Facile Conversion of α-Acyloxy Amides into 3-Hydroxy-lactams

Article abstract of DOI:10.1002/ejoc.201800605

The new synthetic route to α-acyloxy amides based on Passerini multicomponent reaction followed by transformation into the corresponding five-, six-, and seven-membered 3-hydroxy-lactams has been proposed. The influence of the reaction conditions, which includes substrate structure on the reaction course that led to desired lactams, was studied. The use of various oxo components in the Passerini multicomponent reaction (P-MCR) has been evaluated. The first example of a semicyclic O,O-acetal employed as an aldehyde equivalent in the P-MCR has been reported. Finally, the established protocol was successfully applied for the enantioselective synthesis of 3-hydroxy-lactams, which play a crucial role in the synthesis of the number of bioactive compounds.

Full text of DOI:10.1002/ejoc.201800605

A Journal of
Accepted Article
Title: A facile conversion of α-acyloxy amides into 3-hydroxy-lactams
Authors: Ryszard Ostaszewski, Dominik Koszlewski, Damian
Trzepizur, Arleta Madej, Anna Brodzka, Daniel Paprocki, Filip
Borys, Monika Wilk, and Ewelina Zaorska
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800605
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800605
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10.1002/ejoc.201800605
European Journal of Organic Chemistry
FULL PAPER
A facile conversion of α-acyloxy amides into 3-hydroxy-lactams
Dominik Koszelewski,* Damian Trzepizur, Ewelina Zaorska, Arleta Madej, Anna Brodzka, Daniel
Paprocki, Filip Borys, Monika Wilk and Ryszard Ostaszewski*
We would like to dedicate this paper to Professor Mieczysław Mąkosza on occasion of his 84th birthday
Abstract: The novel synthetic route to α-acyloxy amides based on
Passerini multicomponent reaction followed by transformation into
the corresponding five-, six-, and seven-membered 3-hydroxy-
lactams has been proposed. The influence of the reaction conditions
including substrate structure on the reaction course leading to
desired lactams was studied. The use of various oxo components in
the Passerini multicomponent reaction (P-MCR) has been evaluated.
The first example of an semicyclic O,O-acetal employed as an
aldehyde equivalent in the P-MCR has been reported. Finally, the
established protocol was successfully applied for the
enantioselective synthesis of 3-hydroxy-lactams which play crucial
role in the synthesis of the number of bioactive compounds.
the synthesis of the serotonin 5HT1B receptor antagonists
(Figure 1, B1) used in the treatment of depression or for the
synthesis of the selective inhibitors of Factor Xa (Figure 1, B2
and B3), particularly as the antithrombiotic drugs.[9] Finally,
seven-membered N-substituted lactams derivatives (C) were
found as a potential drugs against Gaucher’s disease and
diabetes as well as valuable building blocks for a number of
medicines.[10]
Introduction
An amide functionality is ubiquitous in natural products and its
formation is a fundamental reaction in organic synthesis.[1] In
particular various size hydroxy N-substituted lactams are well
known in nature and can be found in the structure of many
relevant pharmacological compounds.[2] For instance, N-
substituted 2-pyrrolidinones and 2-piperidinones are of interest
for the treatment of neurological disorders.[3] In view of their low
toxicities these have recently attracted much attention in the
pharmaceutical area.[4] In addition, several protocols have been
reported employing 3-hydroxy-2-pyrrolidinones (A) and 3-
hydroxy-2-piperidinones (B) as valuable building blocks for
medicinally important compounds (Figure 1). In the view of these
application importance, synthetic studies on N-substituted 2-
hydroxy-lactams have attracted considerable interest. Recently,
Zhang et al. have reported a total synthesis of actinophyllic acid
applying silyl ether of 3-hydroxy-2-pyrrolidinones (A) as a base
Figure 1. Pharmaceutically relevant compounds possessing 3-hydroxy-lactam
scaffold.
material.[5] Actinophyllic acid was identified in
a coupled
CPU/hippuricase assay as an inhibitor of carboxypeptidase U
(CPU), an endogenous inhibitor of the process the organism
uses to clear fibrin clots (fibrinolysis).[6] The hydroxy substituted
lactams comprise important part of many neurotransmitters like
strychnocarpine,[7] alkaloids e.g. retronecine or vasicinone which
exhibit bronchodilatory and uterine stimulant activity.[8] Moreover,
3-hydroxy-2-piperidinones (B) were found as a building block for
Up to date, several routes have been reported on the
synthesis of 3-hydroxy substituted lactams, particularly 3-
hydroxy-2-pyrrolidinone (A) and 3-hydroxy-2-piperidinone
(B).[4a,11] Unfortunately, most these methods are multi-step
and time consuming. Moreover, protocols used for the synthesis
of the six- and seven-membered of N-substituted 2-hydroxy-
lactams are very scarce, and usually suffer from disadvantages
such as inevitable side-products formed, hazardous reagents
and solvents, as well as harsh reaction conditions.[12] The
development of environmentally benign methods for the
production of fine chemicals has attracted increasing attention in
recent years. Thus, it seems significant to find a method to
overcome these limitations.
Dr. D. Koszelewski,* D. Trzepizur, E. Zaorska, A. Madej, Dr. A.
Brodzka, D. Paprocki, Filip Borys, Monika Wilk, Prof. Ryszard
Ostaszewski*
Institute of Organic Chemistry
Polish Academy of Sciences
Kasprzaka 44/52, 01-224, Warsaw, Poland
E-mail: dominik.koszelewski@icho.edu.pl;
ryszard.ostaszewski@icho.edu.pl
The aim of this study was to develop
practical approach, which would allow
a
novel and
synthetically
www.icho.edu.pl/
Supporting information available: 1H NMR, 13C NMR spectra, HPLC
traces
a
feasible method of preparing five- to seven-membered ring of
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10.1002/ejoc.201800605
European Journal of Organic Chemistry
FULL PAPER
2-hydroxy-lactams including structural variations within
substituents at N-position. The latter would be especially
valuable for combinatorial library synthesis. Therefore we
propose a new three step approach to target lactams 5 which is
based on the retrosynthetic analysis given in Figure 2.
yields 64% and 54%, respectively (Scheme 1). Parallel,
analogous reactions were conducted in DCM providing desired
products 4a and 4b with substantially lower yield, 53% and 41%
respectively. Literature precedents as well as our own
experience suggested that the use of aqueous systems as a
reaction media may have a beneficial impact on the reaction
course.[15c,18] However, when pure water or certain aqueous-
micellar
systems
made
of
Triton
X-100,
didodecyldimethylammonium
bromide
(DDAB),
dioctadecyldimethylammonium bromide (DODAB) or sodium
dodecyl sulfate (SDS) were used the reaction yield of the target
product 4a did not exceed 35%. Owing to the fact of
unacceptable low yields of Passerini reaction as well as the
need for application of non-commercially available aldehydes 1
as starting materials we searched for more efficient building
blocks, which could be used as an oxo component in P-MCR.
On the basis of our own experience[16c] tetrahydropyran-2-ol (7a,
n=1) and tetrahydrofuran-2-ol (7b, n=0) which are semicyclic O-
acetal and exist in an equilibrium with corresponding 5-
hydroxypentanal (8a, n=1) and 4-hydroxybutanal (8b, n=0) have
been selected as an alternative for synthetically laborious
aldehydes 1. Compounds 7a and 7b are easily accessible from
inexpensive 3,4-dihydro-2H-pyran (6a, n=1) and 2,3-dihydro-2H-
furan (6b, n=0) under published procedure (Scheme 2).[19]
Figure 2. Retrosynthetic analysis of N-substituted 2-hydroxy-lactams.
Our strategy involves disconnection of the target lactams 5
to give the key synthon α-acetoxy amides 4, which can be
obtained from isocyanide 3, carboxylic acid 2 and aldehyde 1 in
multicomponent Passerini reaction (P-MCR) (Figure 2).[13] The
MCRs enable to synthesize new compounds from three or more
reactants, where basically all or most of the atoms of the
reactants contribute to the newly formed product.[14] Although
several chemical procedures have been explored toward N-
substituted 3-hydroxy-lactams, none of them consider
isocyanide-based multicomponent reaction (MCR) for the
construction of the cyclic amide scaffolds. Recently, our group
has exploited successfully MCRs for the preparation of various
pharmaceutically relevant peptidomomitecs.[15]
Results and Discussion
Scheme 2. 2,3-Dihydropyran (6) as an aldehyde (8) and carboxylic acid (2a)
supporter.
As it has been shown in Figure 2 5-acetoxypentanal (1a)
and 5-tosyloxypentanal (1b) could be used as oxo components
in Passerini reaction, whilst the required structural diversity
could be easily achieved via carboxylic acid and isocyanide
component variations.
When tetrahydropyran-2-ol (7a, n=1) was used as the oxo
component in P-MCR, respective product 10a (R1= PhCH2,
R2=4-MeOC6H4CH2) was formed in 83% yield (Scheme 3) under
solvent-free procedure. Application of DCM as a solvent in
analogous reaction reduced significantly the yield of 10a to 56%.
When 3,4-dihydro-2H-pyran (6a, n=1) was directly employed in
P-MCR under solvent-free condition product 10a was obtained
only with 2%. Comprehensive studies revealed that water,
particularly one equivalent, is required to reach the highest yield
75% of the desired α-acetoxy amide 10a.
Scheme 1. Synthesis of α-acetoxy amides 4a and 4b from the corresponding
aldehydes in P-MCR.
The aldehydes 1a-b were prepared from 1,5-pentanediol
via a monoacylation and monotosylation, followed by a PCC-
catalyzed oxidation, as previously published.[16] Subsequently,
the solvent-free Passerini condensation[17] of phenylacetic acid
(2a), p-methoxybenzylisocyanide (3a) and prepared aldehydes
1a-b furnished α-acetoxy amide derivatives 4a-b in moderate
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From the three different synthetic strategies toward N-
substituted 2-hydroxy-lactams precursors 10, we chose the
one engaged tetrahydropyran-2-ol (7a,
n=1) and
tetrahydrofuran-2-ol (7b, n=0) and used it for the synthesis of
structurally various α-acetoxy amides 10a-p with the yields
ranging between 92-29% (Table 1, entries 1-10 and 12-16).
However, when trifluoroacetic acid was used the formation of
the expected product 10m has not been observed (Table 1,
entry 11).The successful one-pot preparation of carefully
designed α-acetoxy amides allowed for further attempts
towards the synthesis of the target lactams 5. The first trials
performed
on
the
model
6-hydroxy-1-[(4-
methoxybenzyl)amino]-1-oxohexan-2-yl phenylacetate (10a)
under published conditions and based on DEAD/PPh3
catalyzed intramolecular Mitsunobu reaction as well as
POCl3/Py catalyzed cyclization were unsuccessful leading in
the first case to unreacted substrate 10a or inseparable
complex reaction mixture for the second one.[21] Collected
data revealed that initially applied model compound 10a
possessing in its structure hydroxyl group did not undergo
cyclization toward desired lactam 5a (R2=4-MeOC6H4CH2,
R4=H, n=1) (Scheme 3).
Scheme 3. Synthesis of α-acetoxy amides 10 from tetrahydropyran-2-ol (7a)
and 2-hydroxytetrahydrofuran (7b) in P-MCR and their further functionalization.
Furthermore, we have envisaged that tetrahydro-2H-pyran-2-yl
2-phenylacetate (9), which can be provided with 61% yield from
compound 6a in the reaction catalyzed by pyridinium p-
toluenesulfonate (PPTS), may concomitantly support P-MCR
with two substrates, an aldehyde and carboxylic acid (Scheme
2). This approach would considerably simplify the process and it
would open a new route toward α-acetoxy amide derivatives 10.
Unfortunately, the reaction of tetrahydro-2H-pyran-2-yl 2-
phenylacetate (9) with p-methoxybenzylisocyanide (3a) under
solvent-free condition or with different amount of water (1 to 5
equiv.) resulted in expected α-acetoxy amide formation with
negligible yield, less than 5%. This apparently arose from the
ratio of the hydrolysis of tetrahydropyran-2-yl alkanoates 7 what
has been extensively studied by Hall et al..[20] Finally,
incorporation of the immobilized lipase from Candida antarctica
B (Novozym 435) to the chemoenzymatic tandem reaction
between tetrahydro-2H-pyran-2-yl 2-phenylacetate (9) and p-
methoxybenzylisocyanide (3a) led to the isolated product 10a
with 24% yield. To the best of our knowledge hydrolases has
been never before used for the hydrolysis of tetrahydropyran-2-
yl alkanoates 7. Analogous studies have been performed for 7b
(data not shown).
Table 1. Synthesis of α-acetoxy amides 10 from tetrahydropyran-2-ol (7a)
and 2-hydroxytetrahydrofuran (7b) in P-MCR.[a]
Entry
1
7
R1
R2
Product 10
10a
Yield [%][b]
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
Ph
4-MeOC6H4CH2
PhCH2
83
72
54
92
82
75
89
85
68
50
-
2
10b
10c
3
Ph
4
cyclo-C6H11
n-C6H13
10d
10e
5
6
tert-C4H9
10f
7
n-C4H9
10g
10h
10i
8
CH2CO2Et
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
PhCH2
9
10
11
12
13
14
15
16
CH3
10j
CF3
10k
CH3
10l
56
29
62
54
65
CH3
CH2CO2Et
4-MeOC6H4CH2
PhCH2
10m
10n
10o
10p
PhCH2
PhCH2
PhCH2
CH2CO2Et
[a] Reaction conditions: 7a or 7b (1 mmol), carboxylic acid 2 (1 mmol),
isocyanide 3 (1 mmol), neat, magnetic stirring, r.t. 18 h. [b] Isolated
product.
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10.1002/ejoc.201800605
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FULL PAPER
Table 2. Effect of organic solvent on the cyclization reaction of 4c.[a]
To overcome this inconvenience the synthesis of the
intermediate 10 was revised according to the literature data
regarding the preparation of 3-hydroxypipecolamide.[22] Initially,
the hydroxyl group in compound 10a was modified by the
activation with 4-toluenesulfonyl chloride (p-TsCl) leading to
compound 4b (R1=PhCH2, R2=4-MeOC6H4CH2, R3=OTs, n=1)
with 98% (Scheme 3). Subsequent lactamization of 4b catalyzed
by NaH in THF at -78 °C and 0 °C, according to literature
procedure developed for protected 3-hydroxypiperidin-2-one,[22]
failed leading exclusively to hydrolyzed derivative 11 (R2=4-
MeOC6H4CH2, R3=OTs, n=1) with 62% yield (Scheme 3). By
contrast, the treatment of methanesulfonate-derivative 4c
(R1=PhCH2, R2=4-MeOC6H4CH2, R3=OMs, n=1) with 3 equiv. of
NaH in THF at 0 °C for 18 hours afforded the desired 3-hydroxy-
1-(4-methoxybenzyl)azepan-2-one (5a, R2=4-MeOC6H4CH2,
R4=H, n=1) with 98%. Further increase in NaH amount to four
and five equivalents did not affect the reaction yield. Parallel, six
different bases were tested: 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), 1,4-diazabicyclo[2.2.2]-octane (DABCO), potassium tert-
butoxide, N,N-diisopropyl-ethylamine, n-butyllithium (n-BuLi) and
cesium carbonate. Among them, only the application of
potassium tert-butoxide furnished 5a in 80%. Usage of n-BuLi
resulted in substrate decomposition and for the rest of used
bases 4c was recovered quantitatively. Detailed studies under
reaction conditions revealed that the amount of used NaH
influences the reaction outcome. Application of one equiv. of
Entry
Solvent
5a (R4=H)[b]
1
2
3
4
5
6
7
8
Tetrahydrofuran
Methyl tert-butyl ether
Acetonitrile
98
62
71
84
61
56
81
32
Dimethylformamide
Toluene
Dichloromethane
1,4-Dioxane
N,N-dimethylacetamide
[a] Reaction conditions: 10a (0.5 mmol), NaH (3 equiv.), organic solvent (5
mL), argon, magnetic stirring, 0 °C, 18 h. [b] Isolated product.
Among tested organic solvents, initially selected
tetrahydrofuran revealed to be the best medium for the studied
model reaction (Table 2, entry 1), providing the desired product
5a with 98% yield (Scheme 4). Second best DMF provided 5a in
84% yield, but due to its high boiling point is less convenient.
Inspired by the work of Ranganathan et al. additional
experiments regarding the structure of the intermediate 4 were
performed. The hydroxy group was exchanged by the chlorine
(10c, R1=PhCH2, R2=4-MeOC6H4CH2, R3=Cl, n=1) and bromine
(10d, R1=Ph, R2=4-MeOC6H4CH2, R3=Br, n=1) atoms which are
better leaving groups than -OH one, and therefore have
desirable influence on the cyclization step.[24] Following
lactamization of these two intermediates under optimized
conditions resulted in target lactam 5a with 49% and 32%
respectively. The literature procedure developed for the
homologs of the compounds 10c and 10d possessing N-phenyl
scaffold and based on the cyclization reaction catalyzed by
K2CO3 in N,N-dimethylacetamide resulted exclusively in
recovered substrates after 18 hours.[24]
NaH resulted in
α-hydroxy amide derivative 11 (R2=4-
MeOC6H4CH2, R3=OMs, n=1) formation with 55%, exclusively
(Scheme 3). Doubling the amount of base resulted in target
lactam 5a with 78% what suggested that lactamization is
proceeded by the hydrolytic decomposition of 4c. Indeed, the
application of intermediate 11 for lactamization using just one
equivalent of NaH resulted in target lactam 5a with quantitative
yield after 8 hours at 0 °C. We subsequently studied the effect of
the reaction medium, thus seven common used in N-alkylation
of amides[23] organic solvents were investigated (Table 2).
At this point, to validate our protocol additional
experiments with different methanesulfonate-derivatives
4
(R3=OMs) were conducted under optimized conditions (Scheme
3), providing corresponding seven- and six-membered ring 3-
hydroxy-N-substituted lactams 5a-i with good to excellent yields
up to 98% (Table 3). Moreover, to show the synthetic potential of
P-MCR products also five-membered 3-hydroxy lactam 5j was
prepared under developed protocol from the corresponding α-
acetoxy amide derivative 4 (Scheme 5). The synthesis starting
from 3-benzyloxypropanal (1c) which was obtained according to
the literature procedure from the 1,3-propanediol with 92%
overall yield in two-step procedure involving Swern oxidation.[25]
The same aldehyde 1c was provided from 3-benzyloxypropan-1-
ol in laccase/TEMPO catalyzed transformation with 32% yield.
To the best of our knowledge presented chemoenzymatic
approach to 1c has no precedence in literature. The α-hydroxy
amide 10 was obtained in 91% yield. The subsequent
deprotection and derivatization using methanesulfonyl chloride
furnished intermediate 4 quantitatively. Further, the reaction of 4
Scheme 4. Synthesis of (1-((4-methoxybenzyl)amino)-6-((methylsulfonyl)oxy)-
1-oxohexan-2-yl-2-phenylacetate (4c)
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10.1002/ejoc.201800605
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with NaH under optimized condition provided desired 3-hydroxy-
enantiomeric excess via enzymatic kinetic resolution of 4a
1-(4-methoxybenzyl)pyrrolidin-2-one (5j) in 89% yield.
catalyzed by lipase from hog pancreas in phosphate buffer.
Table 3. Synthesis of 3-hydroxy-N-substituted lactams 5 under optimized
conditions from methanesulfonate-derivatives 4c-k.[a]
Entry
4
Product 5
n
1
1
1
1
1
1
1
1
0
R2
Yield [%][b]
1
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
4-MeOC6H4CH2
PhCH2
98
76
54
97
93
59
95
19
86
Scheme 6. Synthesis of chiral non-racemic 3-hydroxy lactam 5a.
2
3
Ph
The subsequent lactamization of the chiral non-racemic 4a
under developed protocol provided non-racemic chiral 3-hydroxy
lactam with unchanged enantiomeric excess (Scheme 6). The
obtained result shows the synthetic potential of the newly
developed protocol for the preparation of the chiral non-racemic
lactam derivatives. The enzymatic process regarding
optimization of the kinetic resolution of the α-acetoxy amide
derivaties 4 is a subject of ongoing work.
4
cyclo-C6H11
n-C6H13
5
4g
4h
4i
6
tert-C4H9
n-C4H9
7
5g
5h
5i
8
4j
CH2CO2Et
4-MeOC6H4CH2
16
4k
Conclusions
[a] Reaction conditions: 4 (0.5 mmol), NaH (3 equiv.), THF (5 mL), argon,
magnetic stirring, 0 °C, 18 h. [b] Isolated product.
In conclusion, three different protocols based on the usage
of commercially available 3,4-dihydro-2H-pyran and 2,3-dihydro-
2H-furan for the synthesis of 3-hydroxy amides precursors were
developed. According to our knowledge, this is the first example
of the application of a semicyclic O,O-acetals a s an equivalent
of the oxo component in multicomponent Passerini reaction. The
new protocol combining multicomponent Passerini reaction with
intermolecular cyclization was established and successfully
applied to the synthesis of various five-, six- and seven-
membered 3-hydroxy lactams with excellent yield up to 98%.
Careful optimization of the reaction conditions, including the type
of used intermediates enables the enantioselective synthesis of
the desired 3-hydroxy lactams. The protocol reported herein is
an useful alternative to known methods providing lactams with
manifold structure.
The 3-hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one (5j) is a
precursor of (-)-actinophyllic acid which facilitates fibrinolysis
and inhibits the blood clot formation that is a cause of various
cardiovascular disorders.[5]
Experimental Section
General methods. All the chemicals were obtained from
commercial sources and the solvents were of analytical grade. 1H- and
13C-NMR spectra were recorded in CDCl3 solution. Chemical shifts are
expressed in parts per million using TMS as an internal standard. The
coupling constants (J) are given in hertz (Hz). The HPLC analyses were
performed on Chiralcel OD-H chiral column ( 4.6 mm x 250 mm, from
Diacel Chemical Ind., Ltd) equipped with a pre-column ( 4mm×10 mm,
5μm) using an LC-6A Varian ProStar apparatus with UV Varian ProStar
330 detector and Chromatopac C-R6A analyser. The mobile phase was
n-hexane/isopropanol. The elemental analyses were performed on CHN
Perkin-Elmer 240 apparatus. TLC analyses were done on Kieselgel 60
F254 aluminum sheets. Column chromatographies were performed on
Merck silica gel 60/230-400 mesh. Enzymatic reactions were performed
in a vortex (Heidolph Promax 1020) equipped with incubator (Heidolph
Inkubator 1000). To prove the ability of the established protocol each
reaction was repeated at least three times. Immobilized lipase from
Scheme 5. Synthesis of five-member ring 3-hydroxy-lactam 5j.
Due to the fact that most of the reported bioactive
compounds based on the 3-hydroxy-lactam scaffolds are chiral
non-racemic (Figure 1) we were interested if our protocol can be
applied in enantioselective synthesis of the target compounds.
The synthesis of chiral non-racemic intermediates via enzyme
mediated processes has been of considerable interest in our
laboratory.[26] As a continuation of these efforts chiral non-
racemic intermediate 4a has been prepared with 31%
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10.1002/ejoc.201800605
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Candida antarctica B (Novozym 435) was purchased from Novo Nordisk.
Laccase from Trametes versicolor and lipase from hog pancreas were
purchased from Sigma-Aldrich. To prove the ability of the established
protocol each reaction was repeated at least three times.
Tetrahydropyran-2-ol, tetrahydrofuran-2-ol and tetrahydro-2H-pyran-2-yl
2-phenylacetate were obtained according to the literature procedure.[19]
p-Methoxybenzylisocyanide was obtained as previously reported.[15d]
159.19, 144.91, 133.48, 133.14, 130.00, 129.76, 129.14, 129.13, 129.01,
127.98, 127.64, 114.18, 73.65, 70.21, 55.45, 42.68, 41.72, 31.17, 28.48,
21.78, 20.78; Elementary analysis calcd. for C29H33NO7S; C 64.55%, H
6.16%, N 2.60, found C 64.50%, H 6.13%, N 2.55.
General procedure for the synthesis of α-acetoxy amides 10 using
tetrahydropyran-2-ol (7a) or tetrahydrofuran-2-ol (7b). Isocyanide 3 (1
mmol) was added to the suspension of carboxylic acid 2 (1 mmol) and
tetrahydropyran-2-ol (7a) or tetrahydrofuran-2-ol (7b) (1 mmol) at room
temperature. The reaction mixture was stirred at ambient temperature for
18 hours. The crude product was purified by column chromatography on
silica gel (hexanes/EtOAc) to afford the corresponding product 10.
Tetrahydro-2H-pyran-2-yl 2-phenylacetate. Compound was obtained
using literature procedure[19] with 76% yield (335 mg, 1.52 mmol) as a
colourless oil; b.p. 105 °C/0.1 mmHg (76%); 1H NMR (400 MHz, CDCl3) δ
7.25 (m, 5H), 5.99 (s, 1H), 3.61-3.80 (m, 2H), 3.66 (s, 2H), 1.45-1.80 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 170.18,133.96, 129.30, 128.53,
1127.07, 92.95, 63.04, 41.67, 29.08, 24.90, 18.41, HR ESIMS (M+H)+
calcd for C13H17O3 221.1178, found 221.1172.
6-Hydroxy-1-[(4-methoxybenzyl)amino]-1-oxohexan-2-yl
phenylacetate (10a). Colourless oil; (83%, 320 mg, 0.83 mmol); Rf 0.21
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 5H), 7.04 (d,
J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.86 (s, 1H), 5.24 (dd, J = 7.1,
4.6 Hz, 1H), 4.21 (qd, J = 14.6, 5.8 Hz, 2H), 3.81 (s, 3H), 3.67 (s, 2H),
3.59 (t, J = 6.4 Hz, 2H), 1.98-1.79 (m, 2H), 1.53 (dtd, J = 13.1, 6.5, 2.8
Hz, 3H), 1.41-1.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.99, 169.52,
133.60, 129.93, 129.18, 129.01, 127.63, 114.23, 74.14, 55.49, 42.75,
41.82, 32.27, 31.65, 21.09; HR ESIMS (M+H)+ calcd for C22H28NO5
386.1967, found 386.1964; Elementary analysis calcd. for C22H27NO5; C
68.55%, H 7.06%, N 3.63, found C 68.38%, H 6.95%, N 3.49.
General procedure for enzymatic oxidation of 3-benzyloxypropanol
to 3-benzyloxypropanal (1c). A mixture of 3-benzyloxypropanol (0.5
mmol), laccase from Trametes versicolor (20 mg), TEMPO (0.1 mmol)
and DODAB (0.1 mmol) was stirred in phosphate buffer (5 mL, pH = 5.2,
100 mM) at room temperature for 18 hours. The aqueous phase was
extracted with TBME. The organic phase was dried over Na2SO4 and the
solvent was removed under vacuum. Crude product was purified by
column chromatography on silica gel (hexanes/EtOAc) resulted in 3-
benzyloxypropanal (1c) with 32% yield (26 mg, 0.16 mmol). Rf 0.72
(hexanes/EtOAc, 8:2); 1H NMR (400 MHz, CDCl3) δ; 9.80 (t, J = 1.8 Hz,
1H), 7.39 – 7.23 (m, 6H), 4.54 (s, 2H), 3.82 (t, J = 6.1 Hz, 2H), 2.70 (td, J
= 6.1, 1.8 Hz, 2H) 13C NMR (100 MHz, CDCl3) δ 201.3, 138.0, 128.6,
127.93, 127.85, 73.4, 64.0, 44.0. 1H and 13CNMR spectra correspond
with the published one.[27]
6-Hydroxy-1-[(benzyl)amino]-1-oxohexan-2-yl phenylacetate (10b).
Colourless oil; (72%, 256 mg, 0.72 mmol); Rf 0.24 (CH2Cl2/MeOH, 95:5);
1H NMR (400 MHz, CDCl3) δ 7.10-7.32 (m, 10H), 6.03 (t, J = 5.1 Hz, 1H),
5.24 (dd, J = 7.1, 4.6 Hz, 1H), 4.26 (qd, J = 14.8, 5.8 Hz, 2H), 3.66 (s,
2H), 3.56 (t, J = 6.4 Hz, 2H), 1.97-1.78 (m, 2H), 1.52 (dtt, J = 13.0, 6.5,
2.9 Hz, 2H), 1.35 (p, J = 7.3 Hz, 2H).; 13C NMR (100 MHz, CDCl3) δ
169.73, 129.12, 128.93, 128.84, 128.76, 127.87, 127.63, 127.57, 74.08,
62.40, 43.18, 41.70, 32.15, 31.59, 21.04; HR ESIMS (M+H)+ calcd for
C21H26NO4 356.1862, found 356.1861; Elementary analysis calcd. for
C21H25NO4; C 70.96%, H 7.09%, N 3.94, found C 71.05%, H 7.15%, N
3.88.
1-[(4-Metoxybenzyl)amino]-1-oxo-6-(acyloxy)hex-2-yl phenylacetate
(4a). p-Methoxybenzylisocyanide (147.2 mg, 1 mmol) was added to the
suspension of 5-acetoxypentanal (144.2, 1 mmol) and phenylacetic acid
(136.2 mg, 1 mmol) at room temperature. The reaction mixture was
stirred at ambient temperature for 18 hours. The crude product was
purified by column chromatography on silica gel (hexanes/EtOAc) to
afford the corresponding product 4a as a colourless oil with 64% yield
6-Hydroxy-1-[(phenyl)amino]-1-oxohexan-2-yl phenylacetate (10c).
Colourless oil; (54%, 185 mg, 0.54 mmol); Rf 0.21 (CH2Cl2/MeOH, 95:5);
1H NMR (400 MHz, CDCl3) δ 7.21-7.45 (m, 10H), 7.07 (t, J = 5.1 Hz, 1H),
5.34 (dd, J = 7.1, 4.6 Hz, 1H), 3.78 (s, 2H), 3.62 (t, J = 6.4 Hz, 2H), 1.90-
2.00 (m, 2H), 1.40-1.59 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 169.73,
167.70, 136.74, 133.54, 129.34, 129.22, 129.15, 128.87, 128.68, 127.67,
124.70, 119.92, 74.05, 62.37, 41.71, 32.05, 31.52, 20.95; HR ESIMS
(M+Na)+ calcd for C20H23NO4Na 364.1525, found 364.1523; Elementary
analysis calcd. for C20H23NO4; C 70.36%, H 6.79%, N 4.10, found C
70.31%, H 6.68%, N 4.02.
1
(273 mg, 0.64 mmol); Rf 0.35 (hexanes/EtOAc, 7:3); H NMR (400 MHz,
CDCl3) δ 7.24 (s, 5H), 7.07 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H),
5.86 (s, 1H), 5.26 (dd, J = 7.2, 4.5 Hz, 1H), 4.23 (ddd, J = 33.6, 14.6, 5.8
Hz, 2H), 4.03 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.69 (s, 2H), 2.06 (d, J =
3.0 Hz, 3H), 1.99 – 1.80 (m, 2H), 1.69 – 1.52 (m, 3H), 1.42 – 1.26 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 169.80, 169.21, 159.15, 133.39,
129.74, 129.01, 129.00, 128.86, 127.50, 114.08, 73.87, 64.10, 55.32,
42.58, 41.64, 31.47, 28.19, 21.28, 20.95.; Elementary analysis calcd. for
C24H29NO6; C 67.43%, H 6.84%, N 3.28, found C 67.31%, H 6.78%, N
3.15.
6-Hydroxy-1-[(cyclohexyl)amino]-1-oxohexan-2-yl
phenylacetate
(10d). Colourless oil; (92%, 320 mg, 0.92 mmol); Rf 0.28 (CH2Cl2/MeOH,
95:5); 1H NMR (400 MHz, CDCl3) δ 7.38–7.26 (m, 5H), 5.52 (d, J = 8.3
Hz, 1H), 5.14 (dd, J = 7.0, 4.7 Hz, 1H), 3.68 (s, 2H), 3.65-3.54 (m, 3H),
1.94-1.74 (m, 2H), 1.74-1.67 (m, 1H), 1.67-1.47 (m, 6H), 1.41-1.18 (m,
5H), 1.07 (dddd, J = 21.2, 15.4, 8.5, 3.2 Hz, 1H), 0.94-0.68 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 169.81, 168.28, 133.76, 129.31, 129.21,
127.72, 73.66, 69.66, 47.86, 41.89, 37.53, 32.92, 32.79, 31.20, 28.76,
25.55, 24.85, 24.82, 20.75; HR ESIMS (M+Na)+ calcd for C20H29NO4Na
370.1994, found 370.1992; Elementary analysis calcd. for C20H29NO4; C
69.14%, H 8.41%, N 4.03, found C 69.03%, H 8.29%, N 3.95.
1-[(4-Metoxybenzyl)amino]-1-oxo-6-(tosyloxy)hex-2-yl phenylacetate
(4b). p-Methoxybenzylisocyanide (147.2 mg, 1 mmol) was added to the
suspension of 5-(((4-methylphenyl)sulfonyl)oxy)pentanal (256.3, 1 mmol)
and phenylacetic acid (136.2 mg, 1 mmol) at room temperature. The
reaction mixture was stirred at ambient temperature for 18 hours. The
crude product was purified by column chromatography on silica gel
(hexanes/EtOAc) to afford the corresponding product 4b as a colourless
oil with 54% yield (291 mg, 0.54 mmol); Rf 0.27 (CH2Cl2/MeOH, 95:5); 1H
NMR (400 MHz, CDCl3) δ 7.81-7.74 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H),
7.21 (s, 5H), 7.06-7.00 (m, 2H), 6.89-6.82 (m, 2H), 5.87 (t, J = 5.6 Hz,
1H), 5.18 (dd, J = 6.9, 4.6 Hz, 1H), 4.26-4.11 (m, 2H), 3.95 (t, J = 6.4 Hz,
2H), 3.81 (s, 3H), 3.67 (s, 2H), 2.45 (s, 3H), 1.90-1.73 (m, 2H), 1.64-1.55
(m, 2H), 1.36-1.27 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.92, 169.24,
6-Hydroxy-1-[(n-hexyl)amino]-1-oxohexan-2-yl phenylacetate (10e).
Colourless oil; (82%, 286 mg, 0.82 mmol); Rf 0.30 (CH2Cl2/MeOH, 95:5);
1H NMR (400 MHz, CDCl3) δ 7.38–7.26 (m, 5H), 5.52 (d, J = 8.3 Hz, 1H),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800605
European Journal of Organic Chemistry
FULL PAPER
5.14 (dd, J = 7.0, 4.7 Hz, 1H), 3.68 (s, 2H), 3.65-3.54 (m, 3H), 1.94-1.74
(m, 2H), 1.74-1.67 (m, 1H), 1.67-1.47 (m, 6H), 1.41-1.18 (m, 5H), 1.07
(dddd, J = 21.2, 15.4, 8.5, 3.2 Hz, 1H), 0.94-0.68 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 169.81, 168.28, 133.76, 129.31, 129.21, 127.72, 73.66,
69.66, 47.86, 41.89, 37.53, 32.92, 32.79, 31.20, 28.76, 25.55, 24.85,
24.82, 20.75; HR ESIMS (M+Na)+ calcd for C20H31NO4Na 372.2151,
found 372.2149; Elementary analysis calcd. for C20H31NO4; C 68.74%, H
8.94%, N 4.01, found C 68.70%, H 8.85%, N 3.89.
55.28, 42.68, 32.10, 31.58, 21.07, 20.94; HR ESIMS (M+Na)+ calcd for
C16H23NO5Na 332.1474, found 332.1473; Elementary analysis calcd. for
C16H23NO5; C 62.12%, H 7.49%, N 4.53, found C 62.03%, H 7.39%, N
4.46.
6-Hydroxy-1-[(benzyl)amino]-1-oxohexan-2-yl
acetate
(10l).
Colourless oil; (56%, 156 mg, 0.56 mmol); Rf 0.24 (CH2Cl2/MeOH, 95:5);
1H NMR (400 MHz, CDCl3) δ 7.24-7.35 (m, 5H), 6.39 (s, 1H), 5.21 (dd, J
= 7.1, 4.6 Hz, 1H), 4.46 (qd, J = 14.6, 5.8 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H),
2.11 (s, 3H), 1.89-1.92 (m, 2H), 1.55-1.59 (m, 3H), 1.41-1.45 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 169.69, 137.81, 128.78, 127.67, 127.65, 73.95,
62.39, 43.21, 37.59, 32.12, 21.06, 20.96; HR ESIMS (M+Na)+ calcd for
C16H21NO4Na 302.1368, found 302.1367; Elementary analysis calcd. for
C15H21NO4; C 64.50%, H 7.58%, N 5.01, found C 64.38%, H 7.51%, N
4.89.
6-Hydroxy-1-[(tert-butyl)amino]-1-oxohexan-2-yl phenylacetate (10f).
Colourless oil; (75%, 241 mg, 0.75 mmol); Rf 0.28 (CH2Cl2/MeOH, 95:5);
1H NMR (400 MHz, CDCl3) δ 7.31-7.19 (m, 5H), 5.46 (s, 1H), 5.00 (dd, J
= 6.7, 4.9 Hz, 1H), 3.62 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 1.84-1.68 (m,
2H), 1.51-1.41 (m, 2H), 1.31-1.25 (m, 2H), 1.10 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 168.84, 133.72, 129.22, 129.05, 128.60, 127.60, 74.33,
62.36, 51.18, 41.83, 41.24, 32.18, 31.48, 30.94, 28.58, 20.88; HR ESIMS
(M+Na)+ calcd for C18H27NO4Na 344.1838, found 344.1835; Elementary
analysis calcd. for C18H27NO4; C 67.26%, H 8.47%, N 4.36, found C
67.15%, H 8.33%, N 4.21.
Ethyl (2-acetoxy-6-hydroxyhexanoyl) glycinate (10m). Colourless oil;
(29%, 80 mg, 0.29 mmol); Rf 0.18 (CH2Cl2/MeOH, 95:5); 1H NMR (400
MHz, CDCl3) δ 6.65 (s, 1H), 5.20 (dd, J = 7.1, 4.6 Hz, 1H), 4.20 (q, J =
7.2 Hz, 2H), 4.01 (qd, J = 14.6, 5.8 Hz, 2H), 3.61 (t, J = 6.4 Hz, 2H), 2.15
(s, 3H), 1.86-1.89 (m, 3H), 1.55-1.57 (m, 2H), 1.41-1.45 (m, 2H), 1.27 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.08, 169.67, 169.62,
73.69, 62.31, 61.66, 41.00, 32.09, 31.47, 20.93, 20.89, 14.07; HR ESIMS
(M+Na)+ calcd for C12H21NO6Na 298.1267, found 298.1265; Elementary
analysis calcd. for C12H21NO6; C 52.35%, H 7.69%, N 5.09, found C
52.42%, H 7.60%, N 4.98.
6-Hydroxy-1-[(n-butyl)amino]-1-oxohexan-2-yl phenylacetate (10g).
Colourless oil; (89%, 286 mg, 0.89 mmol); Rf 0.27 (CH2Cl2/MeOH, 95:5);
1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 6H), 5.61 (t, J = 5.2 Hz, 1H),
5.18 (dd, J = 7.1, 4.6 Hz, 1H), 3.70 (s, 2H), 3.58 (t, J = 6.4 Hz, 2H), 3.13-
2.98 (m, 2H), 1.94-1.75 (m, 2H), 1.59-1.45 (m, 3H), 1.39-1.29 (m, 3H),
1.29-1.12 (m, 5H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
169.94, 169.64, 133.76, 129.45, 129.27, 129.06, 128.64, 127.66, 127.16,
74.11, 62.45, 32.20, 31.56, 31.40, 21.02, 13.78; HR ESIMS (M+Na)+
calcd for C18H27NO4Na 344.1838, found 344.1837; Elementary analysis
calcd. for C18H27NO4; C 67.26%, H 8.47%, N 4.36, found C 67.08%, H
8.34%, N 4.22.
6-Hydroxy-1-[(4-methoxybenzyl)amino]-1-oxopentan-2-yl
phenylacetate (10n). Colourless oil; (62%, 230 mg, 0.62 mmol); Rf 0.23
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 5H), 7.06 (d,
J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.03 (s, 1H), 5.27 (dd, J = 7.1,
4.6 Hz, 1H), 4.21 (qd, J = 14.6, 5.8 Hz, 2H), 3.82 (s, 3H), 3.68 (s, 2H),
3.61 (t, J = 6.4 Hz, 2H), 1.96-1.90 (m, 2H), 1.55-1.61 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 169.92, 169.54, 159.09, 137.42, 129.69, 129.18,
129.04, 129.01, 128.84, 127.46, 114.17, 73.70, 55.32, 42.61, 41.56,
28.29, 27.71; HR ESIMS (M+Na)+ calcd for C21H25NO5Na 394.1630,
found 394.1629; Elementary analysis calcd. for C21H25NO5; C 67.91%, H
6.78%, N 3.77, found C 67.85%, H 6.71%, N 3.55.
6-Hydroxy-1-[(2-etoxy-2-oxoethyl)amino]-1-oxohexan-2-yl
phenylacetate (10h). Colourless oil; (85%, 299 mg, 0.85 mmol); Rf 0.18
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.30-7.18 (m, 5H),
6.29 (t, J = 5.0 Hz, 1H), 5.16 (dd, J = 6.7, 5.0 Hz, 1H), 4.13 (q, J = 7.1 Hz,
2H), 3.90 (dd, J = 18.2, 5.6 Hz, 1H), 3.75 (dd, J = 18.2, 5.2 Hz, 1H), 3.66
(s, 2H), 3.49 (t, J = 6.4 Hz, 2H), 1.88 – 1.72 (m, 3H), 1.44 (tdd, J = 8.5,
6.9, 4.3 Hz, 2H), 1.29 (p, J = 7.9 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.16, 170.07, 169.49, 133.56, 129.35,
128.93, 127.52, 74.00, 62.41, 61.69, 41.57, 41.02, 32.16, 31.49, 20.88,
14.22; HR ESIMS (M+Na)+ calcd for C18H25NO6Na 374.1580, found
374.1580; Elementary analysis calcd. for C18H25NO6; C 61.52%, H 7.17%,
N 3.99, found C 61.50%, H 7.05%, N 3.86.
6-Hydroxy-1-[(benzyl)amino]-1-oxopentan-2-yl phenylacetate (10o).
Colorless oil; (54%, 184 mg, 0.54 mmol); Rf 0.26 (CH2Cl2/MeOH, 95:5);
1H NMR (400 MHz, CDCl3) δ 7.11-7.32 (m, 10H), 5.97 (s, 1H), 5.28 (dd, J
= 7.1, 4.6 Hz, 1H), 4.27 (qd, J = 14.8, 5.8 Hz, 2H), 3.67 (s, 2H), 3.60 (t, J
= 6.4 Hz, 2H), 1.99-1.94 (m, 2H), 1.55-1.59 (m, 2H).; 13C NMR (100 MHz,
CDCl3) δ 169.84, 169.56, 137.56, 133.39, 129.02, 128.86, 128.70,
128.69, 128.68, 127.66, 127.57, 127.50, 73.70, 61.98, 43.12, 41.62,
28.29, 27.72; HR ESIMS (M+Na)+ calcd for C20H23NO4Na 364.1525,
found 364.1524; Elementary analysis calcd. for C20H23NO4; C 70.36%, H
6.79%, N 4.10, found C 70.31%, H 6.69%, N 4.02.
6-Hydroxy-1-[(4-methoxybenzyl)amino]-1-oxohexan-2-yl
benzoate
(10i). Colourless oil; (68%, 253 mg, 0.68 mmol); Rf 0.23 (CH2Cl2/MeOH,
95:5); 1H NMR (400 MHz, CDCl3) δ 8.04-8.07 (m, 2H), 7.56-7.58 (m, 1H),
7.43-7.47 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.41
(s, 1H), 5.46 (dd, J = 7.1, 4.6 Hz, 1H), 4.40 (qd, J = 14.6, 5.8 Hz, 2H),
3.77 (s, 3H), 3.63 (t, J = 6.4 Hz, 2H), 2.02-2.06 (m, 3H), 1.50-1.61 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 169.71, 159.09, 133.62, 129.89,
129.74, 129.24, 128.93, 128.63, 114.13, 74.40, 62.38, 55.28, 42.72,
32.15, 31.66, 21.24; HR ESIMS (M+Na)+ calcd for C21H25NO5Na
394.1630, found 394.1629; Elementary analysis calcd. for C21H25NO5; C
67.91%, H 6.78%, N 3.77, found C 67.85%, H 6.64%, N 3.59.
6-Hydroxy-1-[(2-etoxy-2-oxoethyl)amino]-1-oxohexan-2-yl
phenylacetate (10p). Colourless oil; (65%, 220 mg, 0.65 mmol); Rf 0.22
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.28-7.37 (m, 5H),
6.41 (s, 1H), 5.29 (dd, J = 6.7, 5.0 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.88
(dd, J = 18.2, 5.6 Hz, 1H), 3.84 (dd, J = 18.2, 5.2 Hz, 1H), 3.75 (s, 2H),
3.60 (t, J = 6.4 Hz, 2H), 1.92-1.99 (m, 3H), 1.59-1.61 (m, 2H), 1.30 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.05, 169.96, 169.38,
133.42, 129.25, 128.84, 127.43, 73.65, 61.97, 61.60, 41.44, 40.93, 28.24,
27.56, 14.11; HR ESIMS (M+Na)+ calcd for C18H23NO6Na 360.1423,
found 360.1421; Elementary analysis calcd. for C17H23NO6; C 60.52%, H
6.87%, N 4.15, found C 60.45%, H 6.81%, N 4.03.
6-Hydroxy-1-[(4-methoxybenzyl)amino]-1-oxohexan-2-yl
acetate
(10j). Colourless oil; (50%, 155 mg, 0.50 mmol); Rf 0.19 (CH2Cl2/MeOH,
95:5); 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.4 Hz, 2H), 6.84 (d, J =
8.4 Hz, 2H), 6.40 (s, 1H), 5.16 (dd, J = 7.1, 4.6 Hz, 1H), 4.36 (qd, J =
14.6, 5.8 Hz, 2H), 3.77 (s, 3H), 3.59 (t, J = 6.4 Hz, 2H), 2.09 (s, 3H),
1.83-1.92 (m, 3H), 1.51-1.57 (m, 2H), 1.38-1.43 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 169.68, 159.12, 129.89, 129.02, 114.14, 73.94, 62.29,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800605
European Journal of Organic Chemistry
FULL PAPER
General procedure for the synthesis of 6-hydroxy-1-[(4-
methoxybenzyl)amino]-1-oxohexan-2-yl phenylacetate (10a) using
3,4-dihydro-2H-pyran (6a). p-Methoxybenzylisocyanide (147.2 mg, 1
mmol) was added to the suspension of phenylacetic acid (136.2 mg, 1
mmol), 3,4-dihydro-2H-pyran (6a) (84.2 mg, 1 mmol) and distilled water
(1 mmol) at room temperature. The reaction mixture was stirred at
ambient temperature for 18 hours. The crude product was purified by
column chromatography on silica gel (hexanes/EtOAc) to afford the
product 10a with 75% yield (289 mg, 0.75 mmol) as colourless oil; Rf
0.21 (CH2Cl2/MeOH, 95:5).
1.81-1.72 (m, 2H), 1.53-1.42 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
169.76, 167.48, 136.80, 133.63, 129.37, 129.04, 127.89, 124.93, 120.07,
73.77, 69.58, 41.87, 37.57, 31.22, 28.75, 20.85; Elementary analysis
calcd. for C21H25NO6S; C 60.13%, H 6.01%, N 3.34, found C 60.10%, H
5.95%, N 3.28.
1-((Cyclohexyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-2-yl-2-
phenylacetate (4f). Colourless oil; (97%, 206 mg, 0.47 mmol); Rf 0.21
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.28 (m, 5H),
5.47 (d, J = 8.1 Hz, 1H), 5.17 (dd, J = 6.7, 4.7 Hz, 1H), 4.18 (t, J = 6.4 Hz,
2H), 3.71 (s, 2H), 3.67 – 3.56 (m, 1H), 2.99 (s, 3H), 1.96 – 1.79 (m, 2H),
1.78 – 1.68 (m, 3H), 1.68 – 1.53 (m, 5H), 1.46 – 1.35 (m, 2H), 1.34 –
1.20 (m, 3H), 1.15 – 1.00 (m, 1H), 0.95 – 0.69 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 169.81, 168.28, 133.76, 129.31, 129.21, 127.72, 73.66,
69.66, 47.86, 41.89, 37.53, 32.92, 32.79, 31.20, 28.76, 25.55, 24.85,
24.82, 20.75; Elementary analysis calcd. for C21H31NO6S; C 59.27%, H
7.34%, N 3.29, found C 59.06%, H 7.28%, N 3.18.
General procedure for the synthesis of 6-hydroxy-1-[(4-
methoxybenzyl)amino]-1-oxohexan-2-yl phenylacetate (10a) via
chemoenzymatic tandem reaction using tetrahydro-2H-pyran-2-yl 2-
phenylacetate. p-Methoxybenzylisocyanide (147.2 mg, 1 mmol) was
added to the suspension of tetrahydro-2H-pyran-2-yl 2-phenylacetate (9)
(220.3 mg, 1 mmol), immobilized lipase from Candida antarctica B
(Novozym 435) (20 mg) and distilled water (1 mmol) at room temperature.
The reaction mixture was stirred at ambient temperature for 18 hours.
The crude product was purified by column chromatography on silica gel
(hexanes/EtOAc) to afford the product 10a with 24% yield (93 mg, 0.24
mmol) as colourless oil; Rf 0.21 (CH2Cl2/MeOH, 95:5).
1-((n-Hexyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-2-yl-2-
phenylacetate (4g). Colourless oil; (99%, 212 mg, 0.49 mmol); Rf 0.23
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.28 (m, 5H),
5.57 (t, J = 5.5 Hz, 1H), 5.19 (dd, J = 6.9, 4.6 Hz, 1H), 4.17 (t, J = 6.4 Hz,
2H), 3.72 (s, 2H), 3.13 – 3.00 (m, 2H), 2.99 (s, 3H), 1.86 (dddd, J = 22.8,
14.3, 6.5, 4.6 Hz, 2H), 1.77 – 1.68 (m, 2H), 1.45 – 1.35 (m, 2H), 1.32 –
1.13 (m, 9H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
169.87, 169.22, 133.74, 129.30, 129.14, 127.75, 73.71, 69.66, 41.87,
39.29, 37.55, 31.51, 31.20, 29.36, 28.76, 26.52, 22.63, 20.83, 14.13;
Elementary analysis calcd. for C21H33NO6S; C 58.99%, H 7.78%, N 3.28,
found C 58.73%, H 7.62%, N 3.15.
General procedure for the synthesis of methanesulfonate
derivatives of α-acetoxy amides 4. To the solution of 10 (0.5 mmol)
and Et3N (83 µL, 0.6 mmol) in CH2Cl2 (5 mL) was added dropwise mesyl
chloride (MsCl) (42 µL, 2.88 mmol) under argon at -18 °C. The mixture
was stirred at the same temperature for 25 minutes and then quenched
with water (2 mL). The organic layer was separated and the aqueous
layer extracted with CH2Cl2 (3x10 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuum. The crude product was purified by column
chromatography on silica gel (hexanes/EtOAc) to afford the
corresponding product 4.
1-((2-Ethoxy-2-oxoethyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-
2-yl-2-phenylacetate (4h). Colourless oil; (96%, 206 mg, 0.47 mmol); Rf
0.21 (CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.26 (m,
5H), 6.30 (t, J = 5.3 Hz, 1H), 5.23 (dd, J = 6.4, 5.2 Hz, 1H), 4.20 (q, J =
7.1 Hz, 2H), 4.14 (t, J = 6.4 Hz, 2H), 3.97 (dd, J = 18.2, 5.7 Hz, 1H), 3.80
(dd, J = 18.2, 5.2 Hz, 1H), 3.73 (s, 2H), 2.97 (s, 3H), 1.95 – 1.80 (m, 2H),
(1-((4-Methoxybenzyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-2-
yl-2-phenylacetate (4c). Colorless oil; (98%, 227 mg, 0.48 mmmo); Rf
0.18 (CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 5H),
7.04 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 5.22 (dd, J
= 6.8, 4.7 Hz, 1H), 4.28-4.10 (m, 4H), 3.80 (s, 3H), 3.67 (s, 2H), 2.96 (s,
3H), 1.98-1.79 (m, 2H), 1.70 (ddt, J = 9.4, 6.8, 3.5 Hz, 2H), 1.39 (pd, J =
7.6, 6.9, 1.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.92, 169.19,
133.49, 129.13, 129.10, 128.98, 127.61, 114.19, 73.66, 69.63, 55.42,
42.67, 41.69, 37.45, 31.18, 28.69, 20.78; Elementary analysis calcd. for
C23H29NO7S; C 59.60%, H 6.31%, N 3.02, found C 59.51%, H 6.37%, N
2.98.
1.75 – 1.65 (m, 2H), 1.40 (p, J = 8.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 170.08, 169.72, 169.37, 133.49, 129.35,
129.00, 127.61, 73.60, 69.61, 61.70, 41.59, 41.02, 37.47, 31.13, 28.68,
20.67, 14.25; Elementary analysis calcd. for C19H27NO8S; C 53.14%, H
6.34%, N 3.26, found C 53.10%, H 6.27%, N 3.14.
1-((Tert-butyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-2-yl-2-
phenylacetate (4i). Colourless oil; (98%, 196 mg, 0.48 mmol); Rf 0.24
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.26 (m, 5H),
5.50 (s, 1H), 5.07 (dd, J = 6.1, 5.2 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 3.70
(s, 2H), 2.98 (s, 3H), 1.84 (ddt, J = 9.5, 6.7, 3.7 Hz, 2H), 1.71 (dt, J = 8.5,
6.4 Hz, 2H), 1.39 (ddt, J = 16.0, 7.0, 4.3 Hz, 2H), 1.17 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 169.89, 168.42, 133.70, 129.28, 129.16, 127.71,
73.93, 69.67, 51.26, 41.88, 37.55, 31.13, 28.78, 28.64, 20.68;
Elementary analysis calcd. for C19H29NO6S; C 57.12%, H 7.32%, N 3.51,
found C 57.10%, H 7.28%, N 3.45.
1-((Benzyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-2-yl-2-
phenylacetate (4d). Colourless oil; (99%, 215 mg, 0.49 mmmo); Rf 0.19
1
(CH2Cl2/MeOH, 95:5); H NMR (400 MHz, CDCl3) δ 7.31 (dddd, J = 9.4,
6.7, 4.6, 2.6 Hz, 3H), 7.21 (d, J = 2.8 Hz, 5H), 7.14-7.07 (m, 2H), 5.99 (t,
J = 5.4 Hz, 1H), 5.24 (dd, J = 6.8, 4.7 Hz, 1H), 4.35-4.19 (m, 2H), 4.15 (t,
J = 6.3 Hz, 2H), 3.68 (s, 2H), 2.96 (s, 3H), 1.98 – 1.81 (m, 2H), 1.71 (dtd,
J = 13.2, 6.4, 3.0 Hz, 2H), 1.45 – 1.35 (m, 2H).; 13C NMR (100 MHz,
CDCl3) δ 169.93, 169.32, 137.70, 133.49, 129.12, 128.98, 128.79,
127.72, 127.67, 127.63, 73.65, 69.62, 43.18, 41.70, 37.46, 31.19, 28.68,
20.80; Elementary analysis calcd. for C22H27NO6S; C 60.95%, H 6.28%,
N 3.23, found C 60.88%, H 6.21%, N 3.18.
1-((n-Butyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-2-yl-2-
phenylacetate (4j). Colourless oil; (99%, 197 mg, 0.49 mmol); Rf 0.26
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.28 (m, 5H),
5.61 – 5.50 (m, 1H), 5.20 (dd, J = 6.9, 4.6 Hz, 1H), 4.18 (t, J = 6.4 Hz,
2H), 3.72 (s, 2H), 3.14 – 3.01 (m, 2H), 2.99 (s, 3H), 1.96 – 1.79 (m, 2H),
1.77 – 1.68 (m, 2H), 1.45 – 1.35 (m, 2H), 1.31 – 1.13 (m, 6H), 0.87 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.88, 169.25, 133.74,
129.30, 129.15, 127.77, 73.72, 69.67, 41.89, 38.98, 37.56, 31.46, 31.21,
28.77, 20.84, 20.03, 13.82; Elementary analysis calcd. for C19H29NO6S;
C 57.12%, H 7.32%, N 3.51, found C 57.04%, H 7.18%, N 3.37.
1-((Phenyl)amino)-6-((methylsulfonyl)oxy)-1-oxohexan-2-yl-2-
phenylacetate (4e). Colourless oil; (98%, 206 mg, 0.48 mmol); Rf 0.17
(CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.31 (m, 7H),
7.32 – 7.16 (m, 6H), 7.13 – 7.07 (m, 1H), 5.34 (dd, J = 6.7, 4.8 Hz, 1H),
4.20 (t, J = 6.3 Hz, 2H), 3.79 (s, 2H), 2.98 (s, 3H), 2.06-1.89 (m, 2H),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800605
European Journal of Organic Chemistry
FULL PAPER
1-[(4-Metoxybenzyl)amino]-1-oxo-6-(chloro)hex-2-yl phenylacetate.
To the solution of 6-hydroxy-1-[(4-methoxybenzyl)amino]-1-oxohexan-2-
yl phenylacetate (385.5 mg, 1 mmol) in dry CH2Cl2 (10 mL) thionyl
chloride (143 mg, 1.2 mmol) was added dropwise at 0 °C. The mixture
was allowed to warm to room temperature and stirred for 6 hours
followed by concentration in vacuum. The crude product was purified by
column chromatography using ethyl acetate/hexanes as an eluent to
afford the corresponding product as a colourless oil with 87% yield (351
mg, 0.87 mmol); Rf 0.41 (hexanes/EtOAc, 7:3); 1H NMR (400 MHz,
CDCl3) δ 7.23 (d, J = 2.1 Hz, 5H), 7.08-7.02 (m, 2H), 6.88-6.82 (m, 2H),
5.89 (t, J = 5.2 Hz, 1H), 5.23 (dd, J = 7.0, 4.6 Hz, 1H), 4.30-4.13 (m,
2H),3.81 (s, 3H), 3.67 (s, 2H), 3.47 (t, J = 6.5 Hz, 2H), 1.97-1.79 (m, 2H),
1.78-1.68 (m, 2H), 1.49-1.37 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
169.91, 169.29, 159.22, 133.51, 129.87, 129.14, 127.61,114.20, 73.86,
55.44, 44.70, 42.70, 41.76, 32.07, 31.10, 22.09; Elementary analysis
calcd. for C22H26ClNO4; C 65.42%, H 6.49%, N 3.47, found C 65.38%, H
6.34%, N 3.37.
1H), 1.95-1.84 (m, 1H), 1.61-1.47 (m, 3H), 1.47-1.35 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 172.09, 138.36, 128.81, 127.93, 127.58, 77.53,
68.45, 42.95, 29.44, 25.79, 23.35; HR ESIMS (M+Na)+ calcd for
C13H17NO2Na 242.1157, found 242.1157; Elementary analysis calcd. for
C13H17NO2; C 71.21%, H 7.81%, N 6.39, found C 71.11%, H 7.69%, N
6.22.
3-Hydroxy-1-(phenyl)azepan-2-on (5c). Colourless oil; (54%, 59 mg,
1
0.27 mmol); Rf 0.26 (CH2Cl2/MeOH, 95:5); H NMR (400 MHz, CDCl3) δ
8.32 (s, 1H), 7.61-7.54 (m, 2H), 7.367.28 (m, 2H), 7.14-7.05 (m, 1H),
4.20-4.06 (m, 1H), 3.89 (dd, J = 11.3, 2.6 Hz, 1H), 3.56 (td, J = 11.4, 3.1
Hz, 1H), 2.26-2.17 (m, 1H), 1.95 (dq, J = 6.9, 2.1 Hz, 1H), 1.60 (tq, J =
9.1, 3.6, 2.7 Hz, 3H), 1.53-1.42 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
170.07, 137.60, 129.09, 124.35, 119.81, 77.55, 68.62, 29.26, 25.75,
23.34; HR ESIMS (M+Na)+ calcd for C12H17NO2Na 228.1000, found
228.0998; Elementary analysis calcd. for C12H15NO2; C 70.22%, H 7.37%,
N 6.82, found C 70.18%, H 7.29%, N 6.77.
1-[(4-Metoxybenzyl)amino]-1-oxo-6-(bromo)hex-2-yl benzoate. To the
3-Hydroxy-1-(cyclohexane)azepan-2-on (5d). Semi-solid; (97%, 102
mg, 0.48 mmol); Rf 0.31 (CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz,
CDCl3) δ 6.43 (s, 1H), 4.06-3.97 (m, 1H), 3.80-3.68 (m, 2H), 3.45 (td, J =
11.3, 3.5 Hz, 1H), 2.15-2.05 (m, 1H), 1.95-1.80 (m, 3H), 1.69 (dt, J = 12.1,
3.7 Hz, 2H), 1.55 (dddd, J = 24.3, 13.2, 5.1, 2.0 Hz, 4H), 1.42-1.26 (m,
3H), 1.22-1.05 (m, 3H); HR ESIMS (M+Na)+ calcd for C12H17NO2Na
234.1470, found 234.1469; Elementary analysis calcd. for C12H21NO2; C
68.21%, H 10.02%, N 6.63, found C 68.15%, H 9.91%, N 6.52.
solution
of
6-hydroxy-1-[(4-methoxybenzyl)amino]-1-oxohexan-2-yl
benzoate (371.4 mg, 1 mmol) in dry THF (10 mL) CBr4 (340 mg, 1.2
mmol). When all of the CBr4 had dissolved, PPh3 (315 mg, 1.2 mmol)
was added and the solution was stirred under nitrogen at room
temperature for 2 hours. At that time the solution was filtered, the filtrate
was concentrated in vacuum. The crude product was purified by column
chromatography using ethyl acetate/hexanes as an eluent to afford the
corresponding product as a colourless oil with 72% yield (313 mg, 0.72
1
mmol); Rf 0.38 (hexanes/EtOAc, 7:3); H NMR (400 MHz, CDCl3) δ 8.04
3-Hydroxy-1-(n-hexane)azepan-2-on (5e). Colourless oil; (93%, 99 mg,
(d, J = 7.1 Hz, 2H), 7.64 – 7.55 (m, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.17 (d,
J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.39 (s, 1H), 5.53 – 5.43 (m,
1H), 4.41 (ddd, J = 33.7, 14.7, 5.8 Hz, 2H), 3.77 (s, 3H), 3.39 (t, J = 6.7
Hz, 2H), 2.10 – 1.98 (m, 2H), 1.97 – 1.86 (m, 2H), 1.67 – 1.54 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 169.42, 165.37, 159.11, 133.68, 129.89,
129.75, 129.17, 128.94, 128.67, 114.16, 74.13, 55.28, 42.73, 33.21,
32.17, 31.05, 23.53; Elementary analysis calcd. for C21H24BrNO4; C
58.07%, H 5.57%, N 3.22, found C 58.02%, H 5.52%, N 3.15.
1
0.47 mmol); Rf 0.32 (CH2Cl2/MeOH, 95:5); H NMR (400 MHz, CDCl3) δ
6.52 (s, 1H), 4.06-3.98 (m, 1H), 3.74 (dd, J = 11.5, 2.5 Hz, 1H), 3.46 (td,
J = 11.3, 3.8 Hz, 1H), 3.30-3.16 (m, 2H), 2.18-2.04 (m, 1H), 1.94-1.81 (m,
1H), 1.60-1.43 (m, 5H), 1.34-1.23 (m, 7H), 0.92-0.81 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.01, 77.55, 68.42, 38.90, 31.59, 29.67, 29.42,
26.68, 25.82, 23.35, 22.64, 14.10; HR ESIMS (M+Na)+ calcd for
C12H17NO2Na 228.1000, found 228.0998; Elementary analysis calcd. for
C12H23NO2; C 67.57%, H 10.87%, N 6.57, found C 67.41%, H 10.72%, N
6.40.
General procedure for the synthesis of N-substituted 3-hydroxy-
lactams (5). To a solution of 4 (0.5 mmol) in dry THF (3 mL) at 0 °C was
added dropwise a suspension of NaH (3 equiv, 60% w/w) in anhydrous
THF (2 mL) over a period of 20 minutes. The mixture was allowed to
warm to room temperature and stirred for 4 hours. The reaction mixture
was quenched with water (5 mL) at 0 °C. The organic layer was
separated and the aqueous layer extracted with ethyl ether (3x20 mL).
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude
product was purified by column chromatography using ethyl acetate/n-
hexanes as an eluent to afford the corresponding product 5.
3-Hydroxy-1-(2-etoxy-2-oxoethyl)azepan-2-on (5f). Colourless oil;
(19%, 21 mg, 0.09 mmol); Rf 0.27 (CH2Cl2/MeOH, 95:5); 1H NMR (400
MHz, CDCl3) δ 7.04 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.10-4.01 (m, 3H),
3.83 (dd, J = 11.3, 2.5 Hz, 1H), 3.49 (td, J = 11.4, 3.1 Hz, 1H), 2.15-2.06
(m, 1H), 1.90 (dtd, J = 7.6, 4.2, 2.0 Hz, 1H), 1.60-1.51 (m, 3H), 1.48-1.37
(m, 1H), 1.29 (t, J = 7.1 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 169.89,
77.34, 68.45, 61.59, 40.86, 29.21, 25.75, 23.27, 14.29; HR ESIMS
(M+Na)+ calcd for C10H17NO2Na 238.1055, found 238.1053; Elementary
analysis calcd. for C10H17NO4; C 55.80%, H 7.96%, N 6.51, found C
55.68%, H 7.84%, N 6.39.
3-Hydroxy-1-(4-methoxybenzyl)azepan-2-on (5a). Colorless oil; (98%,
122 mg, 0.49 mmmo); ); Rf 0.25 (CH2Cl2/MeOH, 95:5); 1H NMR (400
MHz, CDCl3) δ 7.21 (d, J = 8.6 Hz, 2H), 6.90 – 6.83 (m, 2H), 6.78 (s, 1H),
4.46 – 4.30 (m, 2H), 3.99 (dd, J = 11.4, 3.0 Hz, 1H), 3.80 (s, 3H), 3.46
(ddd, J = 14.2, 9.6, 4.3 Hz, 1H), 2.21 – 2.09 (m, 1H), 1.96 – 1.83 (m, 1H),
1.62 – 1.46 (m, 3H), 1.46 – 1.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
171.92, 159.14, 130.47, 129.26, 114.19, 77.50, 68.40, 55.41, 42.40,
29.40, 25.76, 23.33; HR ESIMS (M+Na)+ calcd for C14H19NO3Na
272.1263, found 272.1261; Elementary analysis calcd. for C14H19NO3; C
67.45%, H 7.68%, N 5.62, found C 67.41%, H 7.72%, N 5.49.
3-Hydroxy-1-(tert-butyl)azepan-2-on (5g). Colourless oil; (59%, 55 mg,
0.30 mmmo); Rf 0.30 (CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz, CDCl3) δ
6.40 (s, 1H), 4.23 (t, J = 6.3 Hz, 2H), 3.98 (dd, J = 7.4, 3.7 Hz, 1H), 3.00
(s, 3H), 2.68 (s, 1H), 1.79 (tt, J = 13.5, 5.6 Hz, 3H), 1.64 (dq, J = 19.7,
6.7, 6.2 Hz, 1H), 1.58 – 1.48 (m, 2H), 1.35 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 173.07, 71.74, 70.05, 51.16, 37.53, 34.15, 28.89, 28.86, 20.93;
HR ESIMS (M+Na)+ calcd for C10H19NO2Na 208.1313, found 208.1312;
Elementary analysis calcd. for C10H19NO2; C 64.83%, H 10.34%, N 7.56,
found C 64.77%, H 10.22%, N 7.41.
3-Hydroxy-1-(n-butyl)azepan-2-on (5h). Colourless oil; (95%, 88 mg,
0.46 mmol); Rf 0.29 (CH2Cl2/MeOH, 95:5); H NMR (400 MHz, CDCl3) δ
6.55 (s, 1H), 4.02 (dt, J = 11.7, 2.0 Hz, 1H), 3.76 (dd, J = 11.5, 2.4 Hz,
1H), 3.46 (td, J = 11.2, 3.8 Hz, 1H), 3.25 (q, J = 6.6 Hz, 2H), 2.17-2.07 (m,
3-Hydroxy-1-(benzyl)azepan-2-on (5b). Colourless oil; (54%, 59 mg,
0.27 mmol); Rf 0.28 (CH2Cl2/MeOH, 95:5); H NMR (400 MHz, CDCl3) δ
7.37-7.26 (m, 5H), 6.98-6.71 (m, 1H), 4.46 (d, J = 5.9 Hz, 2H), 4.05-3.93
(m, 1H), 3.83 (dd, J = 11.4, 2.5 Hz, 1H), 3.52-3.43 (m, 1H), 2.21-2.11 (m,
1
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800605
European Journal of Organic Chemistry
FULL PAPER
1H), 1.95-1.82 (m, 1H), 1.60-1.44 (m, 5H), 1.40-1.23 (m, 5H), 0.91 (t, J =
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.21, 129.47, 128.67,
127.23, 77.50, 68.44, 38.64, 31.76, 29.43, 25.82, 23.34, 20.19, 13.86;
HR ESIMS (M+Na)+ calcd for C10H19NO2Na 208.1313, found 208.1313;
Elementary analysis calcd. for C10H19NO2; C 64.83%, H 10.34%, N 7.56,
found C 64.65%, H 10.15%, N 7.51.
temperature under hydrogen pressure (balloon). The catalyst was filtered,
washed with ethyl acetate, and the solvents were removed in vacuum.
The crude product was purified by column chromatography on silica gel
(hexanes/EtOAc) to afford the product as a colourless oil with 99% yield
(179 mg, 0.5 mmol); Rf 0.22 (CH2Cl2/MeOH, 95:5); 1H NMR (400 MHz,
CDCl3) δ 7.21 (s, 5H), 7.05 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H),
6.15 (s, 1H), 5.37 – 5.24 (m, 1H), 4.21 (qd, J = 14.6, 5.8 Hz, 2H), 3.79 (s,
3H), 3.70 – 3.59 (m, 4H), 2.81 (s, 1H), 2.19 – 2.06 (m, 1H), 2.04 – 1.90
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.13, 169.90, 159.11, 133.31,
129.56, 129.04, 129.03, 128.85, 127.49, 114.09, 77.38, 77.06, 76.75,
72.05, 58.49, 55.30, 42.69, 41.45, 34.90; Elementary analysis calcd. for
C20H23NO5; C 67.21%, H 6.49%, N 3.92, found C 67.19%, H 6.40%, N
3.85.
3-Hydroxy-1-(4-methoxybenzyl)-piperidin-2-one (5i). Colourless oil;
(86%, 95 mg, 0.40 mmol); Rf 0.27 (CH2Cl2/MeOH, 95:5); 1H NMR (400
MHz, CDCl3) δ 7.19 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 3H), 4.39 (t,
J = 5.9 Hz, 3H), 3.93-3.76 (m, 5H), 2.37-2.24 (m, 1H), 2.09 (dq, J = 12.8,
6.2 Hz, 1H), 1.88 (tdq, J = 19.2, 14.1, 6.7 Hz, 2H), 1.65 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 173.14, 159.20, 130.41, 129.18, 114.26, 78.67,
69.52, 55.45, 42.54, 30.38, 25.69; HR ESIMS (M+Na)+ calcd for
C14H19NO3Na 272.1263, found 272.1261; HR ESIMS (M+Na)+ calcd for
C13H17NO3Na 258.2728, found 258.2726; Elementary analysis calcd. for
C13H17NO3; C 66.36%, H 7.28%, N 5.95, found C 66.21%, H 7.18%, N
5.87.
3-Hydroxy-1-(4-methoxybenzyl)pyrrolidin-2-one (5j). Compound was
obtained according to general procedure for N-substituted 3-hydroxy-
lactams with 89% yield (98 mg, 0.45 mmol) as a colourless oil; Rf 0.21
1
(CH2Cl2/MeOH, 95:5); H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 9.0 Hz,
2H), 6.87-6.85 (m, 2H), 4.43-4.37 (m, 3H), 4.20-4.19 (m, 1H), 3.79 (s,
3H), 3.25-3.21 (m, 1H), 3.17-3.13 (m, 1H), 2.41-2.38 (m, 1H), 1.95-1.91
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.7, 159.2, 129.5, 127.7, 114.1,
70.1, 55.2, 46.4, 42.8, 27.7; NMR spectra correspond to published
one.[5a]
4-Methylsulphon
5-hydroxy-6-[(4-methoxybenzyl)amino)-6-
oxohehexane. Colourless oil; Rf 0.33 (CH2Cl2/MeOH, 95:5); 1H NMR
(400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H),
7.19 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 3H), 4.37 (d, J = 5.8 Hz, 2H),
4.11 (dd, J =7.7, 3.6 Hz, 1H), 4.01 (t, J = 6.3 Hz, 2H), 3.79 (s, 3H), 2.44
(s, 3H), 1.81 (dtd, J = 13.2, 7.7, 7.1, 3.7 Hz, 1H), 1.72 – 1.57 (m, 3H),
1.47 (td, J = 13.8, 12.6, 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
173.53, 159.23, 144.95, 133.18, 130.19, 130.02, 129.24,127.98, 114.28,
71.77, 70.54, 55.45, 42.82, 34.17, 28.63, 21.76, 21.11; Elementary
analysis calcd. for C15H23NO6S; C 52.16%, H 6.71%, N 4.06, found C
52.02%, H 6.55%, N 3.98.
General procedure for enzymatic kinetic resolution of 4a via
hydrolysis and subsequent lactamization to 5a. To a solution of rac-
4a (0.5 mmol) in PBS/acetone (10%v/v) (100 mM, pH 7.4) (20 mL),
lipase from hog pancreas (20 mg) was added in a 10 mL screw-top vial.
The reaction mixture was stirred for one week at 20 °C. The aqueous
phase was extracted with TBME. The organic phase was dried over
Na2SO4 and the solvent was removed under vacuum. Crude product was
purified by column chromatography on silica gel (n-hexanes/EtOAc)
resulted in enantiomerically enriched 4a (30% ee; 64 mg, 0,14 mmol);
Chiralcel OD-H: hexane/isopropanol (75:25), flow = 1.0 mL/min, λ = 256
4-Methylbenzylsulphon
5-hydroxy-6-[(4-methoxybenzyl)amino)-6-
oxohehexane. Colourless oil; Rf 0.26 (CH2Cl2/MeOH, 95:5); 1H NMR
(400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H),
7.19 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 3H), 4.37 (d, J = 5.8 Hz, 2H),
4.11 (dd, J =7.7, 3.6 Hz, 1H), 4.01 (t, J = 6.3 Hz, 2H), 3.79 (s, 3H), 2.44
(s, 3H), 1.81 (dtd, J = 13.2, 7.7, 7.1, 3.7 Hz, 1H), 1.72-1.57 (m, 3H), 1.47
(td, J = 13.8, 12.6, 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 173.53,
159.23, 144.95, 133.18, 130.19, 130.02, 129.24,127.98, 114.28, 71.77,
70.54, 55.45, 42.82, 34.17, 28.63, 21.76, 21.11; Elementary analysis
calcd. for C21H27NO6S; C 59.84%, H 6.46%, N 3.32, found C 59.72%, H
6.29%, N 3.15.
nm, retention time of the racemic compound (in min): t1 = 37.12, t2
=
51.86. Enantiomerically enriched lactam 5a has been obtained according
to general method with 97% yield and 31% enantiomeric excess;
Chiralcel OD-H: hexane/isopropanol (75:25), flow = 1.0 mL/min, λ = 256
nm, retention time of the racemic compound (in min): t1 = 9.24, t2 = 12.68.
Acknowledgements
1-((4-Methoxybenzyl)amino)-4-((benzylo)oxy)-1-oxohexan-2-yl-2-
phenylacetate. p-Methoxybenzylisocyanide (147.2 mg, 1 mmol) was
added to the suspension of 3-benzyloxypropanal (164.2, 1 mmol) and
phenylacetic acid (136.2 mg, 1 mmol) at room temperature. The reaction
mixture was stirred at ambient temperature for 18 hours. The crude
product was purified by column chromatography on silica gel
(hexanes/EtOAc) to afford the product as a colourless oil with 91% yield
This work was supported by Polish National Science Center
project HARMONIA No. 2014/14/M/ST5/00030.
Keywords: Passerini reaction • multicomponent reaction • 2-
hydroxy lactams • enzymatic reaction• solvent-free
1
(407 mg, 0.91 mmol); Rf 0.38 (hexanes/EtOAc, 7:3); H NMR (400 MHz,
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Key Topic: Multicomponent chemistry
Dominik Koszelewski,* Damian
Trzepizur, Ewelina Zaorska, Arleta
Madej, Anna Brodzka, Daniel Paprocki
and Ryszard Ostaszewski*
The novel synthetic route to α-acyloxy
amides based on P-MCR followed by
transformation into the corresponding
3-hydroxy-lactams has been
Page No. – Page No.
developed. Established protocol was
successfully applied in the synthesis
of various five-, six-, and seven-
membered rings of 3-hydroxy-lactams
which play crucial role in the synthesis
of the number of bioactive
A facile conversion of α-acyloxy
amides into 3-hydroxy-lactams
compounds.
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