Studies on asymmetric synthesis of bicyclomycin precursors. A chemoenzymatic route to chiral 2,5-diketopiperazines and 2-oxa-bicyclo[4.2.2]decane-8,10-diones

Article abstract of DOI:10.1016/j.tetasy.2017.08.004

A novel asymmetric route to bicyclomycin analogues, 2-oxa-bicyclo[4.2.2]decane-8,10-diones, is described. The key chiral synthons 3-(ω-hydroxyalkyl)-2,5-diketopiperazines 3a-c were obtained via enzymatic kinetic resolution of their respective acetates 2a-c using hydrolases (up to >98% ee, E > 200). The chiral 2,5-diketopiperazines were then transformed into their bicyclic derivatives in a stereospecific manner. Circular dichroism and NMR studies were performed to determine the absolute and relative configuration of the obtained products. The biocatalytic approach gave high stereoselectivities in comparison to the chiral pool synthesis from glutamic acid (58% ee) and thus demonstrated the ability of hydrolases to discriminate a remote stereocenter.

Full text of DOI:10.1016/j.tetasy.2017.08.004

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Studies on asymmetric synthesis of bicyclomycin precursors.
A chemoenzymatic route to chiral 2,5-diketopiperazines and
2-oxa-bicyclo[4.2.2]decane-8,10-diones
⇑
Anna Fryszkowska, Dominik Koszelewski, Ryszard Ostaszewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel asymmetric route to bicyclomycin analogues, 2-oxa-bicyclo[4.2.2]decane-8,10-diones, is
Received 5 April 2017
Revised 26 July 2017
Accepted 7 August 2017
Available online xxxx
described. The key chiral synthons 3-( -hydroxyalkyl)-2,5-diketopiperazines 3a-c were obtained via
x
enzymatic kinetic resolution of their respective acetates 2a-c using hydrolases (up to >98% ee, E > 200).
The chiral 2,5-diketopiperazines were then transformed into their bicyclic derivatives in a stereospecific
manner. Circular dichroism and NMR studies were performed to determine the absolute and relative con-
figuration of the obtained products. The biocatalytic approach gave high stereoselectivities in comparison
to the chiral pool synthesis from glutamic acid (58% ee) and thus demonstrated the ability of hydrolases
to discriminate a remote stereocenter.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
methodologies are limited by the cost and the availability of chiral
synthons. Bicyclomycin is
a structurally unique antibiotic
2,5-Diketopierazines are head-to-tail cyclic dipeptides and this
structural motif is frequently present in peptidomimetics with
considerable biological activity,1–4 as well as in many natural
products,5–8 such as bicyclomycin9,10 (Fig. 1). Moreover, they are
important intermediates in the synthesis of amino acids,11,12 piper-
azines13,14 or bicyclic amines.15,16
The synthetic strategies towards chiral non-racemic 2,5-
diketopierazines often take advantage of the chiral pool of amino
acids6,15,17 or chiral auxiliaries.12,18 However, these synthetic
(Fig. 1)9,10 and various approaches towards the synthesis of its
bicyclic skeleton have been reported. Nonetheless there is only
one literature example of the preparation of enantiopure
2-oxa-bicyclo[4.2.2]decane-8,10-dione ring system based on the
physical resolution of its diastereoisomeric derivatives.19
Recently, we reported a novel synthetic route towards racemic
3-x
-hydroxyalkyl-2,5-diketopierazine derivatives 3,20 which are
key intermediates in the synthesis of 2-oxa-bicyclo[4.2.2]decane-
8,10-diones 4 (Scheme 1).8,21 These compounds are used as
building blocks in the synthesis of analogues of bicyclomycin8
and are also known to be potent CNS receptor ligands.1,2 Herein
we report studies on the synthesis of chiral, non-racemic 2,5-dike-
topierazines 2 and 3 and bicyclic ring system 4 (Scheme 1). We
evaluated two routes towards the synthesis of compounds 3: (i)
from chiral amino acids as starting materials and (ii) a chemoenzy-
matic strategy involving kinetic resolution of racemates using
hydrolases. The latter provided an efficient synthesis of 2-oxa-
bicyclo[4.2.2]decane-8,10-diones 4, a remote stereocenter of dike-
topiperazine intermediate, which could be discriminated by an
enzyme (Scheme 1).
OH
R2
O
R1
O
O
HN
O
N
O
NH
N
R3
R4
HO
OH
Me
HO
2,5-diketopiperazine
bicyclomycin
Figure 1. 2,5-Diketopierazine scaffold and the structure bicyclomycin.
2. Results and discussion
In the literature, the preparation of the racemic 2-oxa-bicyclo
[4.2.2]decane-8,10-dione ring 4 of bicyclomycin derivatives is
⇑
Corresponding author.
E-mail address: ryszard.ostaszewski@icho.edu.pl (R. Ostaszewski).
http://dx.doi.org/10.1016/j.tetasy.2017.08.004
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fryszkowska, A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.004

2
A. Fryszkowska et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Ph
Ph
Ph
N
N
O
H
OAc
N
N
O
OAc
O
N
N
O
OH
R2
d
a-b
c
O
R1
N
AcO
+
(
)
n
O
O
N
(
)
n
(
)
n
( )
n
H
O
O
O
C3
*
*
C'1
Ph
R1
4a-c
R1
Ph
R1
Ph
1
2a, n = 1, R1 = H
3a, n = 1, R1 = H
3b, n = 1, R1 = Me
3c
1a
, n = 1
2a
, n = 1, R = H
1b, n = 2
2b, n = 1, R1 = Me
2c, n = 2, R1 = Me
2b, n = 1, R1 = Me
2c, n = 2, R1 = Me
, n = 2, R1 = Me
e
Scheme 1. Chemoenzymatic route to chiral 2,5-diketopiperazines 2a-c and 3a-c, and 2-oxa-bicyclo[4.2.2]decane-8,10-diones 4. Reagents and conditions: (a) ClCH2COOH, Ph
(CH)R1NH2, BnNC, MeOH, 5 d, rt, 62–85%; (b) Cs2CO3, acetonitrile, 2 h, rt, 35–92% (c) acetate (7 mM), enzyme (10–20% mass), phosphate buffer (50 mM, pH 7.4), acetone (25%
vol), 25–50 °C, 12–48 h. (d) N-bromosuccinimide, CHCl3, H2O, 5 h; (e) KOH, MeOH, 30 min, sonication.
achieved via intramolecular cyclisation of a respective alcohol
derivative 3 (Scheme 1).8 Therefore the aim o was to develop an
efficient synthetic route towards enantiopure analogues of 2,5-
diketopierazines 3.
Initially we prepared (S)-N,N’-dibenzyl-3-(3-hydroxypropyl)-
piperazine-2,5-dione 3a in 5 steps from the enantiopure (S)-glu-
tamic acid, as proposed by Weigl and Wünsch2 (see Supplemental
materials, Scheme S1). This protocol provided the product (S)-3a in
10% overall yield and with 59% ee, as racemization was observed
during the synthesis. Thus, we turned our attention to the enzy-
matic approach, since it has been demonstrated that hydrolases
can discriminate a remote stereogenic center,23–25 which is diffi-
cult to achieve in classical asymmetric synthesis.
The enzymatic kinetic resolution of racemates have become a
valuable synthetic tool in organic synthesis.22 We planned to test
the stereoselective enzymatic kinetic resolution of acetates 2a-c
(Scheme 1), which have the stereogenic center five or six bonds
away from the reaction site, with the ester group located on a flex-
ible alkyl chain.
In order to examine the scope of the biocatalytic approach, we
planned to investigate the possibility of the stereoselective enzy-
matic kinetic resolution of (i) racemate 2a, as well as (ii) mixtures
of diastereoisomers with and additional stereogenic center in the
backbone of the compounds 2b-c, which could facilitate chiral
discrimination by enzymes.
acylase, 1 protease and 1 lipoproteinase) for the hydrolysis of acet-
ates 2a-b (Table 1). The absolute configuration of alcohol 3a was
assigned by chiral HPLC by the comparison with alcohol (S)-3a
obtained from (S)-glutamic acid (59% ee). The relative configura-
tions of the diastereoisomeric compounds 2-3b were assigned by
1H NMR spectroscopic analysis.
A high concentration of acetone (25% v/v) was necessary to sol-
ubilize the substrates. Despite the fact that the ester group is
located on a flexible linker, the screening revealed that only 6
enzymes showed activity towards the substrates 3 (Table 1, the
inactive enzymes are not listed). Moreover, the stereoselectivity
and specificity of the enzymes was profoundly affected by the sec-
ond stereogenic center at C10 (2b). The immobilized Candida antarc-
tica type B lipase (Novozym 435, Table 1, entry 2) showed a
stereopreference for hydrolysis of (3S)-enantiomer of ester 2a,
however the enantioselectivity obtained was low (E = 6). The
(3S)-stereopreference of Novozym 435 remained unchanged in
the reaction with diastereoisomers 2b, but the diastereoselectivity
obtained was much higher (D = 22). Lipoproteinase from Chro-
mobacterium viscosum (Table 1, entry 1) exhibited the opposite
(3R)-stereoselectivity and excellent enantioselectivity (E = 27) with
the acetate 2a. The presence of the second stereogenic center in
substrate 2b led to an almost complete loss of diastereoselectivity
(D = 1). Lipases from Pseudomonas cepacia, Pseudomonas fluorescens
and Pseudomonas sp. (Entries 3–5, Table 1), showed moderate
activity and enantioselectivity for compound 2a (E = 6–7), while
no activity was detected towards compound 2b. The lipoproteinase
from Pseudomonas sp. (Entry 6, Table 1), proved to be highly active
towards 2a, but the enantioselectivity was low (E = 1). Two other
enzymes: Rhizopus arrhizus lipase and Aspergillus melleus acylase
exhibited low activity towards 2b (conversion 4%) and low
Acetates 2a-c and the respective racemic alcohols 3 were
synthesized in 2-steps and 30–40% yield from the respective
x
-acetoxyalkyl-aldehydes 1a-b, chloroacetic acid, benzylamine or
(S)-phenylethyl amine and benzyl isonitrile via Ugi reaction, fol-
lowed by base-assisted cyclisation, as reported previously
(Scheme 1).20 We screened a small library of commercially avail-
able hydrolases (9 native and 6 immobilized lipases, 1 esterase, 1
Table 1
Evaluation of hydrolase stereoselectivity in kinetic resolution of the acetate derivatives 2a-ba
Entry
Enzyme
cb [%]
2a
3a
Ed
ce [%]
2b
3b
Dd
% eec (conf.)
%ee (conf.)
% dee (conf.)
% dee (conf.)
1
2
3
4
5
6
Chromobacterium viscosum lipoproteinase
Novozym 435
Pseudomonas cepacia lipase
Pseudomonas fluorescens lipase
Pseudomonas sp. lipase
56
41
29
36
29
98
90 (S)
56 (R)
4 (S)
16 (S)
8 (S)
80 (R)
53 (S)
75 (R)
72 (R)
69 (R)
8 (R)
27
6
7
7
6
45
29
ꢀ3
ꢀ3
ꢀ3
ꢁ
7 (1S,3S)
45 (1S,3R)
11 (1S,3R)
87 (1S,3S)
ꢁ
ꢁ
ꢁ
ꢁ
1
22
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
Pseudomonas sp. lipoproteinase
1 (S)
1
ꢁ
a
b
c
2a-b (7 mM), acetone (25%vol.), phosphate buffer pH = 7.4, enzyme (20%mass), 40 °C, 24 h.
Determined by 1H NMR.
By HPLC on Chiralcel OD column.
E (and D respectively) was calculated using the formula: E = ln[(eeP(1–eeS)/(eeP+eeS)]/ln[eeP(1 + eeS)/(eeP+eeS)].
Determined by HPLC.
d
e
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A. Fryszkowska et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 2
The influence of solvent on the kinetic resolution of the acetate 2b catalyzed by Novozym 435a
Entry
Solvent
cb [%]
(10S,3R)-2b % deb
(10S,3S)–3b % deb
Dc
1
2
3
4
5
6
Acetone
EtOH
Acetonitrile
Dioxane
MeOH
30
28
33
32
31
22
40
27
17
26
21
8
88
85
86
84
69
70
21
16
15
15
7
DMSO
6
a
b
c
2b (7 mM), solvent (25%vol), phosphate buffer pH = 7.4, Novozym 435 (20%mass), 44 °C, 24 h.
By HPLC.
D was calculated using the formula: D = ln[(deP(1-deS)/(deP+deS)]/ln[deP(1 + deS)/(deP+deS)].
diastereoselectivity (D ꢀ 3, data not shown), while the rest of the
tested biocatalysts proved inactive.
We subsequently optimized the reaction conditions for Novo-
zym 435 (Table 2) by testing various co-solvents and temperatures
with substrate 2b (Tables 2 and 3, respectively)
The best disatereoselectivities were obtained in acetone
(Table 2, entry 1) and at room temperature (D = 34), although a
higher co-solvent volume and prolonged reaction times were
required (Table 3, entry 1).
When scaling up to 400 mg and applying Novozym 435 as the
catalyst, the reaction conducted at 26 °C reached 50% conversion
after 68 h to give acetate (10S,3R)-2b with 89% de and alcohol
(10S,3S)-3b with 93% de (D = 83, Table 4, Entry 3). When the same
conditions were applied to the resolution of diastereoisomeric
homologue 2c with an elongated alkyl chain (n = 2, Scheme 1), it
gave low diastereoselectivity (D = 5) and the hydrolysis furnished
the acetate (10S,3R)-2c with 42% de and the respective alcohol
(10S,3S)-3c with 51% de (54% conversion, 43 hours) (Table 4, entry 4).
We used lipoproteinase from Chromobacterium viscosum at 35 °C
to resolve racemic acetate 2a to give alcohol (R)-3a with ꢂ98% ee
and 45% yield and unreacted acetate (S)-2a with 77% ee in 7 h
(E ꢂ 200) (Table 4, entry 1). The acetate (S)-2a was converted into
alcohol (S)-3a (75% ee) with a slight loss in enantiomeric excess
(Scheme 1). The complementary enantiomer of alcohol (S)-3a was
obtained with 51% ee when Novozym 435 was applied for the
kinetic resolution of the racemic acetate 2a (Table 4, entry 2).
Our studies revealed that not only were the hydrolases able to
resolve the C3 stereogenic center of the esters 2a, but also that
the presence of the exo-cyclic stereo center at C’1 considerably
changed enzymatic specificity and selectivity. This result was
somewhat unexpected, especially since that the ester group, which
undergoes the hydrolysis, is located on the alkyl chain with unre-
stricted conformational flexibility, 4–5 bonds remote from the
diketopiperazine ring. It is possible that the methyl group at C1
may have a steric effect or it could induce conformational rigidity
to affects enzymatic activity.
0
Next, we studied the cyclisation of alcohols 3 to 2-oxa-bicyclo
[4.2.2]decane-8,10-diones
4 (Scheme 1). Oxidative cyclisation
using N-bromosuccinimide on similar compounds has been
described to furnish the bicyclic ethers in good yields under mild
conditions.6,8,21,26–29
We found that in absolute chloroform, the intramolecular
cyclisation of alcohol 3b (dr 50:50) with N-bromosuccinimide
was disfavored leading to the formation
x-bromopropyl deriva-
tive (SN2 reaction) as the main product. In contrast, when we
applied biphasic chloroform:water (6:1) conditions to favor the
SN1 reaction, the cyclisation gave the 2-oxa-bicyclo[4.2.2]de-
cane-8,10-diones 4b in 46% isolated yield (dr 50:50 by mass).
The diastereoisomeric products 4b could be easily separated by
column chromatography to give the less polar diastereoisomer
(1R,6R,10S)-4b and the more polar diastereoisomer (1S,6S,10S)-4b.
The reaction using enriched diastereoisomeric mixture (10S,3R)-3b
Table 3
The influence of temperature on the kinetic resolution of the acetate 2b catalyzed by Novozym 435a
cb [%]
(10S,3R)-2b% deS
(10S,3S)-3b% deP
Dc
b
b
Entry
Temp. [°C]
t[h]
1
2
3
4
5
6
7
22d
32
76
72
32
76
19
19
19
54
60
56
ꢀ5
28
ꢀ4
16
78
87
56
ꢁ
87
81
87
ꢁ
34
27
25
ꢁ
42
42e
52
38
ꢁ
84
ꢁ
16
ꢁ
52e
62
7
26
2
a
b
c
2b (7 mM), acetone (25%vol), phosphate buffer pH = 7.4, Novozym 435 (20%mass).
By HPLC.
D was calculated using the formula: D was calculated using the formula: D = ln[(deP(1-deS)/(deP+deS)]/ln[deP(1 + deS)/(deP+deS)].
30%vol. of acetone was added.
Blank reaction, no enzyme.
d
e
Table 4
Reaction times and temperatures for enzymatic hydrolysis of acetates 2 in preparative scale
Entry
2
Enzyme
Temp. [°C]
t [h]
Conv. [%]
Acetate 2
Alcohol 3
Purity (conf.)a
Purity (conf.)a
1
2
3
4
2a
2a
2b
2c
Chromobacterium viscosum lipoproteinase
Novozym 435
Novozym 435
35
26
26
26
7
24
68
43
44
48
50
54
77% ee
51% ee
89% de
42% de
(3S)
(3R)
(1S,3R)
(1S,3R)
ꢂ98% ee
63% ee
93% de
51% de
(3R)
(3S)
(1S,3S)
(1S,3S)
Novozym 435
a
The CD and UV data for the alcohols 3a-b are presented in Figure S3 and in Table S3 (Supplemental materials).
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2.0%
HB
1.1%
AcO
HB
2.9%
C3
2.9%
CH3A
1.6%
3.2%
CH3A
C6
C5
C6
C5
HC
C3
HD
HC
HD
O
O
HB
AcO
2.0%
HB
2b
2b
(1'S,3S)-
(1'S,3R)-
less polar
more polar
Figure 2. Newman projections of the compounds (10S,3R)-2b (less polar, left) and (10S,3S)-2b (more polar, right) based on molecular mechanic optimized lowest-energy
conformation of both diastereoisomers. Shielding effect of the phenyl group on the alkyl chain protons HB and on the proton HC is marked with double arches. NOE effects are
represented with the arrows.
Table 5
Chemical shifts and the multiplicity of the most characteristic signals in 1H NMR spectra of diastereoisomers 2b and 4b
Entry
Compound
Chemical shifts d (ppm) and multiplicity of the signals
HA CH3-(C-10)
HB (OCH2)
HC CH-(C-3)
HD H-(C-10)
1
2
3
4
(10S,3R)-2ba
1.59 (d)
1.64 (d)
1.56 (d)
1.62 (d)
3.67 (t)
4.05 (t)
3.98 (dd)
3.74 (dd)
4.20 (dd)
3.93 (dd)
5.92 (q)
5.79 (q)
5.95 (q)
5.87 (q)
(10S,3S)-2bb
(10S,1R,6R)-4ba
(10S,1S,3S)-4bb
3.18–3.30 (m); 3.70–3.82 (m)
3.34–3.46 (m); 3.85–3.95 (m)
a
Less polar (TLC).
More polar (TLC)
b
(71% de) gave bicyclic ether 4b in 49% yield as a mixture of
diastereoisomers (65% de).
from the less polar counterpart. Thus, one can conclude that they
possess the same relative configurations.
Subsequently, both enantiomers of alcohol 3a: (R)-3a, ꢂ98% ee
and (S)-2a, 77% ee, were converted into the respective bicyclic
ethers (1R,6R)-4a (>98% ee) and (1S,6S)-4a (75% ee), respectively
in approximately 50% yield (ee determined by HPLC using Chiral-
pak AD column, for details see Supplemental materials).
The circular dichroism spectra of the alcohols 3a and ethers 4a
confirmed the mirror image relationship between the obtained
enantiomers (see Supplemental materials, Figs. S4, S5 and Tables
S3, S4).
In order to assign the relative and absolute configurations to the
diastereoisomeric products, we hoped to use circular dichroism
(for the detailed UV and CD data see Supporting materials,
Figs. S4, S5 and Tables S3, S4). For further studies, both
diastereoisomers of alcohol 3b and acetates 2b were required:
the alcohol (10S,3S)-3b (83% de) was transformed into a respective
acetate (10S,3S)-2b (80% de) in reaction with acetic anhydride in
62% yield, whereas compound (10S,3R)-2b (60% de) was quantita-
tively hydrolyzed to (10S,3R)-3b (71% de) by KOH catalyzed reac-
tion in MeOH. The differences in de can be attributed to the
purification procedures (by flash chromatography).
The CD spectra and the Cotton effects observed for the
diastereoisomeric pairs of compounds 2b-c, 3b-c and 4b did not
allow for an unambiguous assignment of the absolute configura-
tion (see Supplemental materials). Therefore, we assigned the rel-
ative configuration of the diastereoisomeric compounds 2–4 using
1H NMR and NOE effects. The most characteristic NMR signals of
acetates 2b and 4b are shown in Table 4 and the NOE effects for
diastereoisomers 2b are represented in Fig. 2 (for details see Sup-
plemental materials, Tables S1, S2 and Figs. S2, S3).
The signals of the proton HC and HD of less polar diastereoiso-
mers are shifted downfield in comparison to their more polar
counterparts (Dd 0.24–0.30 ppm, Entries 1 vs. 2 and Entries 3 vs.
4 Table 5). In contrast, the signals of the protons of acyl and methy-
lene groups of the alkyl chain (HB), are shifted upfield. The analo-
gous differences were observed for the spectra of
diastereoisomers of 2-oxa-bicyclo[4.2.2]decane-8,10-diones 4b.
In order to gain more information about the observed differ-
ences, NOE experiments were recorded for both of diastereoiso-
mers 2b (Fig. 2) with the lowest energy calculated using Chem3D
software equipped with molecular mechanics MM2 force filed
and MMFF94 to perform molecular dynamics (for details see Sup-
plemental materials, Fig. S1). The NOE effects were observed
between HC, HA and HD. for both diastereoisomers. However, for
the less polar diastereoisomer, a medium positive NOE effect
between HB and HA protons was observed, while no such effect
was present in the spectrum of the other diastereoisomer. These
protons can be in spatial proximity only for (10S,3S) or (10R,3R)
diastereoisomers, while such an NOE effect would not be possible
for (10R,3S) or (10S,3R) diastereoisomers. This corroborated the dif-
ferences observed in proton spectra (changes in d due to shielding
effect of the phenyl group).
The NMR spectra suggest that the diastereoisomers must adopt a
preferred conformation(s), resulting from restricted rotational free-
dom induced by substituents at N-atoms, hence observed differ-
ences. It has been previously established that the minimum
energy conformation of 3-substituted-2,5-diketopiperazines is a
boat conformation12,30,31 with the substituents at the axial/
pseudo-axial position, away from the carbonyl oxygen.12
Furthermore, the NMR12,18 and X-ray data17 of 2,5-diketopierazines
demonstrate that the configuration of exocyclic substituents has an
influence on the restricted conformational mobility of these
The analysis of the proton spectra of the diastereoisomeric 2–4
revealed that all less polar diastereoisomers possess the same
characteristic pattern of 1H NMR spectra, significantly differing
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A. Fryszkowska et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
molecules and the C-5 carbonyl group results in HD accommodating
syn-periplanar position, as depicted in Figure 2. These
lipases were purchased from Sigma. All other enzymes used herein,
Chromobacterium viscosum lipoproteinase, Candida rugosa lipase,
Candida cylindracea lipase, Penicillium roqueforti lipase, Mucor
javanicus lipase, wheat germ lipase, Aspergillus melleus lipase;
Aspergillus oryzae lipase; Porcine Liver Esterase, Pseudomonas sp.
lipoporteinase, were purchased as an enzyme kit from Fluka. All
chemicals were obtained from common chemical sources. The sol-
vents were of analytical grade. Dried solvent were prepared accord-
ing to typical laboratory methods.32 Racemic 3-substituted
diketopiperazines 2 and 3 were prepared as we described before.20
Enantiomeric excesses were determined by HPLC analyses using
Chiralcel OD-H (4.6 mm / ꢄ 250 mm, from Diacel Chemical Ind.,
Ltd.) 2a and 3a and Chiralpak AD-H (4.6 mm / ꢄ 250 mm, from Dia-
cel Chemical Ind., Ltd.) columns 4a equipped with a pre-column
a
conformations explain the differences observed in chemical shifts
observed in the proton spectra of both diastereoisomers. For both
of the conformations, the benzyl proton HD of (S)-1-phenyl-ethyl
substituent adopts a syn-periplanar position with respect to the car-
bonyl group C-5, whereas the alkyl substituent at C-3 carbon atom
is in an axial or pseudo-axial position for (10S,3S)-2b and (10S,3S)-2b,
respectively. For the diastereoisomer (10S,3R)-2b a strong anisotro-
pic effect on the protons of alkyl chain should be observed and the
signals of these protons should be shifted upfield. Conversely, for
the diastereoisomer (10S,3S)-2b HC (C-3) proton should be the phe-
nyl ring shielding cone, thus its signal should be in the upper field
than for the counterpart. On the basis of the above analysis and
the data in Table 5, it is evident that more polar diastereoisomers
have HC protons more shielded.
The assignment of the absolute configuration was straightfor-
ward, as (S)-phenylethyl amine was used in the synthesis of
2b-c. Thus, the absolute configuration of bicyclo[4.2.2]decane-
8,10-diones 4b was assigned as (10S,1R,6R) for the less polar
diastereoisomer of 4b, and (10S,1S,6S) for the more polar
counterpart.
(4 mm / ꢄ 10 mm, 5
3b-c were determined by HPLC analyses using a Kromasil, Si 60 col-
). Racemic substrates for enzymatic
l) Diastereoisomeric excesses for 2b-c and
umn (4 mm / ꢄ 250 mm, 7
l
reactions 2a-c and model racemic alcohols 3a-c were obtained as
described previously.20
4.2. Typical experimental procedure for the enzymatic kinetic
resolution. General procedure 1
3. Conclusion
Acetate 2 (0.206 mmol) dissolved in acetone (8 mL) was added
dropwise to a phosphate buffer (50 mM, pH 7.4, 21.5 mL). Enzyme
(20%mass for Novozym 435 and 10% mass for Chromobacterium vis-
cosum lipoproteinase) was added and the reaction was agitated at
120 rpm. The enzyme was filtered off through a Celite plug. The
solution was extracted with EtOAc (3 ꢄ 30 mL), and the combined
organic phases were dried (MgSO4) and the solvent was evapo-
rated in vacuum to give a crude mixture of products 2 and 3. The
products were separated on a silica gel column, using hexane:
EtOAc, 6:4 and CHCl3:MeOH, 100:2 to obtain 2 and 3, respectively.
The conversions were determined by 1H NMR analysis of the crude
reaction mixtures. The ee of the products 2-3a was determined by
HPLC analysis using a Chiralcel OD-H column: hexane:i-PrOH:CF3-
We have developed
a concise asymmetric route to both
enantiomers of 2-oxa-bicyclo[4.2.2]decane-8,10-diones 4a-b and
3-substituted-2,5-diketopiperazines 2–3. The key step, the kinetic
enzymatic resolution of derivatives 2a-c demonstrates the ability
of hydrolytic enzymes to control a remote stereocenter (4 or 5
bonds away from the reaction site). We observed a significant
influence of the second, exocyclic stereogenic center on the enzy-
matic stereoselectivity and activity. Lastly, we demonstrated that
alcohols 3 can be converted into 2-oxa-bicyclo[4.2.2]decane-
8,10-diones 4 with no loss in enantiomeric purity, which to the
best of to our knowledge is the first example of the synthesis of
optically active bicyclo[4.2.2]decane-8,10-diones 4.
COOH, 65:35:0.4, 0.35 mL/min at
a = 254 nm. For compounds 2b
and 3b, the des and conversions were determined by HPLC analysis
using a Kromasil, Si 60 column (Table 4).
4. Experimental
4.1. General
4.2.1. Preparation of (3S)-1,4-dibenzyl-3-(3-acetoxypropyl)-
piperazine-2,5-dione (3S)-2a
This compound was obtained according to General procedure 1
in reaction catalyzed by Chromobacterium viscosum lipoproteinase
NMR spectra were recorded in CDCl3 with TMS as an internal
standard, using a 200 MHz Varian Gemini 200 spectrometer. NOE
experiments were performed using a 500 MHz Bruker DMX 500
Advance spectrometer. Chemical shifts are reported in ppm and
coupling constants (J) are given in hertz (Hz). MS spectra were
recorded on an API-365 (SCIEX) apparatus. IR spectra were recorded
in CHCl3 on a Perkin Elmer FT-IR Spectrum 2000 apparatus. Optical
rotations were measured in 1-dm cell of 1 mL capacity using Jasco
DIP-360 polarimeter operating at 589 nm. CD spectra were mea-
sured using a JASCO J-715 spectropolarimeter in 1-cm and 1-mm
cells in acetonitrile at the concentrations of approximately
(10%mass) in 54% yield: colorless oil; 77% ee; [a]
28 = +13.7 (c 0.51,
D
CH2Cl2); Rf = 0.37 (hexane:EtOAc, 6:4); 1H NMR d 1.51–1.70 (m,
2H), 1.71–2.00 (m, 2H), 2.10 (s, 3H), 3.80–4.18 (m, 5H), 4.15 (d,
J = 15.0 Hz, 1H), 4.45 (d, J = 14.4 Hz, 1H), 4.88 (d, J = 14.4 Hz, 1H),
5.26 (d, J = 14.9 Hz, 1H), 7.20–7.50 (m, 10H); 13C NMR d 21.1,
24.0, 28.7, 47.6, 49.2, 40.7, 59.2, 63.5, 128.3, 128.4, 128.5, 129.1,
135.3, 135.5, 164.2, 166.0, 171.1; ESI–MS: m/z = 417 ([M+Na]+,
100%), 395 ([M+H]+, 4%); ESI–MS HR: m/z calcd for [M+Na]+,
C23H26N2O4Na: 417.1785; UV–VIS kmax (e; MeCN): 257 (420), 209
2ꢃ10ꢁ4 M. HPLC analyses were performed using
a LaCHrom
(16 500). HPLC analysis parameters: Chiralcel OD-H, hexane:
i-PrOH:CF3COOH, 8:2:0.05; tR (S)-2a = 28.1 min. tR (R)-2a =
30.0 min. All spectroscopic data were in accordance with data
reported previously.20
Merck-Hitachi apparatus with L-150 pump, equipped with a
Waters 486 Tunable Absorbance detector and ChromaX analyzer.
Elemental analyses were performed on CHN Perkin-Elmer 240
apparatus. Melting points are uncorrected. All reactions were mon-
itored by TLC on Merck silica gel plates 60 F254. Column chro-
matography was performed on Merck silica gel 60/230-400 mesh.
Novozym 435 (Candida antarctica lipase type B) was purchased
from Novo Nordisk; Chirazyme L-2, c.-f., C3, lyo. (Candida antarctica
lipase type B), Chirazyme L-2, c.-f., C2, lyo. (Candida antarctica lipase
type B) were purchased from Roche, Amano AK and Amano PS
4.2.2. Preparation of (3R)-1,4-dibenzyl-3-(3-acetoxypropyl)-
piperazine-2,5-dione (3R)-2a
This compound was obtained according to General procedure 1
in a reaction catalyzed by Novozym 435 (20%mass) in 52% yield: col-
orless oil; 51% ee; [
were the same as those obtained for (3S)-2a.
a
]
28 = ꢁ12.3 (c 0.89, CH2Cl2); spectroscopic data
D
Please cite this article in press as: Fryszkowska, A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.004

6
A. Fryszkowska et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.2.3. Preparation of 1-benzyl-(3R)-3-(3-acetoxypropyl)-4-((10S)-
1-phenylethyl)-piperazine-2,5-dione (10S,3R)-2b
Rf = 0.14 (hexane:i-PrOH, 8:2); 1H NMR d 0.80–2.00 (m, 6H), 1.63
(d, J = 7.1 Hz, 3H), 3.58 (t, J = 6.0 Hz, 2H), 3.73 (dd, J = 4.1 Hz,
J = 8.7 Hz, 1H), 3.78 (d, J = 17.4 Hz, 1H), 4.00 (d, J = 17.2 Hz, 1H),
4.38 (d, J = 14.4 Hz, 1H), 4.71 (d, J = 14.5 Hz, 1H), 5.78 (q,
J = 7.1 Hz, 1H), 7.10–7.40 (m, 10H); 13C NMR d 17.7, 21.3, 32.3,
34.1, 49.5, 49.7, 52.6, 57.4, 62.3, 127.3, 128.1, 128.2, 128.3, 128.8,
129.0, 135.5, 138.9, 164.9, 166.9. All spectroscopic data were in
accordance with data reported previously.20
This compound was obtained according to General procedure 1
in a reaction with Novozym 435 in 46% yield: colorless oil; 89% de;
Rf = 0.47 (hexane:i-PrOH, 8:2); 1H NMR (500 MHz) d 0.80–1.60 (m,
4H), 1.59 (d, J = 7.1 Hz, 3H), 1.95 (s, 3H), 3.67 (q, J = 6.2 Hz, 2H),
3.78 (d, J = 17.3 Hz, 1H), 3.91 (d, J = 17.3 Hz, 1H), 3.98 (dd,
J = 3.7 Hz, J = 9.6 Hz, 1H), 4.29 (d, J = 14.5 Hz, 1H), 4.86 (d,
J = 14.5 Hz, 1H), 5.92 (q, J = 7.1 Hz, 1H), 7.17–7.50 (m, 10H); 13C
NMR (50 MHz) d 16.2, 21.0, 24.4, 30.0, 49.6, 49.9, 51.4, 56.8, 63.4,
128.1, 128.3, 128.4, 128.8, 129.1, 135.5, 139.4, 164.5, 166.7,
4.3. KOH-catalyzed hydrolysis of the acetates 2 to alcohols 3.
General procedure 2
170.8; UV–VIS kmax (e; MeCN): 257 (490), 208 (25 500). All spectro-
scopic data were in accordance with data reported previously.20
A solution of acetate 2 (0.15 mmol) in MeOH:H2O (9:1, 8 mL)
was treated with KOH (0.30 mmol, 18 mg). The reaction mixture
was sonicated for 20 min. at rt, then brine (5 mL) was added and
the residue was extracted with CH2Cl2 (3 ꢄ 10 mL). The combined
organic layer was washed with brine (30 mL), dried (MgSO4) and
the solvent was evaporated in vacuo. The product was purified
on a silica gel column (hexane:i-PrOH, 8:2).
4.2.4. Preparation of benzyl-(3R)-3-(4-acetoxybutyl)-4-((10S)-1-
phenylethyl)-piperazine-2,5-dione (10S,3R)-2c
This compound was obtained according to General procedure 1
in a reaction with Novozym 435 in 54% yield: colorless oil; de 42%;
Rf = 0.48 (hexane:i-PrOH, 8:2); 1H NMR d 0.80–1.80 (m, 6H), 1.59
(d, J = 7.3 Hz, 3H), 2.00 (s, 3H), 3.70–4.15 (m, 5H), 4.29 (d,
J = 14.5 Hz, 1H), 4.84 (d, J = 14.5 Hz, 1H), 5.90 (q, J = 7.1 Hz, 1H),
7.17–7.50 (m, 10H); 13C NMR d 16.2, 21.4, 28.0, 32.6, 34.1, 49.6,
49.9, 51.4, 57.1, 63.9, 128.1, 128.3, 128.4, 128.8, 129.0, 135.5,
139.4, 164.8, 166.5, 171.1. All spectroscopic data were in accor-
dance with data reported previously.20
4.3.1. Preparation of (3S)-1,4-dibenzyl-3-(3-hydroxypropyl)-
piperazine-2,5–dione (3S)-3a
This compound was prepared 65% yield, according to General
procedure 2 from the acetate (3S)-2a (77% ee), obtained via hydrol-
ysis catalyzed by Chromobacterium viscosum, 75% ee, [
(c 0.52, CH2Cl2). Alternatively, (3S)-3a (63% ee) was obtained
according to General procedure in reaction catalyzed by
a]
28=+4.8
D
4.2.5. Preparation of (3R)-1,4-dibenzyl-3-(3-hydroxypropyl)-
piperazine-2,5–dione (3R)-3a
1
Novozym 435 (20%mass). Colorless oil; Rf = 0.32 (hexane:i-PrOH,
8:2); spectroscopic data were the same as those obtained for
(3R)-3a.
This compound was obtained according to General procedure 1
in a reaction catalyzed by Chromobacterium viscosum lipopro-
teinase (10%mass) in 44% yield: >98% ee; [
a
]
D
28 = ꢁ9.7 (c 0.52, CH2-
Cl2). Alternatively (3R)-3a (51% ee) was prepared in 96% yield
according to General procedure 3 from (3R)-2a (51% ee) obtained
in enzymatic hydrolysis catalyzed by Novozym 435. Colorless
oil;; Rf = 0.32 (hexane:i-PrOH, 8:2); 1H NMR d 1.20–1.60 (m, 2H),
1.70–2.00 (m, 2H), 2.50 (brs, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.71–
3.98 (m, 3H), 3.97 (d, J = 14.7 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H),
4.70 (d, J = 14.4 Hz, 1H), 5.12 (d, J = 14.9 Hz, 1H), 7.14–7.40 (m,
10H); 13C NMR d 27.4, 28.6, 47.4, 49.1, 59.6, 59.1, 61.8, 128.1,
128.3, 128.4, 129.0, 129.1, 135.1, 135.5, 164.2, 166.5; ESI–MS:
m/z = 376 ([M+Na]+, 8%), 375 ([M+Na]+, 100%), 353 ([M+H]+,
40%); ESI–MS HR: m/z calcd for [M+Na]+, C21H24N2O3Na:
4.3.2. Preparation of 1-benzyl-(3R)-3-(3-hydroxypropyl)-4-((10S)-
1–phenyl-ethyl)-piperazine-2,5–dione (10S,3R)-3b
This product (10S,3R)-2b was synthesized according to General
procedure 2 from the acetate (10S,3R)-2b (60% de) in 62% yield: col-
orless oil; 71% de; Rf = 0.25 (hexane:i-PrOH, 8:2); 1H NMR d 0.80–
1.90 (m, 5H), 1.59 (d, J = 7.1 Hz, 3H), 3.28 (t, J = 6.0 Hz, 2H), 3.76
(d, J = 17.2 Hz, 1H), 3.92 (d, J = 17.1 Hz, 1H), 4.12 (dd, J = 3.8 Hz,
J = 8.7 Hz, 1H), 4.30 (d, J = 14.5 Hz, 1H), 4.81 (d, J = 14.4 Hz, 1H),
5.89 (q, J = 7.1 Hz, 1H), 7.16–7.50 (m, 10H); 13C NMR d 16.3, 21.3,
32.3, 49.5, 49.7, 51.4, 57.4, 62.4, 127.4, 128.2, 128.3, 128.4, 128.8,
128.9, 135.6, 139.0, 164.6, 166.9; UV–VIS kmax (e; MeCN): 257
375.1684; Found: 375.1699; UV–VIS kmax (e; MeCN): 257 (420),
(380), 204 (17 600). All spectroscopic data were in accordance with
209 (16 500). All spectroscopic data were in accordance with data
reported previously for the racemic compound 3a.20,21 HPLC anal-
ysis parameters: Chiralcel OD, hexane:i-PrOH:CF3COOH, 8:2:0.05;
tR (S)-3a = 19.1 min.; tR (R)-3a = 21.9 min.
data reported previously.20
4.4. Preparation of 1-benzyl-(3S)-3-(3-acetoxypropyl)-4-((10S)-
1-phenylethyl)-piperazine-2,5–dione (10S,3S)-2b
4.2.6. Preparation of 1-benzyl-(3S)-3-(3-hydroxypropyl)-4-((10S)-
1-phenylethyl)-piperazine-2,5–dione (10S,3S)-3b
To a solution cooled to 0 °C of alcohol (10S,3S)-3b (0.09 mmol,
89% de), DMAP (cat.) and pyridine (100
drous dichloromethane (3 mL), acetic anhydride (100
l
l, 1.24 mmol) in anhy-
This compound was obtained according to General procedure 1
in a reaction with Novozym 435 in 50% yield: colorless oil; 93% de;
Rf = 0.15 (hexane:i-PrOH, 8:2); 1H NMR d 0.80–2.20 (m, 5H), 1.64 (d,
J = 7.2 Hz, 3H), 3.56 (t, J = 5.2 Hz, 2H), 3.80 (d, J = 17.2 Hz, 1H), 3.82
(dd, J = 4.0 Hz, J = 9.3 Hz, 1H), 4.01 (d, J = 17.4 Hz, 1H), 4.41 (d,
J = 14.5 Hz, 1H), 4.67 (d, J = 14.5 Hz, 1H), 5.79 (q, J = 7.1 Hz, 1H),
7.17–7.50 (m, 10H); 13C NMR d 17.6, 28.0, 30.9, 49.5, 49.7, 52.5,
57.0, 62.0, 127.3, 128.2, 128.3, 128.8, 129.0, 135.5, 139.1, 164.9,
ll,
1.05 mmol) was added dropwise. After stirring for 3 h at rt, the
mixture was washed with HClaq (1 M, 2 mL), the organic layer
was dried (MgSO4) and the solvent was evaporated. Acetate
(10S,3S)–2b was purified on a silica gel column to give a colorless
oil (56%): 80% de; Rf = 0.42 (hexane:i-PrOH, 8:2); 1H NMR
(500 MHz) d 1.20–2.00 (m, 4H), 1.63 (d, J = 7.2 Hz, 3H), 2.04 (s,
3H), 3.74 (dd, J = 3.6 Hz, J = 9.3 Hz, 1H), 3.81 (d, J = 17.4 Hz, 1H),
3.98 (d, J = 17.4 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 4.39 (d,
J = 14.5 Hz, 1H), 4.71 (d, J = 14.5 Hz, 1H), 5.79 (q, J = 7.2 Hz, 1H),
7.19–7.40 (m, 10H); 13C NMR (50 MHz) d 17.6, 21.0, 24.4, 30.8,
49.5, 49.7, 52.6, 57.0, 63.5, 127.3, 128.0, 128.3, 128.8, 129.1,
167.1; UV–VIS kmax (e; MeCN): 257 (590), 202 (29 900). All
spectroscopic data were in accordance with data reported
previously.20
4.2.7. Preparation of benzyl-(3S)-3-(4-hydroxybutyl)-4-((10S)-1-
phenylethyl)-piperazine-2,5–dione (10S,3S)-3c
135.5, 139.8, 164.8, 166.5, 171.0; UV–VIS kmax (e; MeCN): 257
(590), 204 (23 200). All spectroscopic data were in accordance with
This compound was obtained according to General procedure 1
in a reaction with Novozym 435 in 44% yield: colorless oil; 51% de;
data reported previously.20
Please cite this article in press as: Fryszkowska, A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.004

A. Fryszkowska et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
4.5. Typical experimental procedure for the synthesis of 2-oxa-
7,9-diaza-bicyclo[4.2.2]decane-8,10-diones 4. General procedure 3
J = 14.7 Hz, 1H), 5.18 (s, 1H), 5.95 (q, J = 7.2 Hz, 1H), 7.26–7.50 (m,
10H); 13C NMR d 16.1, 25.5, 34.0, 47.5, 51.1, 55.4, 64.4, 83.1, 128.1,
128.2, 128.7, 128.8, 128.9, 129.0, 135.2, 138.8, 164.9, 170.6; ESI–
MS: m/z = 751 ([2M+Na]+, 3%), 387 ([M+Na]+, 100%), 365 ([M+H]+,
4%); ESI–MS HR: m/z calcd for [M+Na]+, C22H24N2O3Na: 387.1679;
Found: 387.1602.
Alcohol 3 (0.12 mmol) and N-bromosuccinimide (0.13 mmol,
23 mg) in CHCl3:H2O (6:1, 7 mL) were vigorously stirred at rt. After
2 h, the mixture turned orange and stirring was continued until the
mixture became colorless. The organic phase was separated,
washed with brine (5 mL) and dried (MgSO4). The solvent was
evaporated in vacuo and the product was purified by flash chro-
matography (hexane:Et2O, 1:3) followed by recrystallization from
Et2O/hexane to give pure bicyclo[4.2.2]decane 4. The diastere-
omeric ratio of the obtained compounds 4b was established by
the mass of isolated compounds. UV and CD data for compounds
4 are presented in Figure S4 and are summarized in Table S5
(Supplementary data).
4.5.4.2. (1S,6S)-9-Benzyl-7-((10S)-1-phenylethyl)-2-oxa-7,9-diaza-
bicyclo[4.2.2]decane-8,10-dione (1S,6S,10S)-4c.
tals: mp 139–140 °C (Et2O/hexane); 100% de (NMR); [a D
White crys-
]
30 = ꢁ74.0
(c 0.15, CHCl3); Rf = 0.75 (Et2O); 1H NMR d 0.80–2.20 (m, 4H), 1.62
(d, J = 7.1 Hz, 3H), 3.34–3.46 (m, 1H), 3.85–3.95 (m, 1H), 3.93 (dd,
J = 1.8 Hz, J = 6.6 Hz, 1H), 4.05 (d, J = 14.6 Hz, 1H), 5.06 (d,
J = 14.6 Hz, 1H), 5.20 (s, 1H), 5.87 (q, J = 7.2 Hz, 1H), 7.20–7.45 (m,
10H); 13C NMR d 16.9, 25.8, 35.5, 47.3, 52.1, 55.9, 64.4, 83.0,
127.2, 128.2, 128.4, 128.5, 129.0, 129.1, 135.3, 138.7, 165.4, 170.3;
ESI-MS: m/z = 751 ([2M+Na]+, 15%); 387 ([M+Na]+, 100%), 365 ([M
+H]+, 6%), ESI-MS HR: m/z calcd for [M+Na]+, C22H24N2O3Na:
387.1679; Found: 387.1695.
4.5.1. Preparation of rac-7,9-dibenzyl-2-oxa-7,9-diaza-bicyclo
[4.2.2]decane-8,10-dione ( )–4a33
The product was prepared according to General procedure 3 in
46% yield: white crystals; mp 180–180.5 °C (Et2O/hexane) (lit.
171–17233); Rf = 0.50 (Et2O); 1H NMR d 1.45–1.82 (m, 2H), 1.83–
2.20 (m, 2H), 3.35–3.46 (m, 1H), 3.78–3.89 (m, 1H), 4.09–4.16
(m, 2H), 4.31 (d, J = 14.7 Hz, 1H), 4.86 (d, J = 14.7 Hz, 1H), 4.86 (d,
J = 14.7 Hz, 1H), 5.12 (d, J = 14.7 Hz, 1H), 5.23 (s, 1H), 7.24–7.40
(m, 10H); 13C NMR d 25.7, 32.6, 47.5, 48.1, 59.0, 64.5, 82.7, 128.2,
128.4, 128.6, 128.8, 129.0, 129.2, 129.3, 135.2, 135.4, 165.2,
170.1; ESI–MS: m/z = 373 ([M+Na]+, 100%), 374 ([M+H]+, 4%), 723
([2M+Na]+, 15%); ESI–MS HR: m/z calcd for [M+Na]+, C21H22N2O3-
Na: 373.1528; Found: 373.1518; Anal. Calcd for C21H22N2O3: C,
71.98; H, 6.33; N, 7.99; Found: C, 71.60; H, 6.26; N, 7.77. All spec-
troscopic data were in accordance with data reported previously.21
Acknowledgements
This work was supported by Polish National Science Center Pro-
ject No. 2013/11/B/ST5/02199 and the COST action CM1303 for
providing a stimulating environment which led to this research.
The authors thank to prof. Jadwiga Frelek, Institute of Organic
Chemistry PAS for performing CD measurements.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.08.
004.
4.5.2. Preparation of (1S,6S)-7,9-dibenzyl-2-oxa-7,9-diaza-bicyclo
[4.2.2]decane-8,10-dione (1S,6S)-4a
The product was prepared according to General procedure 3
from alcohol (3S)-3a (75% ee) in 51% yield: white crystals; mp
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4.5.3. Preparation of (1R,6R)-7,9-Dibenzyl-2-oxa-7,9-diaza-
bicyclo[4.2.2]decane-8,10-dione (1R,6R)-4a
The product was prepared according to General procedure 3
from alcohol (3R)-3a (>98% ee) in 51% yield: white crystals; mp
130 °C (Et2O/hexane);
[
a
]
30 = ꢁ5.9 (c 0.22, CHCl3); >98% ee;
D
Rf = 0.50 (Et2O). Spectroscopic data were the same as the ones
obtained for racemic 4a. Anal. Calcd for C21H22N2O3: C, 71.98; H,
6.33; N, 7.99; Found: C, 71.57; H, 6.22; N, 7.68.
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4.5.4. Preparation of (1RS,6RS)-9-Benzyl-7-((10S)-1-phenylethyl)-
2-oxa-7,9-diaza-bicyclo[4.2.2]decane-8,10-dione (1RS,6RS,10S)-4c
The product was prepared according to General procedure 3 in
45%. The diastereoisomers were separated on a silica gel column
(hexane:Et2O, 1:4), and then recrystallized from Et2O/hexane.
4.5.4.1. (1R,6R)-9-Benzyl-7-((10S)-1-phenylethyl)-2-oxa-7,9-diaza-
bicyclo[4.2.2]decane-8,10-dione (1R,6R,10S)-4c.
White crys-
]
tals: mp 182–184 °C (Et2O/hexane); 100% de (NMR); [a D
30 = ꢁ100.0
(c 0.60, CHCl3); Rf = 0.85 (Et2O); 1H NMR d 0.70–1.80 (m, 4H), 1.56
(d, J = 7.1 Hz, 3H), 3.18–3.30 (m, 1H), 3.70–3.82 (m, 1H), 4.11 (d,
J = 14.7 Hz, 1H), 4.20 (dd, J = 1.8 Hz, J = 6.4 Hz, 1H), 5.04 (d,
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Berlin Heidelberg, 2004. Chapter 1 and 2.
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Please cite this article in press as: Fryszkowska, A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.004