straight line regressions. This concludes
that the kinetic order in -chloroglycine 6a for the reaction must be one while the reaction’s kinetic follows a
second-order rate law.21 When a larger excess of N-methyl indole nucleophile was used (3 eq; green stars) while
maintaining the concentration of -chloroglycine [6a] at [0.1 M], the reaction appears to the reach a pseudo-first
order condition as shown by the exponential plot of reciprocal concentration in [6a]t versus time (Scheme 3B).
More surprisingly, the kinetic plots of reciprocal concentration in [Nu]t versus time also fit some straight line
regressions that correlates to the same a kinetic order one in N-methyl indole (see supporting information Figures
SI-3a, SI-7a, SI-10a, SI-14a). Taken together, these results support that the reaction displays first-order
dependence on both concentrations of -chloroglycine ester electrophile, [6a], and the N-methyl indole
nucleophile [Nu]. The results are consistent with an SN1-like mechanism (or SN2C+ with a rate = k [6a] x [Nu]),
which can be rationalized by suggesting that -chloroglycine [6a] might undergo heterolysis to the corresponding
iminium 9, in a tight ionic-pair with the chloride anion which likely reduces the iminium reactivity, hence the
increase of energy barrier for the nucleophilic attack to occur in the second step. In this scenario, the SN1-like
mechanism supports the fact that both steps of heterolysis and C–C bond formation are rate determining.35
Furthermore the reaction with two equivalents of N-methyl indole nucleophile was reproduced with the addition
of an external source of chloride anion to test for a possible ion return to the iminium 9 (tetrabutyl ammonium
chloride: 20 mol%). This experiment shown in Figure 3 demonstrates that ion return might be evoked in this
reaction while the overall rate acceleration of the reaction is likely due to a salt effect on the solvent ionic
strength.36 The plot of a general second-order expression ln{[푁푢][6푎]0/[6푎][푁푢]0} with time for the reaction without
additive fits with the straight line, suggesting that the reaction follows a second-order kinetic (see Eq. 1).
1
2
3
4
5
6
7
8
9
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
ACS Paragon Plus Environment

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
A general second-order integrated rate law can be expressed as follows:
4
5
6
][
]
]
y = 푙 푛 [[
(Eq. 1)
푵풖 ퟔ풂
0
([
] )
= 푘표푏푠 푵풖 0 − ퟔ풂 푡
0
]
[
][
ퟔ풂 푵풖
0
7
8
where [6a]0 ≠ [Nu]0 and slope = Kobs * [xs]; where [xs] = ( [Nu]0 –[6a]0)
9
Figure 3. Salt effect on Friedel-Crafts reaction of α-chloroglycine
and N-methyl Indole to prove the reaction mechanism
On the other hand, the presence of a chloride
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
source provocked a significant deviation from the
linear regression which could be attributed to a
change in solvent polarity over time (ionic strength
leading to increased rate), while a more
pronounced equilibrium between the iminium ionic
pair 9 and chloroaminal 6a might simultaneously
occurred (SN2C+).
0.9
y = 0.0013x
R² = 0.9528
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
y = 0.0006x + 0.0896
R² = 0.9909
0
100
200
300
400
500
600
Time (min)
Complementary Method C: use of an H-bond donor catalyst. Both methods (A and B) employed for a
stepwise multicomponent synthesis of -aryl -amino esters 8a-m, were then expanded upon to other types of
non-aromatic -nucleophiles (silylenols and silyl ketene acetals). We rapidly faced the issues of silylated-
nucleophile stability due to the enhanced acidity of the reaction media resulting from the stoichiometric amounts
of HCl and AcOH generated overtime. A practical solution to this problem, arose from our abilities to generate
the stable -chloroaminal intermediate 9, which can be stripped to dryness to remove traces of acids, therefore
Scheme 4. One-pot Synthesis of non-proteinogenic α-amino esters P using a tandem catalysis:
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 23
allowing for successive functionalization to occur in the same pot under neutral reaction conditions catalyzed by
an hydrogen bond-donor catalysts (Scheme 4). By doing so, we postulated that addition of an achiral H-bond
donor thiourea catalyst T could facilitate the chloroaminal X intermediate activation to generate in situ the reactive
N-carbamoyl iminium (e.g. 9) in a tight ionic pair specie I. The Schreiner’s thiourea catalyst T was selected for
its abilities of anion-binding to promote this complementary approach (Method C) which relies on the chloride
leaving group activation by the catalyst to assist the functionalization stage and deliver the -amino ester product
P. This third method represents a merging of two successive catalysis in the same pot. To test this method, both
arenes 1,3-dimethoxybenzene and indole nucleophiles have been tested and were successfully reacted to afford
products 8n and 8o 71% and 66% yields respectively under the thiourea catalysis approach (Scheme 5). As
mentioned above, the reactivity of N-Fmoc-protected chloroglycine is much less than its N-Cbz-protected
counterpart (Table 2, entries 6 & 10) which demonstrates the strength of the achiral thiourea catalyst T. This
expansion of the methodology also allowed us to prepare -amino esters orthogonally protected (N-Fmoc and
benzyl ester) and incorporate different acid-labile side chains nucleophiles that could not be installed otherwise.
Thus seven novel products 8p-8v have been synthesized with yields ranging from 41% to 90% and
diastereoselectivity up to >20:1 (Scheme 5). Interestingly the -Butyrolactone-derived product 8p was obtained
in 70% yield as a single syn-diastereomer37 while the other dimedone-derived product 8u which could also be
1
2
3
4
5
6
7
8
9
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
Scheme 5. Method C: One-pot synthesis of α-amino esters 8n-8u catalyzed by thiourea a-c
formed through a Diels–Alder-like
transition state was obtained as a
1:1 mixture of diastereomers in
74% yield. Furthermore, silylenol
ethers and silyl ketene acetals
could be added smoothly to
synthesize the -amino ester
products 8q, 8r and 8s in 90%,
41% and 61% yields respectively.
Noticeably, in each case, the
reactions catalyzed by the achiral
Schreiner’s thiourea were much
1H NMR yields of uncatalyzed versus catalyzed reactions were calculated from crude reaction
a
mixtures using mesitylene as internal standard. b Isolated yields from catalyzed reactions.. c Isolated
yield from the uncatalyzed reaction.
ACS Paragon Plus Environment

Page 11 of 23
The Journal of Organic Chemistry
more efficient and faster as shown by the synthesis of 8t isolated in 55% yield as a single regioisomer (cat.
1
2
3
100% conv. versus uncat. 56% conv.). Finally, selected compounds were derivatized to show the applicability of
4
5
Scheme 6. Direct derivatization of non-proteinogenic -amino esters
our method in producing non-proteinogenic -
6
amino esters with site-specific designed
7
8
9
protecting groups (Scheme 6). -Butyrolactone-
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
derived -amino ester 8p was transformed to a
rearranged product analogue to pipecolic ester
12 in one-pot and 98% yield.37 Spectral analysis
of the cyclic product 12 confirmed the relative
syn-stereochemical assignment made for the -
butyrolactone-derivative 8p. Homo-Phe-OEt 13
was prepared from -amino ester 8r by a simple and efficient hydrogenation protocol. Also, the -monoprotected
derivative of -amino adipic acid 14 was prepared in 83% yield by hydrogenation of the synthetic -amino ester
8t.
In summary, we reported a general strategy for the one-pot synthesis of non-proteinogenic -amino esters
bearing orthogonal N-carbamoyl protecting groups (Cbz or Fmoc) from commercially inexpensive starting
materials. Our results demonstrate that an autocatalytic-like approach for the synthesis of the pivotal -
chloroglycine ester intermediate was efficient and practical. This general strategy entails two distinct methods: i)
a multicomponent-like process in which the three components are mixed in a temporally manner (Methods A/B:
in CH3CN or CHCl3 respectively), and ii) a one-pot synthesis catalyzed through anion-abstraction by a hydrogen-
bond donor thiourea catalyst (Method C: in CH2Cl2). These approaches are complementary and presumed to
proceed via an activated iminium intermediate 9 that has been empirically characterized with an electrophilic
value E = -6.4 (Mayr’s scale). Our findings through the initial kinetic profiling support an SN1-like mechanism (or
SN2C+) which is consistent with the effect of solvent on the reaction rates and the effect of the thiourea catalyst
in facilitating the addition of weaker silylated nucleophiles. The discovery of the innate reactivity of -
chloroglycine esters via an SN1-like mechanism and the corresponding N-carbamoyl iminium–chloride tight ionic
pair supports that the scope of this reaction will not be only limited to relatively strong nucleophiles. Therefore,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 23
the development of a reaction catalyzed by hydrogen-bond donors appears attractive to enable less reactive
nucleophile to be incorporated (enantioselectively).17 This one-pot synthesis of -amino esters proved to be
efficient and versatile as highlighted by the synthetic scope of -aryl and -alkyl amino esters 8a-g prepared and
the simplicity of functionalizations (e.g. 12-14) due to the protecting groups’ orthogonality. Ongoing studies are
aimed at developing an asymmetric variant of this transformation and expanding the scope to additional classes
of nucleophiles to prepare non-proteinogenic amino acids for non-ribosomal peptide synthesis.
1
2
3
4
5
6
7
8
9
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
ACS Paragon Plus Environment

Page 13 of 23
The Journal of Organic Chemistry
EXPERIMENTAL SECTION:
Instrumentation and methods:
1
2
3
4
Infrared spectra were recorded on a Nicolet IS5 FT-IR spectrophotometer. 1H NMR spectra were recorded on a
5
6
7
8
Varian Mercury400 (400 MHz) spectrometer and are reported in ppm using solvent as an internal standard
1
(CDCl3 at 7.26 ppm and CD3CN at 1.94 ppm). Quantitative H NMR spectra were performed using standard
9
parameter (Pw = 90, at = 5, d1 = 15) and recorded on a Varian Mercury400; careful treatment of the NMR signal
is required to proceed to quantification. Data are reported as: (b = broad, s = singlet, d = doublet, t = triplet, q =
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
13
quartet, p = pentet, m = multiplet; coupling constant(s) in Hz, integration). C NMR spectra were recorded on
Varian Mercury400 (100 MHz) spectrometer. Chemical shifts are reported in ppm, with solvent resonance
employed as the internal standard (CDCl3 at 77.0 ppm, CD3CN at 1.9 ppm, 118.7 ppm and DMSO-d6 at 39.5
ppm). Melting points were determined using an MPA 160 digital melting point apparatus. The low resolution ES-
API mass spectra performed on FTICR mass spectrometer. Accurate mass (High resolution HRMS) was
obtained from University of Florida using Agilent 6210 TOF instrument.
Reactions were performed in flame-dried glassware under a positive pressure of argon. Yields refer to
chromatographically and spectroscopically pure compounds, unless otherwise noted. Analytical TLC was
performed on 0.25 mm glass backed 60Å F-254 TLC plates. Flash chromatography was performed using 200-
400 mesh silica gels (Silicycle, Inc.) or 60-325 mesh neutral alumina (Fisher, Inc.). Neutralized silica gel was
prepared by adding 5 wt % of triethylamine in methylene chloride solution to normal-phase silica gel and mixed
30 mins at room temperature. The plates were visualized by exposure to UV light (254 nm) and developed by a
solution of phosphomolybdic acid in ethanol, or vanillin/sulfuric acid in ethanol, or ninhydrin in ethanol, or
potassium permanganate in water/potassium carbonate/sodium hydroxide or cerium-ammonium-molybdate in
water/sulfuric acid and heat.
Reagents and solvents:
All reagents used in the present paper were acquired from Alfa Aesar or Sigma Aldrich. All bulk solvents were
acquired from Fischer Scientific. Freshly distillated solvents were used in the reactions presented herein.
Chloroform was dried over CaCl2 overnight prior to distillation (B.P. 61°C) and transferred under argon to a dark
glass bottle with 3Å molecular sieves for storage. Tetrahydrofuran was purified by refluxing with and distilling
from sodium with benzophenone and transferred under argon to a dark glass bottle for storage. Dichloromethane
was dried over CaCl2 overnight, prior to distillation (B.P. 40°C) and transferred under argon to a dark glass bottle
with 3Å molecular sieves for storage. Toluene was dried over CaH2 and molecular sieves and transferred under
argon to a dark glass bottle for storage. Full procedures can be found in Purification of Laboratory Chemicals by
Armarego, W. L.F.; and Chai C. L. L., Elsevier (Sixth Edition).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 23
General procedures A/B for the one-pot preparation of -Amino Ester (Methods A/B):
1
In a flame dried round bottom flask under argon, a mixture of benzyl carbamate 2a (76 mg, 0.50 mmol, 1.0
equiv.), ethyl glyoxylate 3a (108 μL, 0.05 mmol, and 1.05 equiv.), acetyl chloride (95 μL, 1.25 mmol, and 2.5
equiv.), and acetic acid (3 μL, 10 mol %, 0.1 equiv.), in CHCl3 (Method A) or CH3CN (Method B) solvent (5.0
mL; [0.1 M]) were stirred for 24 h or 12 h respectively (steps 1/2) at 60 °C. After that point, the reaction mixture
was cooled down to RT then the arene nucleophile (1.5 equiv.) was added to the reaction mixture (step 3) and
stirred at the indicated temperature for the appropriate time (x h). After full consumption of chloroaminal
intermediate 5 (observed by TLC caution: same Rf value as the hydroxyaminal 3), the reaction mixture was
quenched with a saturated solution of sodium bicarbonate (20.0 mL) and extracted with CH2Cl2 (3 x 10.0 mL).
The combined organic layers were then dried over sodium sulfate, filtered and concentrated under vacuum to
afford the crude reaction mixture. The crude mixture was then purified by flash chromatography using an
appropriate elution.
2
3
4
5
6
7
8
9
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
General procedure C (Method C): One-pot synthesis of -amino esters 8n-8u catalyzed by the
Schreiner’s thiourea:
In a flame dried round bottom flask under argon, a mixture of primary carbamate 2 (0.50 mmol, 1.0 equiv.),
glyoxylate 3 (0.05 mmol, and 1.05 equiv.), acetyl chloride (95 μL, 1.25 mmol, and 2.5 equiv.), and acetic acid (3
μL, 10 mol %, 0.1 equiv.), were stirred in CHCl3 solvent (5.0 mL; [0.1 M]) for the appropriate time (x h: steps 1/2)
at 60 °C. The reaction mixture was then cooled down to RT and the solvent was evaporated under vacuum. The
crude reaction mixture was dissolved in appropriate solvent (5.0 mL; [0.1 M]) and Schreiner’s thiourea catalyst
(10 mol %) was added consecutively with nucleophile (1.5 equiv.) (step 3) in the reaction mixture and stirred at
the indicated temperature for the appropriate time (x h). After full consumption of chloroaminal intermediate 6
(observed by TLC caution: same Rf value as the hydroxyaminal 5), the reaction mixture was quenched with a
saturated solution of sodium bicarbonate (20.0 mL) and extracted with CH2Cl2 (3 x 10.0 mL). The combined
organic layers were then dried over sodium sulfate, filtered and concentrated under vacuum to afford the crude
reaction mixture. The crude mixture was then purified by flash chromatography using an appropriate elution.
A. Compounds Characterization
The synthesis and characterization of compounds 8a-8m (except 8g) was previously reported by our group. 18
Benzyl glyoxylate 3b:
Dibenzyl 2,3-dihydroxysuccinate (330 mg, 1.0 mmol, 1.0 equiv.) was dissolve in methanol (6.0
ml) and a solution of NaIO4 (321 mg, 1.5 mmol, 1.5 equiv.) in H2O (3.0 ml) was added. The
reaction was stirred for 6 h at 0 °C until the full consumption of the starting material. After that
point, the reaction was partitioned between H2O and diethyl ether. The organic phase was dried
(MgSO4) and the solvent removed under reduced pressure to give mixture of benzyl glyoxylate
hydrate 3b and aldehyde SI-1 (13:1) as a colorless liquid. The product was used without further
purification in the synthesis for the next step.
Rf = 0.35 (hexanes/ethyl acetate 70:30; UV Active. IR (Neat) νmax = 696, 737, 847, 908, 967, 1078, 1212, 1278,
1356, 1455, 1498, 1744, 3438 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) δ 7.53 – 7.32 (m, 5H), 5.25 (q, J = 12.1
Hz, 2H), 4.90 (d, J = 11.1 Hz, 1H), 3.78 (bs, 1H). (Note: Integration value does not match exactly due to the
exchangeable –OH group.). 13C NMR (100 MHz, CDCl3): δ (ppm) 183.7, 170.5, 168.8, 168.8, 134.8, 134.7,
ACS Paragon Plus Environment

Page 15 of 23
The Journal of Organic Chemistry
134.7, 128.6, 128.6, 128.5, 128.4, 128.39, 90.9, 88.7, 87.1, 67.9, 67.9, 67.6. HRMS (DART) m/z: [M + NH4]+
Calcd for C9H14NO4 200.0917; Found 200.0913 (-2.0 ppm).
1
2
3
4
5
6
Compound SI-1: Prepared by adding CD3OD to the crude reaction mixture of benzyl glyoxylate hydrate 3b.
1H NMR (400 MHz, CD3OD): δ (ppm) 7.47 – 7.25 (m, 5H), 5.20 (s, 2H), 4.92 (s, 1H).
7
8
9
Compound SI-2: Prepared by adding methanol (1.0 equiv.) in the CDCl3 solution of the crude
reaction mixture of benzyl glyoxylate hydrate 3b. H NMR (400 MHz, CDCl3): δ (ppm) 7.44 –
1
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
7.30 (m, 5H), 5.34 – 5.15 (m, 2H), 4.90 (d, J = 11.3 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.47 (s,
3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.2, 134.8, 128.7, 128.6, 93.4, 67.8, 55.4. HRMS
(DART) m/z: [M + NH4]+ Calcd for C10H16NO4 214.1074, Found 214.1072 (-0.9 ppm). SMILES:
OC(O)C(OCC1=CC=CC=C1)=O
N-Fmoc-Gly(α-Cl)-OBn 6b: Protected -chloroglycine benzyl ester 6b was synthesized using following
procedure: In a flame dried scintillation vial, a mixture of 9-Fluorenylmethyl carbamate 2b (120
mg, 0.50 mmol, 1.0 equiv.), benzyl glyoxylate hydrate 3b (109 mg, 0.60 mmol, 1.2 equiv), acetyl
chloride (107 μL, 1.50 mmol, 3.0 equiv.) and acetic acid (3 μL, 0.05 mmol, 10 mol%) were stirred
under argon in anhydrous chloroform (5.0 mL) for 24 hours at 60 °C. The reaction mixture was
cooled down to RT and directly evaporated under vacuum to obtain the desired product 6b as a white solid (211
mg, 0.50 mmol, quant. yield). Compound 6b can be stored in an amber glass container at RT for 7 days in a
desiccator without major decomposition <5-10%). Rf = 0.30 (EtOAc/hexanes 30:70; UV active, stains green-
yellow with vanillin) Caution!! Compound 6b is not stable on silica gel; it hydrolyses back to the corresponding
hemiaminal which can be observed by TLC at the Rf mentioned above. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.78
(d, J = 7.6 Hz, 2H), 7.57 (s, 2H), 7.45 – 7.30 (m, 10H), 6.22 (s, 1H), 5.30 (s, 2H), 4.48 (d, J = 6.4 Hz, 2H), 4.24
(t, J = 6.4 Hz, 1H).
SMILES:[H][C@](Cl)(C(OCC1=CC=CC=C1)=O)NC(OCC2C(C=CC=C3)=C3C4=C2C=CC=C4)=O
N-Cbz( -Cl)-OBn 6c: Protected -chloroglycine benzyl ester 6c was synthesized using following procedure:
In a flame dried scintillation vial, a mixture of benzyl carbamate 2a (76 mg, 0.50 mmol, 1.0 equiv.),
benzyl glyoxylate hydrate 3b (109 mg, 0.60 mmol, 1.2 equiv), acetyl chloride (107 μL, 1.50 mmol,
3.0 equiv.) and acetic acid (3 μL, 0.05 mmol, 10 mol%) were stirred under argon in anhydrous
chloroform (5.0 mL) for 16 hours at 60 °C. The reaction mixture was cooled down to RT and
directly evaporated under vacuum to obtain the desired product 6c as a white solid (167 mg, 0.50 mmol, quant.
yield). Compound 6c can be stored in an amber glass container at RT for 7 days in a desiccator without major
decomposition <5-10%). Rf = 0.25 (EtOAc/hexanes 30:70; UV active, stains green-yellow with vanillin) Caution!!
Compound 6c is not stable on silica gel; it hydrolyses back to the corresponding hemiaminal which can be
observed by TLC at the Rf mentioned above. 1H NMR (400 MHz, CD3CN): δ (ppm) 7.48 – 7.26 (m, 10H), 7.05
(bs, 1H), 6.25 (d, J = 10.4 Hz, 1H), 5.25 (dd, J = 12.3 Hz, 2H), 5.15 (s, 2H). 13C NMR (100 MHz, CD3Cl3): δ
(ppm) 165.8, 153.9, 135.3, 134.3, 128.9, 128.8, 128.7, 128.7, 128.7, 128.6, 128.5, 128.4, 68.7, 68.1, 63.4.
SMILES: [H][C@](Cl)(C(OCC)=O)NC(OCC1C(C=CC=C2)=C2C3=C1C=CC=C3)=O
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 23
Ethyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(2,4-dimethoxyphenyl)acetate 8g:
1
2
3
4
Product 8g was synthesized following the general procedure A.
Steps 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 12 h.
Step 3: 1, 3-dimethoxy benzene (52 mg, 0.37 mmol, 1.5 equiv.) as nucleophile at 60 °C for 36 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent
system of EtOAc/hexanes (15:85) to deliver the desired product 8g (10:1 rr) as a white solid (141
mg, 0.31 mmol, 61% yield). Rf = 0.25 (Ethyl acetate/Hexanes 75:25; UV Active, stains pink red
in vanillin). Mp = 82-85 °C, IR (Neat) νmax = 659, 694, 728, 740, 758, 789, 828, 884, 935, 985,
1020, 1043, 1086, 1103, 1120, 1160, 1181, 1207, 1242, 1260, 1296, 1320, 1446, 1507, 1533,
5
6
7
8
9
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
1
1589, 1614, 1685, 1732, 3320 cm-1. H NMR (400 MHz, CD3CN): δ (ppm) 7.85 (d, J = 7.5 Hz, 2H), 7.68 (d, J =
7.4 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.39 – 7.30 (m, 2H), 7.18 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.52
(d, J = 8.3 Hz, 1H), 6.30 (d, J = 8.1 Hz, 1H), 5.38 (d, J = 8.4 Hz, 1H), 4.40 – 4.28 (m, 2H), 4.25 (t, J = 6.6 Hz,
1H), 4.14 (q, J = 7.1 Hz, 2H), 3.81 (s, 6H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CD3CN): δ (ppm) 171.4,
161.5, 158.4, 156.1, 144.4, 144.3, 141.4, 130.5, 127.9, 127.4, 125.4, 120.2, 118.0, 104.8, 98.9, 66.6, 61.4, 55.6,
55.3, 54.0, 47.2, 13.7. HRMS (ESI-TOF) m/z: [M + Na] + Calcd for C27H27NO6Na 484.1731, Found 484.1723
(-1.6 ppm).
SMILES: O=C(OCC1C2=C(C=CC=C2)C3=C1C=CC=C3)N[C@H](C(OCC)=O)C4=C(OC)C=C(OC)C=C4
Benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(2,4-dimethoxyphenyl)acetate 8n:
Product 8n was synthesized following the general procedure C.
Steps 1/2: Solvent: chloroform (2.5 mL) at 60 °C for 24 h.
Step 3: Dimethoxy benzene (52 mg, 0.37 mmol, 1.5 equiv.) as nucleophile at 40 °C for 60 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent
system of EtOAc/hexanes (15:85) to deliver the desired product 8n (14:1 rr) as a white solid (92
mg, 0.18 mmol, 71% yield). Rf = 0.30 (EtOAc/hexanes 30:70; UV Active, stains pink red in
vanillin). Mp = 75-78 °C, IR (Neat) νmax = 659, 694, 727, 739, 757, 790, 985, 1007, 1031, 1043,
1085, 1108, 1120, 1145, 1160, 1180, 1208, 1231, 1260, 1276, 1320, 1450, 1475, 1508, 1533, 1685, 1709, 1732,
2852, 2922 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.75 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H), 7.39 (t,
J = 7.5 Hz, 2H), 7.32 – 7.18 (m, 8H), 6.47 – 6.42 (m, 1H), 6.42 (s, 1H), 5.92 (d, J = 8.7 Hz, 1H), 5.52 (d, J = 8.7
Hz, 1H), 5.22 (d, J = 12.5 Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H), 4.48 – 4.35 (m, 1H), 4.34 – 4.26 (m, 1H), 4.22 (t, J
= 7.2 Hz, 1H), 3.81 (s, 3H), 3.63 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 171.4, 161.4, 158.2, 156.1, 144.2,
144.1, 141.5, 131.3, 128.6, 128.4, 128.2, 127.9, 127.3, 125.4, 125.4, 118.3, 104.5, 99.2, 67.4, 67.2, 55.7, 55.5,
55.2, 47.4, 30.0. HRMS (ESI-TOF) m/z: [M + Na] + Calcd. for C32H29NO6Na 546.1887, Found 546.1879 (-1.5
ppm).
SMILES:O=C(N[C@H](C(OCC1=CC=CC=C1)=O)C2=C(OC)C=C(OC)C=C2)OCC3C(C=CC=C4)=C4C5=C3C
=CC=C5
Benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(2,4-dimethoxyphenyl)acetate 8o:
Product 8o was synthesized following the general procedure C.
Step 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 24h.
Step 3: Indole (84 mg, 0.37 mmol, 1.5 equiv.) as nucleophile at -78°C for 0.5 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent
system of EtOAc/hexanes (15:85). Another purification performed by flash chromatography using
solvent system of ether and dichloromethane (2:98) to obtain the pure desired products 8o as a
white solid (84 mg, 0.13 mmol, 66% yield). Rf = 0.36 (Ethyl Acetate/hexanes 30:70; UV Active,
stains green in vanillin). Mp = 139-142 °C, IR (Neat) νmax = 697, 739, 1010, 1045, 1103, 1182,
1216, 1277, 1324, 1450, 1498, 1704, 3400 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 1H NMR 8.20 (s, 1H), 7.73
(dd, J = 17.2, 7.8 Hz, 3H), 7.57 (d, J = 7.4 Hz, 2H), 7.39 (dd, J = 7.4, 6.8 Hz, 3H), 7.29 (s, 8H), 7.14 (dd, J =
15.5, 8.1 Hz, 3H), 5.74 (s, 1H), 5.28 – 5.10 (m, 2H), 4.50 – 4.31 (m, 2H), 4.22 (t, J = 7.1 Hz, 1H). 13C NMR (100
MHz, CD3CN): δ (ppm) 171.4, 155.8, 143.8, 141.4, 141.3, 136.4, 135.3, 128.6, 128.4, 128.2, 127.8, 127.2, 125.4,
125.2, 125.2, 123.6, 122.9, 120.5, 120.1, 119.3, 111.6, 110.9, 67.5, 67.3, 51.6, 47.2. HRMS (ESI-TOF) m/z: [M
+ Na] + Calcd for C32H26N2O4Na 525.1785; Found 525.1779 (+1.1 ppm).
ACS Paragon Plus Environment

Page 17 of 23
The Journal of Organic Chemistry
SMILES:[H]N1C2C(C=CC=C2)C([C@@H](C(OCC3=CC=CC=C3)=O)NC(OCC4C(C=CC=C5)=C5C6=C4C=C
C=C6)=O)=C1
Ethyl 2-(((benzyloxy)carbonyl)amino)-2-(5-oxo-2,5-dihydrofuran-2-yl)acetate 8p:
1
2
3
4
Product 8p was synthesized following the general procedure C.
Steps 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 12 h
5
Step 3: 2-(Trimethylsiloxy)furan (117 mg, 0.75 mmol, 1. 5 equiv.) as nucleophile at 0 °C for 24 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent
system of CH2Cl2/ether (95:5) to deliver the desired product 8p as a colorless liquid (112 mg, 0.35
mmol, 70% yield). Rf = 0.25 (CH2Cl2/ether 95:5; UV Active, stains pink red in vanillin). IR (Neat)
νmax = 697, 733, 775, 800, 829, 875, 918, 982, 1026, 1044, 1062, 1100, 1156, 1205, 1248, 1323,
6
7
8
9
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
1
1370, 1455, 1530, 1603, 1699, 1746, 2936, 3311 cm-1. H NMR (400 MHz, CDCl3): δ (ppm) 7.49 (dd, J = 5.7,
1.6 Hz, 1H), 7.37 – 7.28 (m, 5H), 6.13 – 6.01 (m, 1H), 5.57 (dd, J = 3.6, 1.7 Hz, 1H), 5.48 (bs, 1H), 5.06 (s, 2H),
4.77 (dd, J = 8.1, 2.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, 3H).13C NMR (100 MHz, CDCl3): δ (ppm) 172.3,
167.9, 156.1, 152.9, 135.9, 128.6, 128.4, 128.1, 122.9, 82.9, 67.4, 62.9, 54.6, 14.2. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C16H17NO6Na 342.0948, Found 342.0951(+0.9 ppm).
SMILES: O=C(C=C1)O[C@@H]1[C@@H](C(OCC)=O)NC(OCC2=CC=CC=C2)=O
4-ethyl 1-methyl 3-(((benzyloxy)carbonyl)amino)-2,2-dimethylsuccinate 8q:
Product 8q was synthesized following the general procedure C.
Steps 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 12 h
Step 3: trimethyl((3-methylbut-2-en-2-yl)oxy)silane (119 mg, 0.75 mmol, 1.5 equiv.) as
nucleophile at 0 °C for 12 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent
system of hexanes/ethylacetate (70:30) to deliver the desired product 8q as a colorless liquid
(152 mg, 0.45 mmol, 90% yield). Rf = 0.30 (hexanes/ethylacetate 70:30; UV Active). IR (Neat)
νmax = 683, 702, 729, 757, 787, 824, 848, 875, 919, 983, 1003, 1025, 1046, 1135, 1171, 1207, 1242, 1278, 1332,
1371, 1392, 1455, 1469,1526, 1713, 2982, 3363 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.45 – 7.27 (m, 5H),
5.62 (d, J = 9.5 Hz, 1H), 5.12 (s, 2H), 4.66 (d, J = 9.7 Hz, 1H), 4.16 (ddd, J = 14.2, 7.1, 2.7 Hz, 2H), 3.70 (s, 3H),
13
1.29 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.16 (s, 3H). C NMR (100 MHz, CDCl3): δ (ppm) 176.0, 170.6, 156.6,
136.4, 128.8, 128.5, 128.4, 67.5, 61.9, 60.0, 52.4, 45.9, 23.3, 21.6, 14.26. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C17H23NO6Na 360.1418; Found 360.1422 (+1.1 ppm).
SMILES: O=C(OC)C(C)(C)[C@@H](C(OCC)=O)NC(OCC1=CC=CC=C1)=O
Ethyl 2-(((benzyloxy)carbonyl)amino)-4-oxo-4-phenylbutanoate 8r:
Product 8r was synthesized following the general procedure C.
Steps 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 12 h.
Step 3: 1-Phenyl-1-trimethylsiloxyethylene (144 mg, 0.75 mmol, and 1.5 equiv.) as nucleophile at
-78 °C for 3 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent system
of hexanes/ethylacetate (85:15) to deliver the desired product 8r as a colorless liquid (81 mg, 0.23
mmol, 46% yield). Rf = 0.25 (hexanes/ethylacetate 70:30; UV Active). IR (Neat) νmax = 690, 879, 1045, 1086,
1217, 1272, 1378, 1450, 1709, 2889, 2973, 3342 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.94 (d, J = 7.8 Hz,
2H), 7.63 – 7.56 (m, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.38 – 7.29 (m, 5H), 5.89 (d, J = 8.0 Hz, 1H), 5.16 – 5.06 (m,
2H), 4.78 – 4.70 (m, 1H), 4.21 (q, J = 7.0 Hz, 2H), 3.67 (ddd, J = 83.7, 18.2, 4.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H22NO5 356.1492; Found 356.1496 (+1.1 ppm).
SMILES: O=C(C1=CC=CC=C1)C[C@@H](C(OCC)=O)NC(OCC2=CC=CC=C2)=O
The spectral data is consistent with the reported compound in the literature.38
Ethyl 2-(((benzyloxy)carbonyl)amino)-2-(-2-oxocyclopentyl)acetate 8s:
Product 8s was synthesized following the general procedure C.
Steps 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 12 h.
Step 3: (cyclopent-1-en-1-yloxy)trimethylsilane (117 mg, 0.75 mmol, and 1.5 equiv.) as nucleophile
at 0 °C for 60 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent system
of hexanes/ethylacetate (80:20) to deliver the desired product in mixture of diastereomers (42:58)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 23
8s as a colorless liquid (97 mg, 0.30 mmol, 61% yield). Rf = 0.20 (hexanes/ethylacetate 70:30; UV Active). IR
1
2
3
4
5
6
7
8
1
(Neat) νmax = 1322, 1370, 1401, 1454, 1520, 1721, 2965, 3340 cm-1. H NMR (400 MHz, CD3CN): diastereomers
(42:58) δ (ppm) 7.46 – 7.21 (m, 5H), 6.08 – 5.83 (m, 1H), 5.08 (dd, J = 8.4, 2.1 Hz, 2H), 4.65 – 4.47 (m, 1H),
4.23 – 4.08 (m, 2H), 2.75 – 2.58 (m, 1H), 2.31 – 2.18 (m, 1H), 2.11 – 1.98 (m, 2H), 1.85 – 1.70 (m, 2H), 1.62
(ddd, J = 23.4, 11.6, 6.7 Hz, 1H), 1.20 (t, J = 9.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): diastereomers (42:58) δ
(ppm) 217.7, 217.3, 170.9, 170.5, 156.4, 155.8, 136.2, 136.1, 128.4, 128.4, 128.1, 128.0, 128.0, 127.9, 66.9,
66.9, 61.7, 61.6, 61.6, 53.2, 53.0, 51.6, 50.8, 37.9, 37.7, 25.9, 25.6, 20.5, 20.3, 14.0. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C17H21NO5Na 342.1312; Found 342.1318 (+1.8 ppm).
SMILES: O=C(CCC1)[C@H]1[C@@H](C(OCC)=O)NC(OCC2=CC=CC=C2)=O
9
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
6-benzyl 1-methyl-5-(((benzyloxy)carbonyl)amino) (E)hex-2-enedioate 8t:
Product 8t was synthesized following the general procedure C.
Steps 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 12 h.
Step 3: (E)-((1-methoxybuta-1,3-dien-1-yl)oxy)trimethylsilane39 (129 mg, 0.75 mmol, 1.5 equiv.)
as nucleophile at -78 °C for 3 h.
The crude reaction mixture showing one regioisomer was purified by flash chromatography
using an isocratic solvent system of hexanes/ethylacetate (80:20) to deliver the desired product
8t as a colorless liquid (109 mg, 0.27 mmol, 55% yield). Rf = 0.30 (hexanes/ethylacetate 70:30;
UV Active). IR (Neat) νmax = 696, 737, 775, 844, 910, 977, 1044, 1082, 1173, 1265, 1340, 1386, 1435, 1455,
1523, 1660, 1715, 2951, 3344 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.42 – 7.28 (m, 10H), 6.92 – 6.68 (m,
1H), 5.83 (dd, J = 15.6, 0.9 Hz, 1H), 5.69 (d, J = 7.9 Hz, 1H), 5.17 (dd, J = 23.7, 12.2 Hz, 2H), 5.10 (s, 2H), 4.57
(dd, J = 13.2, 6.4 Hz, 1H), 3.69 (d, J = 0.9 Hz, 3H), 2.75 (dt, J = 12.6, 6.1 Hz, 1H), 2.68 – 2.58 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 170.9, 166.1, 155.7, 142.2, 136.1, 134.9, 128.6, 128.6, 128.5, 128.5, 128.4, 128.2,
128.0, 124.6, 67.5, 67.0, 52.9, 51.5, 34.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H23NO6Na 420.1418;
Found 420.1418 (0 ppm).
SMILES: O=C(N[C@H](C(OCC1=CC=CC=C1)=O)C/C=C/C(OC)=O)OCC2=CC=CC=C2
Ethyl 2-(((benzyloxy)carbonyl)amino)-2-(4-ethoxy-2-oxocyclohex-3-en-1-yl)acetate 8u:
Product 8u was synthesized following the general procedure C.
Steps 1/2: Solvent: chloroform (5.0 mL) at 60 °C for 12 h.
Step 3: ((5-ethoxycyclohexa-1,5-dien-1-yl)oxy)trimethylsilane40 (159 mg, 0.75 mmol, 1.5 equiv.)
as nucleophile at -20 °C for 12 h.
The crude reaction mixture was purified by flash chromatography using an isocratic solvent
system of hexanes/ethylacetate (70:30) to deliver the mixture of two diastereomer (1:1) of 8u as
a colorless liquid (129 mg, 0.37 mmol, 74% yield). Two diasteromers were separated on
preparative TLC (same plate were run 3 times) using solvent system of hexanes and
ethyacetate (80:20) to obtain the pure two diasteromers in 1:1 ratio. Rf = 0.20
(hexanes/ethylacetate 70:30; UV Active). IR (Neat) νmax = 697, 738, 776, 819, 851, 892, 1026, 1051, 1191, 1328,
1379, 1454, 1499, 1600, 1645, 1716, 2938, 3348 cm-1. syn-diastereomer :1H NMR (400 MHz, CD3CN): δ ppm
7.55 – 7.22 (m, 5H), 5.62 (d, J = 9.4 Hz, 1H), 5.27 (s, 1H), 5.20 – 5.00 (m, 2H), 4.44 (dd, J = 9.6, 3.0 Hz, 1H),
4.12 (q, J = 7.1 Hz, 2H), 3.98 – 3.81 (m, 2H), 3.20 – 3.03 (m, 1H), 2.63 (ddd, J = 17.5, 12.6, 4.7 Hz, 1H), 2.37
(ddd, J = 17.7, 4.9, 2.2 Hz, 1H), 2.08 – 1.97 (m, 1H), 1.83 (ddd, J = 25.9, 12.9, 5.0 Hz, 1H), 1.30 (t, J = 7.0 Hz,
3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CD3CN): δ ppm 198.5, 179.2, 172.1, 157.7, 138.1, 129.4,
128.9, 128.6, 102.7, 67.3, 65.7, 62.0, 55.2, 49.2, 29.6, 25.4, 14.4, 14.4. anti-diastereomer : 1H NMR (400 MHz,
CD3CN): δ ppm 7.48 – 7.22 (m, 5H), 5.98 (d, J = 7.7 Hz, 1H), 5.29 (d, J = 1.2 Hz, 1H), 5.19 – 5.00 (m, 2H), 4.60
(dd, J = 9.3, 4.2 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H), 4.02 – 3.85 (m, 2H), 2.76 (dt, J = 12.2, 4.8 Hz, 1H), 2.61 –
2.47 (m, 1H), 2.41 – 2.32 (m, 1H), 2.08 – 1.97 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CD3CN): δ ppm 197.9, 178.9, 172.5, 157.1, 138.1, 129.4, 128.9, 128.7, 102.7, 67.2, 65.6, 62.0, 54.9,
48.9, 29.5, 24.7, 14.4. HRMS (ESI-TOF) m/z: [M - H]- Calcd for C20H25NO6 374.1609; Found 374.1608 (-0.3
ppm).
SMILES: O=C(C=C1O)CC[C@H]1[C@@H](C(OCC)=O)NC(OCC2=CC=CC=C2)=O
ACS Paragon Plus Environment

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
Ethyl 3-hydroxy-6-oxopiperidine-2-carboxylate 12:
4
5
6
7
8
9
To a solution of 8p (96 mg, 0.3 mmol, 1.0 equiv.) in ethanol (10.0 mL), 10% Pd/C (30 mg, 0.03
mmol, 0.1 equiv.) was added. The reaction mixture was hydrogenated at RT under hydrogen
pressure (balloon: 1.0 atm). The starting material 8p was consumed after 3 h, as indicated by
TLC. The hydrogen balloon was removed and the reaction mixture was stirred another 12 h at
RT until full consumption of the intermediate (Rf = 0.1 in ethylacetate/methanol 90:10; stains
yellow in ninhydrin). The reaction mixture was then filtered through celite and washed with
ethanol (5.0 mL). The filtrate was evaporated under vacuum to obtain 12 in a pure form (55 mg, 0.29 mmol, 98%
yield) as pale yellow liquid. Rf = 0.2 (methanol/dichloromethane 5:95; not UV active, stains yellow brown in
ninhydrin solution). IR (Neat) νmax = 860, 881, 939, 968, 1024, 1072, 1177, 1445, 1574, 1650, 1731, 1773, 2981,
3368 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 4.94 (td, J = 7.2, 3.1 Hz, 1H), 4.23 (qd, J = 7.1, 1.5 Hz, 2H), 3.47
(d, J = 3.1 Hz, 1H), 2.74 – 2.62 (m, 1H), 2.53 (ddd, J = 17.9, 10.3, 7.9 Hz, 1H), 2.40 – 2.27 (m, 2H), 1.30 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 177.1, 172.5, 80.8, 61.8, 57.6, 28.6, 24.2, 14.2. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C8H14NO4 188.0917; Found 188.0919 (+1.1 ppm).
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
SMILES: O=C1N[C@]([H])(C(OCC)=O)[C@@](O)([H])CC1
Ethyl 2-amino-4-phenylbutanoate 13:
To a solution of 8r (71 mg, 0.2 mmol, 1.0 equiv.) in ethanol (5.0 mL), 1 N HCl (200 µL) was added
followed by 10% Pd/C (20 mg, 0.02 mmol, 0.1 equiv.). The mixture was hydrogenated at 55°C
under hydrogen pressure (balloon: 1.0 atm). The reaction was completed after 3 h as determined
by TLC, the mixture was then filtered through celite and washed with ethanol (5.0 mL). The filtrate
was evaporated under vacuum to obtain the crude reaction mixture as a solid. The solid was
suspended in diethyl ether (3.0 mL) and sonicated for 5 minutes and finally filtered to obtain 13
(41 mg, 0.17 mmol, 89% yield) as a white solid. Rf = 0.1 (ethylacetate/methanol 90:10; UV Active, stains yellow
in ninhydrin). IR (Neat) νmax = 672, 702, 737, 759, 981, 1019, 1033, 1062, 1084, 1104, 1156, 1199, 1238, 1266,
1
1377, 1454, 1497, 1752, 2843, 2866, 2973 cm-1. H NMR (400 MHz, D2O): δ (ppm) 7.33 – 7.23 (m, 2H), 7.19
(d, J = 7.5 Hz, 3H), 4.16 – 4.06 (m, 2H), 3.99 (t, J = 6.3 Hz, 1H), 2.76 – 2.54 (m, 2H), 2.27 – 2.03 (m, 2H), 1.16
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, D2O): δ (ppm) 170.1, 139.8, 128.8, 128.4, 126.6, 63.5, 52.3, 31.3, 30.2,
13.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H18NO2 208.1332; Found 208.1331 (-0.5 ppm). SMILES:
[NH3+]C(C(OCC)=O)CCC1=CC=CC=C1.[Cl-]
2-amino-6-ethoxy-6-oxohexanoic acid 14:
To a solution of 8t (80 mg, 0.2 mmol, 1.0 equiv.) in ethanol (5.0 mL), HCl ([1 N], 200 µL) was
added followed by 10% Pd/C (20 mg, 0.02 mmol, 0.1 equiv). The mixture was hydrogenated
at RT under hydrogen pressure (balloon: 1.0 atm). When the reaction was completed as
determined by TLC, the mixture was filtered through Celite and washed with ethanol (5.0 mL).
The filtrate was evaporated under vacuum to obtain the crude reaction mixture. The solid was
suspended in diethyl ether (3.0 mL) and sonicated for 5.0 minutes and finally filtered to obtain
14 in a pure form (36 mg, 0.17 mmol, 83% yield) as white solid. Rf = 0.35 (n-butanol: acetic acid: water 3: 1: 1(by
volume); stains yellow brown in ninhydrin). IR (Neat) νmax = 739, 804, 827, 888, 943, 985, 1093, 1141, 1183,
1203, 1220, 1260, 1352, 1437, 1481, 1602, 1727, 2982 cm-1. 1H NMR (400 MHz, D2O): δ (ppm) 3.95 (t, J = 6.2
13
Hz, 1H), 3.71 (s, 3H), 2.49 (t, J = 7.2 Hz, 2H), 2.04 – 1.85 (m, 2H), 1.83 – 1.64 (m, 2H). C NMR (100 MHz,
D2O): δ (ppm) 176.2, 172.0, 52.6, 52.2, 32.7, 29.0, 19.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C7H14NO4
176.0917; Found 176.0918 (+0.6 ppm).
SMILES: [NH3+]C(C(O)=O)CCCC(OC)=O.[Cl-]
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 23
.
ASSOCIATED CONTENT
1
2
3
4
* Supporting Information
Copies of 1H and 13C NMR spectra for all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
5
6
7
8
9
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
.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sroche2@fau.edu
Notes
The authors declare no competing financial interest.
.
ACKNOWLEDGMENTS
The authors thank Ms. M. J. Gosselin (FAU) for her initial work on the scope of the Friedel-Crafts reaction. This
research was supported by the National Institutes of Health (R15GM116025).
.
REFERENCES
[1] (a) Fenteany, G.; Standeart, R. F.; Lane W. S.; Choi, S.; Corey, E. J.; Schreiber, S. L. Science 1995, 268,
726; (b) Marahiel, M. A.; Stachelhaus, T.; Mootz, H. D. Chem. Rev. 1997, 97, 2651; (c) Walsh, C. T. Science
2004, 303, 1805; (d) Fischbach, M. A.; Walsh, C. T. Chem. Rev. 2006, 106, 3468; (e) Walsh, C. T.; O'Brien, R.
V.; Khosla, C. Angew. Chem. Int. Ed. 2013, 52, 7098.
[2] (a) Kaneko, I.; Kamoshida, K.; Takahashi, S. J. Antibiot. 1989, 42, 236; (b) Kleinkauf, H.; Von Doehren, H.
Eur. J. Biochem. 1990, 192, 1; (c) Boman, H. G. Annu. Rev. Immunol. 1995, 13, 61; (d) Vertesy, L.; Aretz, W.;
Knauf, M.; Markus, A.; Vogel, M.; Wink, J. J. Antibiot. 1999, 52, 374; (e) Chiu, H.-T.; Hubbard, B. K.; Shah, A.
N.; Eide, J.; Fredenburg, R. A.; Walsh, C. T.; Khosla, C. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 8548.
[3] (a) Soloshonok, V. A.; Izawa, K.; Asymmetric synthesis and application of α-amino acids; Oxford University
Press: Washington, DC, 2009. (b) Blaskovich, M. A. Handbook on syntheses of amino acids: general routes for
the syntheses of amino acids; Oxford University Press: Oxford; New York, 2010.
[4] (a) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013-3028; (b) Lygo, B.; Andrews, B. I. Acc. Chem. Res.
2004, 37, 518-525; (c) O'Donnell, M. J. Acc. Chem. Res. 2004, 37, 506-517.
[5] (a) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154; Trost, B. M.; Ariza, X. J. Am. Chem. Soc.
1999, 121, 10727; (b) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard, S.; Joergensen, K. A. J. Am.
Chem. Soc. 2008, 130, 12031; (c) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009, 131, 3430;
(d) Avila, E. P.; Justo, R. M. S.; Goncalves, V. P.; Pereira, A. A.; Diniz, R.; Amarante, G. W. J. Org. Chem. 2015,
80, 590.
[6] (a) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066; (b) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.;
Zhou, Q.-L. J. Am. Chem. Soc. 2007, 129, 5834.
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
[7] For selected examples of Strecker Reaction, see: (a) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun,
W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284. (b) Zuend, S. J.;
Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature 2009, 461, 968 and references cited herein.
5
6
7
8
[8] For selected examples of Mannich reaction, see: (a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc.
1998, 120, 2474. (b) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. (c)
Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2001, 40, 2995. (d) Córdova, A.; Notz, W.;
Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1843.
9
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
[9] (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445; (b) Beenen, M. A.; Weix, D. J.; Ellman,
J. A. J. Am. Chem. Soc. 2006, 128, 6304-6305.
[10] (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106; (b) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.;
Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T. J. Am. Chem. Soc. 1989, 111, 9134; (c) Burk, M.
J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125; (d) van den Berg, M.;
Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem.
Soc. 2000, 122, 11539.
[11] For selected examples of Friedel-Crafts reaction see: (a) Johannsen, M. Chem. Commun. 1999, 2233. (b)
Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 4114. (c) Uraguchi, D.;
Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126, 11804. (d) Shirakawa, S.; Berger, R.; Leighton, J. L. J.
Am. Chem. Soc. 2005, 127, 2858.
[ 12 ] For a discussion on protecting groups compatibility in peptide synthesis and -iminoglycinate
functionalization, see: Nakamura, Y.; Matsubara, R.; Kiyohara, H.; Kobayashi, S. Org. Lett. 2003, 5, 2481.
[13] For the use of N-acylimino ester generated from -bromoglycine esters in metal-catalyzed Mannich
reactions, see: (a) Kobayashi, S.; Kitagawa, H.; Matsubara, R. J. Comb. Chem. 2001, 3, 401 (b) Kobayashi, S.;
Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143. (c) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa,
H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. (d) Nakamura, Y.; Matsubara, R.; Kiyoara, H.; Kobayashi,
S. Org. Lett. 2003, 5, 2481. (e) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem. Int. Ed. 2004, 43,
1679; and in organocatalyzed Mannich reaction, see: (f) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 2896.
[14] (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew. Chem. Int. Ed. 2005,
44, 7975. (b) Palomo, C.; Oiarbide, M.; Laso, A.; López, R. J. Am. Chem. Soc. 2005, 127, 17622. (c) Song, J.;
Shih, H. W.; Deng, L. Org. Lett. 2007, 9, 603. (d) Gianelli, C.; Sambri, L.; Carlone, A.; Bartoli, G.; Melchiorre, P.
Angew. Chem. Int. Ed. 2008, 47, 8700. (e) Takada, K.; Tanaka, S.; Nagasawa, K. Synlett 2009, 1643. (f)
Galzerano, P.; Agostino, D.; Bencivenni, G.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem. Eur. J. 2010, 16,
6069. (g) Gao, J.; Chuan, Y.; Li, J.; Xie, F.; Peng, Y. Org. Biomol. Chem. 2012, 10, 3730.
[15] For asymmetric Mannich-3CRs, see: (a) Córdova, A. Chem. Eur. J. 2004, 10, 1987-1997; (b) Hamashima,
Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem. Int. Ed. 2005, 44, 1525;
(c) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem. Int. Ed. 2005, 44, 4079; (d) Ramasastry, S.
S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2007, 129, 288; For asymmetric Mannich-
3CRs, see: (e) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762; (f)
Pan, S. C.; List, B. Org. Lett. 2007, 9, 1149; For asymmetric Petasis-3CR, see: (g) Lou, S.; Schaus, S. E. J. Am.
Chem. Soc. 2008, 130, 6922; For asymmetric Friedel-Crafts-3CRs (h) Saaby, S.; Bayon, P.; Aburel, P. S.;
Jorgensen, K. A. J. Org. Chem. 2002, 67, 4352; (i) Kang, Q.; Zhao, Z.-A.; You, S.-L. Tetrahedron 2009, 65, 1603.
[16] For multicomponent syntheses of -amino esters, using a Petasis reaction, see: (a) Petasis, N. A.;
Goodman, A.; Zavialov, I. A. Tetrahedron, 1997, 53, 16463. Using a Barbier Reaction: (b) Le Gall, E.; Pignon,
A. J. Chem. Educ. 2012, 89, 1190. (c) Singh, V. K.; Bisai, A. Tetrahedron, 2012, 68, 3480. Using a Mannich
Reaction: (d) Akiyama, T.; Takaya, J.; Kagoshima, H. Adv. Synth. Catal. 2002, 344, 338. (e) Hamashima, Y.;
Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. J. Am. Chem. Soc. 2005, 44, 1525. Using a
Friedel-Crafts reaction: (f) Bensel, N.; Pevere, V.; Desmurs, J. R.; Wagner, A.; Mioskowski, C. Tetrahedron Lett.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
1999, 40, 879. (g) Grundmann, P.; Fessner, W-D. Adv. Synth. Catal. 2008, 350, 1729. (h) Csütörtöki, R.;
Szatmári, I; Mándi, A; Kurtán, T.; Fülöp, F. Synlett 2011, 13, 1940 and references cited therein.
4
5
6
[17] Wasa, M.; Liu, R. Y.; Roche, S. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2014, 136, 12872.
[18] Roche, S. P.; Samanta, S. S.; Gosselin, M. M. J. Chem. Commun. 2014, 50, 2632.
7
8
9
[19] For the synthesis of -chloroglycines, see: (a) Mooiweer, H. H.; Hiemstra, H.; Speckamp, W. N., Tetrahedron
1989, 45, 4627. (b) Mooiweer, H. H.; Ettema, K. W. A.; Hiemstra, H.; Nico Speckamp, W., Tetrahedron 1990,
46, 2991. (c) Williams, R. M.; Aldous, D. J.; Aldous, S. C., J. Org. Chem. 1990, 55, 4657. (d) Kobayashi, S.;
Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. (e) Hafez, A. M.;
Dudding, T.; Wagerle, T. R.; Shah, M. H.; Taggi, A. E.; Lectka, T., J. Org. Chem. 2003, 68, 5819.
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
[20] Xu, F.; Devine, P. Org. Process Res. Dev. 2010, 14, 666.
[21] See Supporting Information for complete experimental details.
[22] Claridge, T. D. W. In High Resolution NMR Techniques in Organic Chemistry; Baldwin, J. E.; Williams, R.
M., Series Eds.; Pergamon Press: Oxford, 1999, Vol. 19, pp 114.
[23] Addition of MS 3Å (1 g/mol) to the reaction mixture drastically decreases the reaction’ rate, probably due to
sequestration of HCl in the sieves. Also -chloroglycine ester 6a was found to be unstable upon silica gel
chromatography or exposure to water leading in both cases to the spontaneous formation of -hydroxyglycine
ester 5a.
[24] (a) Williams, R. M.; Aldous, D. J.; Aldous, S. C. J. Org. Chem. 1990, 55, 4657; (b) Coqueron, P.-Y.; Didier,
C.; Ciufolini, M. A. Angew. Chem. Int. Ed. 2003, 42, 1411; (c) Hafez, A. M.; Dudding, T.; Wagerle, T. R.; Shah,
M. H.; Taggi, A. E.; Lectka, T. J. Org. Chem. 2003, 68, 5819; (d) Kobayashi, S.; Matsubara, R.; Nakamura, Y.;
Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507; (e) Zhang, J.; Ciufolini, M. A. Org. Lett. 2009, 11,
2389.
[25] Using excess of ethyl glyoxylate 3a, or in a “true” multicomponent direct reaction between arene and ethyl
glyoxylate, mono and bis-aryl Friedel-Crafts products 3a are observed.
[26] (a) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66; (b) Mayr, H. Angew. Chem. Int. Ed.
2011, 50, 3612.
[27] Mayr, H.; Kempf, B.; Ofial, A. R., Acc. Chem. Res. 2003, 36, 66
[28] Ammer, J.; Nolte, C.; Mayr, H., J. Am. Chem. Soc. 2012, 134, 13902.
[29] Gotta, M. F.; Mayr, H., J. Org. Chem. 1998, 63, 9769.
[30] Lakhdar, S.; Mayr, H., Chem. Commun. 2011, 47, 1866.
[31] Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker, T.; Ofial, A. R.; Mayr, H., J. Org. Chem.
2006, 71, 9088.
[32] Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.;
Remennikov, G.; Schimmel, H., J. Am. Chem. Soc. 2001, 123, 9500.
[33] (a) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.;
Remennikov, G.; Schimmel, H., J. Am. Chem. Soc. 2001, 123, 9500; (b) Mayr, H.; Kempf, B.; Ofial, A. R., Acc.
Chem. Res. 2003, 36, 66; (c) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker, T.; Ofial, A. R.;
Mayr, H., J. Org. Chem. 2006, 71, 9088; (d) Nigst, T. A.; Westermaier, M.; Ofial, A. R.; Mayr, H., Eur. J. Org.
Chem. 2008, 2008, 2369; (e) Ammer, J.; Nolte, C.; Mayr, H., J. Am. Chem. Soc. 2012, 134, 13902.
[34] Roos, E. C.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Kamphuis, J.; Schoemaker, H. E. Synlett 1992,
451.
[35] Examples of third order kinetics in Friedel-Crafts: (a) Choi, S. U.; Brown, H. C., J. Am. Chem. Soc. 1963,
85, 2596; (b) DeHaan, F. P.; Delker, G. L.; Covey, W. D.; Ahn, J.; Cowan, R. L.; Fong, C. H.; Kim, G. Y.; Kumar,
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
A.; Roberts, M. P., J. Org. Chem. 1986, 51, 1587; (c) DeHaan, F. P.; Chan, W. H.; Chang, J.; Ferrara, D. M.;
Wainschel, L. A., J. Org. Chem. 1986, 51, 1591.
4
5
6
[36] For salt effect, see: (a) Fainberg, A. H.; Winstein, S., J. Am. Chem. Soc. 1956, 78, 2763. (b) McLennan, D.
J., Acc. Chem. Res. 1976, 9, 281 and references cited herein.
7
8
9
[37] (a) Oudeyer, S.; Dudot, B.; Royer, J. Heterocycles 2005, 65, 823; (b) Landelle, G.; Claraz, A.; Oudeyer, S.;
Levacher, V., Tetrahedron Lett. 2012, 53, 2414.
[38] Yang, C.-F.; Shen, C.; Wang, J.-Y.; Tian, S.-K., Org. Lett. 2012, 14, 3092.
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
[39] Starting material was prepared using following protocol: Ratjen, L.; García-García, P.; Lay, F.; Beck, M. E.;
List, B., Angew. Chem. Int. Ed. 2011, 50, 754.
[40] Starting material was prepared using following protocol from corresponding starting material : Perkins, J. R.;
Carter, R. G., J. Am. Chem. Soc. 2008, 130, 3290.
ACS Paragon Plus Environment