Cyclic sulfates as useful tools in the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2015.09.013

The enantiomers of 4-(2-methoxyethyl)-1,3,2-dioxathiolane-2,2-dioxide and 4-(methoxymethyl)-1,3,2-dioxathiolane-2,2-dioxide have been used as 'epoxide-like' synthons during the asymmetric alkylation of oxazinone-derived glycine equivalents. Using a fully stereoselective synthesis, eight stereoisomers of the spiro derivatives of the glycine equivalents were obtained. The relative configurations of the spiro compounds obtained were easily determined using nuclear magnetic resonance spectroscopy and two dimensional nuclear Overhauser effect experiments. Additionally, one of the spiro derivatives obtained was hydrolyzed to its corresponding amino acid, which was a derivative of 1-aminocyclopropano-1-carboxylic acid, a very important building block that is present in many compounds, which have interesting biological activity.

Full text of DOI:10.1016/j.tetasy.2015.09.013

Tetrahedron: Asymmetry 26 (2015) 1261–1267
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cyclic sulfates as useful tools in the asymmetric synthesis
of 1-aminocyclopropane-1-carboxylic acid derivatives
a
b
a,
⇑
_
Anna Jakubowska , Grzegorz Zuchowski , Katarzyna Kulig
a Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland
b NMR Laboratory, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiomers of 4-(2-methoxyethyl)-1,3,2-dioxathiolane-2,2-dioxide and 4-(methoxymethyl)-1,3,2-
dioxathiolane-2,2-dioxide have been used as ‘epoxide-like’ synthons during the asymmetric alkylation
of oxazinone-derived glycine equivalents. Using a fully stereoselective synthesis, eight stereoisomers of
the spiro derivatives of the glycine equivalents were obtained. The relative configurations of the spiro
compounds obtained were easily determined using nuclear magnetic resonance spectroscopy and two
dimensional nuclear Overhauser effect experiments. Additionally, one of the spiro derivatives obtained
was hydrolyzed to its corresponding amino acid, which was a derivative of 1-aminocyclopropano-1-
carboxylic acid, a very important building block that is present in many compounds, which have
interesting biological activity.
Received 3 September 2015
Accepted 28 September 2015
Available online 21 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
this modification. Using 1-aminocyclopropane-1-carboxylic acid
instead of L-valine has allowed even better pharmacokinetic prop-
In 2004, according to the literature, more than 20% of drugs
belonging to the top 200 sales were based on compounds that
possess a peptidic nature.1 In addition, more than 200 peptides,
proteins, and antibodies were launched for sale in 2010.2 At the
same time 40% of failures in clinical trials are caused by the low
bioavailability and poor pharmacokinetics of the test compounds.2
In particular, compounds that possess a peptidic nature have
several drawbacks due to their rapid proteolysis and measures
have to be taken to modify their structure in order to improve their
pharmacokinetic properties, for example, the introduction of
unnatural amino acids into their structure.1–3
1-Aminocyclopropane-1-carboxylic acid building blocks are
present in many compounds, which have interesting biological
activity (Fig. 1). The first example of a compound containing the
1-aminocyclopropane-1-carboxylic acid building block was cyto-
trienin A, an ansamycin-type anticancer drug, which was isolated
from a species of Steptomyces.4 Cytotrienin A induces apoptosis
in human promyelocytic leukemia HL-60 cell line.5 Another
important example is the modification of the antiviral agent,
Valacyclovir, which is an ester derivative of Acyclovir. Valacylovir
erties to be obtained.6 1-Aminocyclopropane-1-carboxylic acid is
also found as a part of Simeprevir, an inhibitor of NS3/4A protease
inhibitors, which was registered in 2014 as a new drug to treat
hepatitis C.7–9 1-Aminocyclopropane-1-carboxylic acid was also
used in investigations to improve the biological activity in factor
Xa inhibitors10 and atypical retinoids (anti-tumor activity).11
Therefore, it is necessary to search for new synthetic methods
and various derivatives of 1-aminocyclopropane-1-carboxylic acid,
which may be used as building blocks to improve the pharmacoki-
netic properties of biologically active compounds.
This work is a continuation of our efforts directed toward meth-
ods for the asymmetric synthesis of aminocycloalkane carboxylic
acid derivatives.12,13 The synthesis of the stereoisomers of
1-aminocyclopropane-1-carboxylic acid derivatives were based
on glycine equivalent 1, which was developed by Wanner et al.14
Herein, we have focused our attention on cyclic sulfates 2 and 3
as they are emerging as important ‘epoxide-like’ synthons and
should lead us to obtain the target compounds 4 and 5 with excel-
lent diastereoselectivity. Compounds 4 and 5 can be hydrolyzed to
their corresponding amino acids 6 and 7 (Scheme 1).
is the L-valine ester of Acyclovir (prodrug) and has an oral bioavail-
ability that is 5-fold higher than the original drug as a result of
2. Results and discussion
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol 8 and (2,2-dimethyl-
1,3-dioxolan-4-yl)methanol 9 were selected as starting materials
⇑
Corresponding author. Tel.: +48 12 620 54 52; fax: +48 12 657 02 62.
E-mail address: mfkkulig@cyf-kr.edu.pl (K. Kulig).
http://dx.doi.org/10.1016/j.tetasy.2015.09.013
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

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A. Jakubowska et al. / Tetrahedron: Asymmetry 26 (2015) 1261–1267
OH
OH
O
O
S
NH2
O
S
NH
HN
N
N
NH
O
HO
O
H2N
O
N
HN
N
O
O
O
O
O
O
N
O
H
N
O
N
O
O
(+)-Cytotrienin A
Cl
analogue of valacylovir
Simeprevir
COOH
O
F
H
N
TFA-
+H3N
N
H
N
R
SO2CH3
O
O
O
factor Xa inhibitors
Atypical retinoid
Figure 1. Examples of using 1-aminocyclopropane-1-carboxylic acids derivatives as a building block.
OMe
OMe
O
S
O
O
N
N
O
H2N
HO
n
+
O
O
O
O
O
n
O
O
O
n
1
2
n = 2
4
6
n = 2
n = 2
3 n = 1
5 n = 1
7 n = 1
Scheme 1. Scheme of planned synthesis.
to prepare sulfates 2 and 3, since they are both easily available in a
single enantiomeric form. Firstly, 8 and 9 were converted into their
methoxy derivatives 10 and 11 using methyl iodine and potassium
hydroxide in dimethyl sulfoxide as a solvent.15 The deprotection to
give compounds 12 and 13 was carried out in a mixture of 1 M
hydrochloric acid and acetone.16 Compounds 12 and 13 were
reacted with thionyl chloride to give cyclic sulfites 14 and 15, which
were further oxidized using sodium periodate and a catalytic
amount of ruthenium trichloride to their corresponding cyclic sul-
fates 2 and 3.17,18 In this way a racemic mixture and two enan-
tiomers of compound 2, and a racemic mixture of compound 3
and enantiomer (S)-3 were obtained.
The as-prepared cyclic sulfates 2 and 3 were used as the alkylat-
ing agents of glycine equivalents (S)-1 and (R)-1. The deprotona-
tion agent, sodium bis(trimethylsilyl)amide (NaHMDS) was used.
The enantiomer of the glycine equivalent 1 was deprotonated at
À30 °C for 30 min, the cyclic sulfate 2 or 3 was added and the reac-
tion mixture stirred for 2 h. The last portion of NaHMDS was added
dropwise for 1 h after which the mixture was stirred overnight and
purified (Scheme 2).
When a racemic mixture of compound 2 was used, two
stereoisomers of compound 4 were obtained (as determined by
proton nuclear magnetic resonance 1H NMR spectroscopy). The
separation of these stereoisomers was not easy to carry out and
so we decided to use the single enantiomers of compound 2, which
were easily obtained from the enantiomers of 2-(2,2-dimethyl-1,3-
dioxolan-4-yl)ethanol 8. This led us to obtain four stereoisomers of
the spiro-derivatives 4 as single diastereoisomers in good yields
(44–51%) (Scheme 3).
The relative configurations within compound
4
were
determined using NMR spectroscopy based on the nuclear
Overhauser effects (NOEs) experiments with the absolute configu-
rations determined by the absolute configuration of 1.12,13,19 The
most important interaction observed was between the protons of
the tert-butyl group with methoxyethyl group (compounds 4a
and 4d) or the absence of these interactions (compounds 4b and
4c) (Fig. 2). In each reaction only one stereoisomer of compound
4 was formed and its stereoselectivity was dependent on the
absolute configuration of the cyclic sulfate. We obtained two pairs
of enantiomers of compound 4 in series I: from glycine equivalent
O
S
O
OH
n
O
O
a
O
b
c
d
S
O
O
OH
O
O
O
HO
O
O
O
O
O
n
n
n
n
8 n = 2
10 n = 2
11
12 n = 2
14 n = 2
15
2 n = 2
9
13
3
n = 1
n = 1
n = 1
n = 1
n = 1
a: MeI, KOH; DMSO, RT; 24 h
b: 1 M HCl; acetone; reflux; 1 h
c: SOCl2; CHCl3; 0oC-reflux; 1 h
d: NaIO4, RuCl3xH2O; CHCl3; MeCN, H2O; 0oC-RT; 3 h
Scheme 2. Synthesis of cyclic sulfate 2 and 3.

A. Jakubowska et al. / Tetrahedron: Asymmetry 26 (2015) 1261–1267
1263
OMe
O
OMe
OMe
O
N
(R)
N
O
N
(S)
S
a
O
(S)
(S)
+
and
(S)
(R)
O
O
O
O
O
O
O
O
O
(S)-1
(S)-2
(R)-2
4a from (S)-2
4b from (R)-2
OMe
N
O
OMe
OMe
N
O
N
O
a
S
O
(S)
(R)
(R)
+
and
(R)
(S)
(R)
O
O
O
O
O
O
O
O
O
(R)-1
(S)-2
(R)-2
4c from (S)-2
4d from (R)-2
a: NaHMDS, THF, -30oC, 18 h
Scheme 3. Products of the alkylation of glycine equivalent 1 with cyclic sulfite 2—series I.
Figure 2. Sample of NOESY spectra for compound 4a.
(S)-1 and cyclic sulfate (S)-2, we obtained compound 4a, which
was the enantiomer of compound 4d obtained from glycine equiv-
alent (R)-1 and cyclic sulfate (R)-2. From glycine equivalent (S)-1
and cyclic sulfate (R)-2 we obtained compound 4b, which was
the enantiomer of compound 4c obtained from the reaction
between glycine equivalent (R)-1 and cyclic sulfate (S)-2.
On the other hand, when we used a racemic mixture of com-
pound 3, two diastereoisomers of compound 5 were also obtained,
which were easily separated using simple column chromatography.
The same situation was observed for both enantiomers of glycine
equivalent 1. After separation of the stereoisomers of compound
5, the absolute configuration at position C-3 was determined using
the NOE experiments and similar interactions were observed; the
absolute configuration at position in C-1 was determined by com-
parison to the first series and was also confirmed after the reactions
using the enantiomers of compound 3 (Scheme 4).
In the final stage, a two-step hydrolysis was employed to
provide the free amino acid 7. The reactions were carried out in

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A. Jakubowska et al. / Tetrahedron: Asymmetry 26 (2015) 1261–1267
OMe
LabMate (CEM Corporation). Optical rotations were measured on
a polarimeter Jasco, model P-2000 using a sodium lamp, emitting
light at a wavelength of 589 nm and a 10 cm polametric tube.
Elemental analyses (C, H, N) were performed on an Elementar
Vario EL III (Elementar Analysensystem, Hanau, Germany). NMR
spectra were measured in CDCl3 or D2O on a Varian Mercury-VX
300 spectrometer operating at 300.08 MHz (1H) and 75.46 MHz
OMe
O
O
N
N
(S)
a
(R)
1
3
3
(S)-
+
+
and
(S)
(R)
(S)
(S)
O
O
O
O
O
5a
5b
OMe
OMe
(
13C). Chemical shifts (d in ppm) were referenced to the lock signal
a
N
N
(S)
1
(R)-
(R)
of the solvent. Coupling constants, J, are expressed in Hz. Sample
concentrations were in the range of 20 mg/ml. All spectra were
acquired at ambient temperature, for each 1H NMR spectrum, 16
scans were accumulated with spectral width of 4.2 kHz and 32 k
data points. 13C NMR spectra were recorded with spectroscopic
width of 18 kHz and 64 k data points. All 2D experiments were per-
formed using standard pulse sequences of spectrometer. Spectral
widths of the 1H and 13C dimensions were 2.7 kHz and 13.5 kHz
respectively, data matrix for FT 1 k  1 k Mixing time for NOESY
experiment was 500 ms.
and
(R)
(R)
(R)
(S)
O
O
O
O
O
5c
5d
a: NaHMDS, THF, -30oC, 18 h
a
(S)-3
+
(R)-1
Scheme 4. Products of the alkylation of glycine equivalent 1 with cyclic sulfite 3—
series II.
3.2. Synthesis
3.2.1. General procedure 1
pressure tubes using microwave heating. Compound 5c was first
dissolved in a mixture of water and hydrochloric acid, and then
heated in a microwave at 100 °C for 3 h. This process resulted in
the complete cleavage of the imidate functionality. Next, the cleav-
age obtained was treated with sodium hydroxide in methanol at
100 °C for 3 h to hydrolyze the remaining ester functionality. After
work-up with 2 M hydrochloric acid and subsequent purification
by ion exchange chromatography, the free (1S,2R)-1-amino-2-
Acetonide 8 or 9 (13.7 mmol) was dissolved in 10 mL of DMSO,
after which powdered KOH was added (1.00 g, 17.8 mmol), and the
mixture was stirred for 30 min. Next, MeI (1.00 mL, 16.4 mmol)
was added and mixture was stirred at room temperature for
24 h. In the next step, the mixture was dissolved in 20 mL of water
and extracted with diethyl ether (3 Â 30 mL). Each organic layers
was washed with brine (1 Â 30 mL), combined, dried over
anhydrous Na2SO4, and evaporated. The obtained product 10 or
11 was used in the next step without purification.
(methoxymethyl)cyclopropanecarboxylic acid
(Scheme 5).
7
was obtained
3.2.2. General procedure 2
Methoxy acetonide 10 or 11 (5 mmol) was dissolved in 15 mL of
acetone after which 12 ml of 1 M HCl were added. The mixture was
stirred at reflux for 1 ho, and then evaporated. Product 12 or 13
was purified by column chromatography using ethyl acetate as
the eluent.
OMe
O
O
N
H2N
(S)
a-c
(R)
(R)
(R)
(S)
HO
O
O
O
5c
7
3.2.3. General procedure 3
a: HCl, H2O, MW, 100oC, 3 h
b: NaOH, MeOH, MW, 100oC, 3 h
c: Dowex 50WX8
Thionyl chloride (0.95 mL, 14.5 mmol) was added to
a
suspension of the enantiomer of 4-methoxybutane-1,2-diol 12
(1.06 g, 8.83 mmol) in chloroform (16 mL) and the solution was
refluxed for 1 h. Next, the solution was cooled to 0 °C, and
acetonitrile (10 mL), NaIO4 (2.00 g, 9.35 mmol), RuCl3ÁH2O (0.01 g,
0.05 mmol) and water (15 mL) were added. The resulting mixture
was stirred for 3 h, and then diluted with diethyl ether (20 mL)
and water (10 mL). The organic layer was washed with water
(3 Â 20 mL), saturated aqueous NaHCO3 (20 mL) and brine
(20 mL), dried over anhydrous Na2SO4, and evaporated in a vac-
uum. The crude product was kept under argon in a freezer because
of its fragility without purification.
Scheme 5. Hydrolysis to free amino acid.
3. Experimental
3.1. General
All experiments were carried out in oven-dried glassware under
a dry argon atmosphere and standard vacuum techniques were
used. Analytical grade chemicals were obtained from commercial
sources and used without further purification. Solvents were dried
under a dry argon atmosphere using standard methods and were
freshly distilled before use. Thionyl chloride was distilled under
low pressure up to three weeks before use. Chromatography was
performed with silica gel (Sigma Aldrich Si60 0.040–0.063 mm).
Thin layer chromatography (TLC) was performed on precoated sil-
ica gel 60–F254 plates (Merck). The products were detected on the
TLC plates by one of the following methods/detection reagents or a
combination of them: UV light, ammonium cerium(IV)hepta-
molybdate (5% (NH4)ÂMo7O24 and 0.2% Ce(SO4)2 dissolved in
400 mL of a 5% H2SO4 solution), ninhydrin (0.3 g ninhydrin dis-
solved in 100 mL n-propanol and 3 mL acetic acid). Reactions
under microwave irradiation were carried out using a Discover
3.2.4. General procedure 4
Thionyl chloride (0.57 mL, 8.7 mmol) was added to
a
suspension of 3-methoxypropane-1,2-diol 13 (0.63 g, 5.94 mmol)
in chloroform (9 mL) and the solution was refluxed for 1 h. Next,
the solvent was evaporated in vacuo and the remaining oil was
purified by column chromatography using diethyl ether.
3.2.5. General procedure 5
To
a
solution of 4-(methoxymethyl)-1,3,2-dioxathiolane
2-oxide 15 (0.58 g, 3.81 mmol) in a mixture of acetonitrile (5 mL)
and chloroform (5 mL) was added NaIO4 (1.20 g, 5.65 mmol),
followed by RuCl3ÁH2O (0.01 g, 0.05 mmol) and water (7 mL). The

A. Jakubowska et al. / Tetrahedron: Asymmetry 26 (2015) 1261–1267
1265
resulting mixture was stirred for 3 h, and then diluted with diethyl
ether (15 mL) and water (10 mL). The organic layer was washed
with water (3 Â 15 mL), saturated aqueous NaHCO3 (15 mL) and
brine (15 mL), dried over anhydrous Na2SO4, and evaporated in a
vacuum. The crude product (oil) was purified by flash chromatog-
raphy using diethyl ether.
yellow oil. TLC: Rf = 0.55 (diethyl ether). C5H10O5S (182.19) calcd
C, 32.96; H, 5.53; S, 17.60; found: C, 33.10; H, 5.61; S, 17.74.
[
a
]
20 = À14.5 (c 1.270, CH2Cl2). 1H NMR (300 MHz, CDCl3)
D
d = 2.06–2.22 (m, 2H, CH2CH2CH), 3.33 (s, 3H, CH3O) 3.47–3.60
(m, 2H, OCH2CH2), 4.46 (dd, J = 8.85, 8.34 Hz, 1H, CHCH2O), 4.73
(dd, J = 8.98, 5.90 Hz, 1H, CHCH2O), 5.06–5.19 (m, 1H) ppm. 13C
NMR (75.5 MHz, CDCl3) d = 32.50 (CH2CH2CH), 58.96 (CH3O),
67.39 (CHCH2O), 73.50 (OCH2CH2), 81.25 (CH) ppm.
3.2.6. General procedure 6
A solution of glycine equivalent (0.20 g, 1.00 mmol) in THF
(4 mL) was cooled to À30 °C, treated with NaHMDS (1 M in hexane,
1.2 mL, 1.00 mmol), and stirred for 30 min. Next, cyclic sulfate 2 or
3 (1.50 mmol) dissolved in 1 mL of THF was added and the stirring
was continued for 1.5 h, after which NaHMDS (1 M in hexane,
1.2 mL, 1.00 mmol) was added dropwise (for approximately 1 h).
The reaction was stirred at À30 °C overnight. The reaction was
quenched by the addition of a phosphate buffer pH = 7.0 (6 mL),
and allowed to warm to room temperature. The inorganic layer
was extracted with diethyl ether (4 Â 10 mL). The combined
organic layer was dried over anhydrous Na2SO4 and evaporated
in vacuo. The crude product was purified by column chromatogra-
phy using petroleum ether/ethyl acetate 7:3.
3.3.6. (R)-4-(2-Methoxyethyl)-1,3,2-dioxathiolane-2,2-dioxide (R)-2
Product was obtained according to general procedure 3, from
(R)-12 (0.93 g, 7.74 mmol). Yield: 0.93 g (66%, 5.10 mmol) as a yel-
low oil. TLC: Rf = 0.55 (diethyl ether). C5H10O5S (182.19) calcd C,
20
32.96; H, 5.53; S, 17.60; found: C, 32.81; H, 5.69; S, 17.32. [
a
]
=
D
+15.5 (c 1.310, CH2Cl2). NMR data were identical to those of the
enantiomer (S)-2.
3.3.7. (1S,3S,6S)-6-(tert-Butyl)-5-methoxy-1-(2-methoxyethyl)-6-
methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-one 4a
Product was obtained according to general procedure 6, from
glycine equivalent (S)-1 and (S)-2. Yield: 0.14 g (44%, 0.44 mmol)
as a yellow oil. TLC: Rf = 0.65 (petroleum ether/ethyl acetate 7:3).
C15H25NO4 (283.36) calcd: C, 63.58; H, 8.89; N, 4.94; found: C,
3.3. Synthesis of series I
63.49; H, 8.93; N, 4.87. [a]
20 = +0.6 (c 1.952, CH2Cl2). 1H NMR
D
(300 MHz, CDCl3) d = 0.97–1.03 (m, 10H, ((CH3)3, CCH2CH3OCH3),
1.53 (s, 3H, CH3C), 1.67–1.75 (m, 1H, CCH2CH3OCH3), 1.82–1.91
(m, 3H, CCH2CH), 3.33 (s, 3H, CH2OCH3), 3.45 (t, J = 6.67 Hz, 2H,
CH2CH2O), 3.63 (s, 3H, OCH3) ppm. 13C NMR (75.5 MHz, CDCl3)
d = 20.81 (CH3C), 25.46 ((CH3)3), 27.34 (CHCH2CH2), 28.10 (CCH2-
CH), 29.17 (CCH2CH), 39.44 (((CH3)3C),), 41.70 (CCH2CH), 52.84
(CH3O), 58.65 (CH3OCH2), 71.93 (CH2OCH3), 88.33 (CH3C), 161.35
(COCH3), 171.44 (CO) ppm.
3.3.1. (S)-4-(2-Methoxyethyl)-2,2-dimethyl-1,3-dioxolane (S)-10
Product was obtained according to general procedure 1, from
(S)-8 (2.00 g, 13.7 mmol). Yield: 2.06 g (94%, 12.8 mmol) as a yel-
low oil. TLC: Rf = 0.52 (petroleum ether/ethyl acetate 7:3).
C8H16O3 (160.21). 1H NMR (300 MHz, CDCl3) d = 1.32 (s, 3H,
CH3C), 1.37 (s, 3H, CH3C), 1.74–1.88 (m, 2H, CH2CH2CH), 3.30 (s,
3H, CH3O), 3.40–3.46 (m, 2H, OCH2CH2), 3.52 (dd, J = 7.95,
7.44 Hz, 1H, CHCH2O), 4.02 (dd, J = 7.95, 5.90 Hz, 1H, CHCH2O),
4.09–4.20 (m, 1H, CH) ppm. 13C NMR (75.5 MHz, CDCl3) d = 25.71
(CH3C), 26.89 (CH3C), 33.72 (CH2CH2CH), 58.66 (CH3O), 69.36
(CHCH2O), 69.55 (OCH2CH2), 73.70 (CH), 108.52 ((CH3)C) ppm.
3.3.8. (1R,3R,6S)-6-(tert-Butyl)-5-methoxy-1-(2-methoxyethyl)-
6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-one 4b
Product was obtained according to general procedure 6, from glycine
equivalent (S)-1 and (R)-2. Yield: 0.15 g (50%, 0.50 mmol) as a yellow oil.
TLC: Rf = 0.65 (petroleum ether/ethyl acetate 7:3). C15H25NO4 (283.36)
calcd: C, 63.58; H, 8.89; N, 4.94; found: C, 63.51; H, 8.77; N, 4.84.
3.3.2. (R)-4-(2-Methoxyethyl)-2,2-dimethyl-1,3-dioxolane (R)-10
Product was obtained according to general procedure 1, from
(R)-8 (2.00 g, 13.7 mmol). Yield: 2.00 g (91%, 12.5 mmol) as a
yellow oil. TLC: Rf = 0.53 (petroleum ether/ethyl acetate 7:3).
C8H16O3 (160.21). NMR data were identical to those of the
enantiomer (S)-10.
[a]D
20 = +6.6 (2.572, CH2Cl2). 1H NMR (300 MHz, CDCl3) d = 0.93 (dd,
J = 7.05, 4.23 Hz, 1H, CCH2CH3OCH3), 1.00 (s, 9H, (CH3)3), 1.51 (s, 3H,
CH3C), 1.73 (dd, J = 9.49, 4.10 Hz, 1H, CCH2CH3OCH3), 1.83–2.00 (m,
3H, CCH2CH), 3.32 (s, 3H, CH2OCH3), 3.42 (t, J = 6.80 Hz, 2H, CH2CH2O),
3.63 (s, 3H, OCH3) ppm. 13C NMR (75.5 MHz, CDCl3) d = 20.81 (CH3C),
25.46 ((CH3)3), 27.34 (CHCH2CH2), 28.10 (CCH2CH), 29.17 (CCH2CH),
39.44 ((CH3)3C), 41.70 (CCH2CH), 52.84 (CH3O), 58.65 (CH3OCH2),
71.93 (CH2OCH3), 88.33 (CH3C), 161.35 (COCH3), 171.44 (CO) ppm.
3.3.3. (S)-4-Methoxybutane-1,2-diol (S)-12
Product was obtained according to general procedure 2, from
(S)-10 (1.71 g, 11.7 mmol). Yield: 1.08 g (84%, 9.00 mmol) as a
yellow oil. TLC: Rf = 0.15 (ethyl acetate). C5H12O3 (120.15) calcd
C, 49.98; H, 10.07; found: C, 50.11; H, 10.12. [
a
]
20 = À8.4 (c
D
1.280, CH2Cl2). 1H NMR (300 MHz, CDCl3) d = 1.65–1.87 (m, 2H,
CH2CH2CH), 2.51 (br s, 2H, OH), 3.36 (s, 3H, CH3O), 3.46–3.54 (m,
1H, OCH2CH2), 3.56–3.63 (m, 3H, OCH2CH2CHCH2), 3.86–3.94 (m,
1H, CH) ppm. 13C NMR (75.5 MHz, CDCl3) d = 32.99 (CH2CH2CH),
58.92 (CH3O), 66.47 (CHCH2O), 70.65 (OCH2CH2), 71.13 (CH) ppm.
3.3.9. (1S,3S,6R)-6-(tert-Butyl)-5-methoxy-1-(2-methoxyethyl)-
6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-one 4c
Product was obtained according to general procedure 6, from
glycine equivalent (R)-1 and (S)-2. Yield: 0.16 g (51%, 0.51 mmol)
as a yellow oil. TLC: Rf = 0.65 (petroleum ether/ethyl acetate 7:3).
C
15H25NO4 (283.36) calcd C, 63.58; H, 8.89; N, 4.94; found: C,
63.67; H, 8.94; N, 4.81. [
were identical to those of the enantiomer 4b.
a]
20 = À6.9 (c 2.474, CH2Cl2). NMR data
3.3.4. (R)-4-Methoxybutane-1,2-diol (R)-12
D
Product was obtained according to general procedure 2, from
(R)-10 (1.72 g, 11.7 mmol). Yield: 0.96 g (75%, 8.00 mmol) as a
yellow oil. TLC: Rf = 0.175 (ethyl acetate). C5H12O3 (120.15) calcd
3.3.10. (1R,3R,6R)-6-(tert-Butyl)-5-methoxy-1-(2-methoxyethyl)-
6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-one 4d
C, 49.98; H, 10.07; found: C, 50.20; H, 10.23. [a]
20 = +8.3 (c 1.170,
D
CH2Cl2). NMR data were identical to those of the enantiomer (S)-12.
Product was obtained according to general procedure 6, from
glycine equivalent (R)-1 and (R)-2. Yield: 0.16 g (51%, 0.51 mmol)
as a yellow oil. TLC: Rf = 0.65 (petroleum ether/ethyl acetate 7:3).
3.3.5. (S)-4-(2-Methoxyethyl)-1,3,2-dioxathiolane-2,2-dioxide
(S)-2
Product was obtained according to general procedure 3, from
(S)-12 (1.06 g, 8.83 mmol). Yield: 1.21 g (75%, 6.65 mmol) as a
C
15H25NO4 (283.36) calcd: C, 63.58; H, 8.89; N, 4.94; found: C,
63.65; H, 8.73; N, 5.04. [
a]
20 = À0.7 (c 2.466, CH2Cl2). NMR data
D
were identical to those of the enantiomer 4a.

1266
A. Jakubowska et al. / Tetrahedron: Asymmetry 26 (2015) 1261–1267
3.4. Synthesis of series II
28.57; H, 4.79; S, 19.07; found: C, 28.35; H, 4.89; S, 19.17. 1H
NMR (300 MHz, CDCl3) d = 3.43 (s, 3H, OCH3), 3.70 (d, J = 4.87 Hz,
2H, CH3OCH2), 4.59 (dd, J = 8.85, 7.05 Hz, 1H, CHCH2), 4.71 (dd,
J = 8.85, 6.54 Hz, 1H, CHCH2), 4.99–5.09 (m, 1H, CH) ppm. 13C
NMR (75.5 MHz, CDCl3) d = 59.75 (CH3O), 69.67 (CHCH2O), 69.99
(CH3OCH2), 79.92 (CH) ppm.
3.4.1. 4-(Methoxymethyl)-2,2-dimethyl-1,3-dioxolane 11
Product was obtained according to general procedure 1, from 9
(1.80 g, 13.7 mmol). Yield: 1.81 g (91%, 12.5 mmol) as a yellow oil.
TLC: Rf = 0.69 (petroleum ether/ethyl acetate 7:3). C7H14O3
(146.18). 1H NMR (300 MHz, CDCl3) d = 1.34 (s, 3H, CH3C), 1.41
(s, 3H, CH3C), 3.37 (s, 3H, CH3O), 3.39–3.50 (m, 2H, CH3OCH2CH),
3.68 (dd, J = 8.21, 6.41 Hz, 1H, CHCH2O), 4.03 (dd, J = 8.21,
6.41 Hz, 1H, CHCH2O), 4.21–4.31 (m, 1H, CH) ppm. 13C NMR
(75.5 MHz, CDCl3) d = 25.33 (CH3C), 26.73 (CH3C), 59.33 (CH3O),
66.62 (CHCH2O), 73.74 (OCH2CH), 74.57 (CH), 109.41 ((CH3)C)
ppm.
3.4.8. (S)-4-(Methoxymethyl)-1,3,2-dioxathiolane-2,2-dioxide (S)-3
Product was obtained according to general procedure 5, from
(4S)-15 (0.32 g, 2.1 mmol). Yield: 0.27 g (77%, 1.62 mmol) as a yel-
low oil. TLC: Rf = 0.50 (diethyl ether). C4H8O5S (168.17) calcd: C,
28.57; H, 4.79; S, 19.07; found: C, 28.39; H, 4.67; S, 18.93.
[
a
]
20 = À7.4 (c 1.365, CH2Cl2). NMR data were identical to those
D
of the compound 3.
3.4.2. (S)-4-(Methoxymethyl)-2,2-dimethyl-1,3-dioxolane (S)-11
Product was obtained according to general procedure 1, from 9
(0.90 g, 6.85 mmol). Yield: 0.77 g (78%, 5.34 mmol) as a yellow oil.
TLC: Rf = 0.69 (petroleum ether/ethyl acetate 7:3). C7H14O3
(146.18). NMR data were identical to those of the compound 11.
3.4.9. (1R,3S,6S)-6-(tert-Butyl)-5-methoxy-1-(methoxymethyl)-
6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-one 5a and (1S,3R,
6S)-6-(tert-butyl)-5-methoxy-1-(methoxymethyl)-6-methyl-7-
oxa-4-azaspiro[2.5]oct-4-en-8-one 5b
Product was obtained according to general procedure 6, from
glycine equivalent (S)-1 and 3. Stereoisomer 5a and 5b were
separated using column chromatography. Total yield: 0.143 g
(53%, 0.53 mmol) as a yellow oil. C14H23NO4 (269.34).
3.4.3. 3-Methoxypropane-1,2-diol 13
Product was obtained according to general procedure 2, from 11
(1.75 g, 12.0 mmol). Yield: 0.95 g (75%, 9.00 mmol) as a yellow oil.
TLC: Rf = 0.2 (ethyl acetate). C4H10O3 (106.12) calcd: C, 45.27; H,
9.50; found: C, 45.20; H, 9.36. 1H NMR (300 MHz, CDCl3) d = 2.51
(br s, 2H, OH), 3.39 (s, 3H, CH3O), 3.44–3.50 (m, 2H, OCH2CH),
3.58–3.66, (m, 1H, OCHCH2O), 3.67–3.74 (m, 1H, OCHCH2O),
3.83–3.91 (m, 1H, CH) ppm. 13C NMR (75.5 MHz, CDCl3) d = 59.17
(CH3O), 63.94 (CHCH2O), 70.62 (OCH2CH), 74.14 (CH) ppm.
Compound 5a: Yield: 0.076 g (28%, 0.28 mmol) TLC: Rf = 0.70
(petroleum ether/ethyl acetate 7:3). C14H23NO4 (269.34) calcd: C,
20
62.43; H, 8.61, N, 5.20; found: C, 62.59; H, 8.83, N, 5.24. [
a
]
=
D
+4.9 (c 2.000, CH2Cl2). 1H NMR (300 MHz, CDCl3) d = 1.00 (s, 9H,
(CH3)3), 1.12 (dd, J = 7.69, 4.10 Hz, 1H, CCH2CH), 1.52 (s, 3H,
CH3C), 1.87 (dd, J = 9.49, 4.10 Hz, 1H, CCH2CH), 2.08–2.16 (m, 1H,
CH), 3.29 (s, 3H, CH2OCH3), 3.54 (dd, J = 6.80, 4.49 Hz, 2H,
CHCH2O), 3.63 (s, 3H, OCH3). 13C NMR (75.5 MHz, CDCl3)
d = 20.77 (CH3C), 25.42 (CCH2CH), 25.45 ((CH3)3), 30.46
(CCH2CH), 39.71 ((CH3)3C), 41.95 (CCH2CH), 52.83 (CH3O), 58.22
(CH2OCH3), 70.58 (CH2OCH3), 88.52 (CH3C), 161.63 (COCH3),
171.00 (CO) ppm.
3.4.4. (R)-3-Methoxypropane-1,2-diol (R)-13
Product was obtained according to general procedure 2, from
(S)-11 (0.77 g, 5.26 mmol). Yield: 0.46 g (82%, 4.31 mmol) as a
yellow oil. TLC: Rf = 0.2 (ethyl acetate). C4H10O3 (106.12) calcd: C,
45.27; H, 9.50; found: C, 45.10; H, 9.40. [
CH2Cl2). NMR data were identical to those of the compound 13.
a]
20 = À2.2 (c 1.065,
D
Compound 5b: Yield: 0.067 g (25%, 0.25 mmol) TLC: Rf = 0.63
(petroleum ether/ethyl acetate 7:3). C14H23NO4 (269.34) calcd: C,
20
62.43; H, 8.61, N, 5.20; found: C, 62.40; H, 8.75, N, 5.17. [
a
]
D
=
3.4.5. 4-(Methoxymethyl)-1,3,2-dioxathiolane 2-oxide 15
Product was obtained according to general procedure 4, from 13
(0.63 g, 5.94 mmol). Yield: 0.59 g (66%, 3.92 mmol) as a yellow oil.
TLC: Rf = 0.80 (diethyl ether). C4H8O4S (152.17) calcd: C, 31.57; H,
5.30; S, 21.07; found: C, 31.87; H, 5.20; S, 20.87. Mixture of
diastereoisomers 60:40. 1H NMR (300 MHz, CDCl3) d = 3.39 (s,
3H, CH3O), 3.47–3.58 (m, 2H, CH3OCH2CH), 4.29 (dd, J = 8.34,
5.26 Hz, 1H, CHCH2), 4.70 (dd, J = 8.46, 6.67 Hz, 1H, CHCH2),
5.01–5.09 (m, 1H, CH) (diastereoisomers 1); 3.42 (s, 3H, CH3O),
3.68–3.81 (m, 2H, CH3OCH2CH), 4.48–4.57 (m, 2H, CHCH2), 4.59–
4.67 (m, 1H, CH) (diastereoisomers 2) ppm. 13C NMR (75.5 MHz,
CDCl3) d = 59.52 (CH3O), 68.67 (CHCH2O), 70.93 (CH3OCH2), 78.32
(CH) (diastereoisomers 1); 59.52 (CH3O), 69.11 (CHCH2O), 72.62
(CH3OCH2), 80.98 (CH) (diastereoisomers 2).
+33.7 (c 1.872, CH2Cl2). 1H NMR (300 MHz, CDCl3) d = 0.97–1.02
(m, 10H, (CH3)3, CCH2CH), 1.51 (s, 3H, CH3C), 1.74 (dd, J = 9.75,
4.36 Hz, 1H, CCH2CH), 2.18–2.29 (m, 1H, CH), 3.32 (s, 3H,
CH2OCH3), 3.58–3.67 (m, 5H, CHCH2O, OCH3) ppm.
13C NMR (75.5 MHz, CDCl3) d = 20.51 (CH3C), 24.66 (CCH2CH),
25.49 ((CH3)3), 30.26 (CCH2CH), 39.74 ((CH3)3C), 41.87 (CCH2CH),
52.84 (CH3O), 58.29 (CH2OCH3), 70.28 (CH2OCH3), 88.41 (CH3C),
161.66 (COCH3), 170.93 (CO) ppm.
3.4.10. (1R,3S,6R)-6-(tert-Butyl)-5-methoxy-1-(methoxymethyl)-
6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-one 5c and (1S,3R,
6R)-6-(tert-butyl)-5-methoxy-1-(methoxymethyl)-6-methyl-7-
oxa-4-azaspiro[2.5]oct-4-en-8-one 5d
Product was obtained according to general procedure 6, from
glycine equivalent (R)-1 and 3. Stereoisomer 5c and 5d were
separated using column chromatography. Total yield: 0.137 g
(50%, 0.50 mmol) as a yellow oil. C14H23NO4 (269.34).
3.4.6. (4S)-4-(methoxymethyl)-1,3,2-dioxathiolane 2-oxide (4S)-15
Product was obtained according to general procedure 4, from
(R)-13 (0.39 g, 3.68 mmol). Yield: 0.38 g (68%, 2.50 mmol) as a yel-
low oil. TLC: Rf = 0.81 (diethyl ether). C4H8O4S (152.17) calcd: C,
31.57; H, 5.30; S, 21.07; found: C, 31.77; H, 5.21; S, 21.01.
Compound 5c: Yield: 0.061 g (22%, 0.22 mmol) TLC: Rf = 0.60
(petroleum ether/ethyl acetate 7:3). C14H23NO4 (269.34) calcd: C,
62.43; H, 8.61; N, 5.20; found: C, 62.24; H, 8.79; N, 5.04.
20 = À34.0 (c 1.714, CH2Cl2). NMR data were identical to those
[
a
]
20 = À42.6 (c 1.295, CH2Cl2). Mixture of diastereoisomers
D
[a]
D
60:40. NMR data were identical to those of the compound 15.
of the compound 5b.
Compound 5d: Yield: 0.076 g (28%, 0.28 mmol) TLC: Rf = 0.71
(petroleum ether/ethyl acetate 7:3). C14H23NO4 (269.34) calcd: C,
3.4.7. 4-(Methoxymethyl)-1,3,2-dioxathiolane-2,2-dioxide 3
Product was obtained according to general procedure 5, from
(4S)-15 (0.32 g, 2.1 mmol). Yield: 0.27 g (77%, 1.62 mmol) as a yel-
low oil. TLC: Rf = 0.50 (diethyl ether). C4H8O5S (168.17) calcd: C,
20
62.43; H, 8.61; N, 5.20; found: C, 62.59; H, 8.82; N, 5.27. [a]
D
= À4.2 (c 2.144, CH2Cl2). NMR data were identical to those of the
compound 5c.

A. Jakubowska et al. / Tetrahedron: Asymmetry 26 (2015) 1261–1267
1267
3.4.11. (1R,3S,6R)-6-(tert-Butyl)-5-methoxy-1-(methoxymethyl)-
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_
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Acknowledgements
Financial support of this work by the National Science Centre,
Poland no N N 405 620938 is gratefully acknowledged.