Synthetic Access to All Four Stereoisomers of Oxetin

Article abstract of DOI:10.1021/acs.joc.6b01795

A short synthesis of all four stereoisomers of 3-amino-2-oxetanecarboxylic acid (oxetin) is described. The oxetane core is built using a Paternò-Büchi photochemical [2 + 2] cycloaddition; from the key intermediates, complementary resolution protocols provide access to enantiomerically pure oxetin and epi-oxetin on gram-scale.

Full text of DOI:10.1021/acs.joc.6b01795

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Synthetic access to all four stereoisomers of oxetin
Ahmad F Kassir, Sherif Shaban Ragab, Thao Anh Minh Nguyen, Florence Charnay-
Pouget, Régis Guillot, Marie-Christine Scherrmann, Thomas Boddaert, and David J. Aitken
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01795 • Publication Date (Web): 23 Sep 2016
Downloaded from http://pubs.acs.org on September 29, 2016
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The Journal of Organic Chemistry
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Synthetic access to all four stereoisomers of oxetin
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Ahmad F. Kassir,Ɨ Sherif S. Ragab,Ɨ,ǂ Thao A. M. Nguyen,Ɨ Florence Charnay-Pouget,Ɨ Régis
Guillot,ǁ Marie-Christine Scherrmann,Ɨ Thomas BoddaertƗ and David J. AitkenƗ,*
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Ɨ CP3A Organic Synthesis Group, ICMMO, CNRS UMR 8182, Université Paris Sud, Université Paris Saclay,
15 rue Georges Clemenceau, 91405 Orsay Cedex, France.
ǂ
Photochemistry Department, Chemical Industries Research Division, National Research Centre, P.O.
Box 12622, Dokki, Giza, Egypt.
ǁ
Services Communs, ICMMO, CNRS UMR 8182, Université Paris Sud, Université Paris Saclay, 15 rue
Georges Clemenceau, 91405 Orsay Cedex, France.
TOC graphic & Abstract
A short synthesis of all four stereoisomers of 3-amino-2-oxetanecarboxylic acid (oxetin) is described. The
oxetane core is built using a Paternò-Büchi photochemical [2+2]-cycloaddition; from the key
intermediates, complementary resolution protocols provide access to enantiomerically pure oxetin and
epi-oxetin on gram-scale.
The β-aminoacid (2R,3S)-cis-3-amino-2-oxetanecarboxylic acid, named oxetin, was first isolated by
Ōmura et al. in 1984 from the soil bacterium Streptomyces sp. OM-2317 (Figure 1). It showed herbicidal
activity through inhibition of plant glutamine synthetase and exhibited anti-bacterial activity against
Bacillus subtilis, Piriculaia oryzae and other microorganisms.1 The same authors described a synthesis of
(2R,3S)-oxetin from D-glucose which also provided the three other stereoisomers, in more than ten
steps for each stereoisomer and a combined overall yield of 7%.2 In 1997, Bach and Schröder applied the
Paternò-Büchi [2+2]-photocycloaddition reaction to the synthesis of oxetin; this synthesis required only
four steps and provided oxetin in 14% overall yield, but only the racemic cis stereoisomer was
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obtained.3 More recently, Blauvelt and Howell investigated an approach to oxetin starting from L-serine;
the unexpected diastereoselectivity observed during the reduction of a spiroepoxide intermediate led to
a single enantiomer of the trans diastereoisomer, epi-oxetin, in ten steps and 1.5% overall yield.4
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Figure 1 The four stereoisomers of oxetin
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Functionalized oxetanes are important building blocks for the synthesis of complex molecules and drug
discovery,5 and as a cyclic β-aminoacid, oxetin has further potential for inclusion in biologically active
peptides.6,7,8 These observations, alongside the initial reports of biological activity for natural (2R,3S)-
oxetin, warrant further development of a short, reliable access to all stereoisomers on exploitable scale.
A comparison of the three previous studies suggested to us that the Paternò-Büchi reaction was the
most promising strategy;9,10,11 we describe herein its successful application, employing an N-formyl
enamine 212 and a glyoxylate ester 3,13 to provide to the core oxetane skeleton 4, from which the
requisite targets are obtained as single enantiomers on gram-scale (Scheme 1).
Scheme 1
We began by investigating the influence of the alkyl moiety of the glyoxylate ester on the course of the
Paternò-Büchi reaction. To this end we prepared the n-butyl, methyl, and t-butyl esters (3a-c): the
former two were obtained by periodate-mediated oxidative cleavage of the corresponding dialkyl
tartrates,14 the latter by ozonolysis of tert-butyl acrylate.15 These compounds had to be freshly distilled
from P2O5 immediately before use; even so, their marked propensity for hydrate or hemiacetal
formation imposed the use of a dry aprotic solvent in the photochemical reaction. Our first choice of
enamine partner was N-vinylformamide 2a, a stable, commercially available material.
Freshly distilled glyoxylates 3a-c in anhydrous acetonitrile (75 mM) were each engaged in a [2+2]-
photocycloaddition reaction with two equivalents of 2a in a Pyrex® reaction vessel (200 mL) using a 400
W Hg-vapor lamp for 24 h, to furnish oxetanes 5-7 in 34-37% yields (Table 1). In each case, complete
regioselectivity was observed while the cis/trans ratio was close to 1:1; in no case could the a/b
diastereoisomers be separated on a preparative scale. The moderate efficiency is typical of Paternò-
Büchi reactions where the carbonyl reagent is not an aromatic aldehyde and is quite acceptable given
the intrinsic low stability of glyoxylates and their sensitivity to photodecomposition.16 The high
regioselectivity and poor diastereoselectivity are in agreement with mechanistic arguments on the
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The Journal of Organic Chemistry
Paternò-Büchi reaction.17 Most literature precedents featuring a glyoxylate in Paternò-Büchi reactions
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employ the n-butyl ester 3a;13 we likewise retained it for subsequent studies.
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Table 1 Influence of the nature of the glyoxylate ester
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Entry
R
Glyoxylate
Ratio a/ba
5a/5b 51:49
6a/6b 50:50
7a/7b 54:46c
Yield (%)b
1
2
3
n-Bu
Me
3a
3b
3c
37
37
34
t-Bu
aRatio a/b determined from the crude 1H NMR spectra. bIsolated yield of inseparable diastereoisomeric mixture.
cDiastereoisomers were not unambiguously assigned.
The influence of concentration and scale were investigated next (Table 2). Whereas concentration had
no effect on the efficiency (entries 1-3), working on a larger scale was perceptibly beneficial (entries 4,
5). The best result was obtained by employing 3a (100 mM) and two equivalents of 2a in acetonitrile in a
large Pyrex® reaction vessel (1 L) using a 400 W Hg-vapor lamp, which gave the photoadducts 5a/5b in
46% yield on multigram-scale (9.3 g, 46 mmol). The same reaction was also examined using a Rayonet
apparatus, but the efficiency was significantly lower (entry 6).
Table 2 Scaling of the reaction between 2a and 3a
Entry
Conc.
75 mM
20 mM
150 mM
75 mM
100 mM
75 mM
Scale
200 mL
200 mL
200 mL
1000 mL
1000 mL
100 mL
Ratio 5a/5ba
51:49
Yield (%)b
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2
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43
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47:53
3
51:49
4
50:50
5
50:50
6c
48:52
a Determined from crude 1H NMR spectra. b Isolated yield of diastereoisomeric mixture. c Performed using Rayonet apparatus
RPR-200.
Four-membered ring β-aminoacids are susceptible to ring opening when the amine function is not
deactivated by a protecting group.18 To facilitate subsequent manipulations, we decided to introduced a
carbamate protecting group onto 5a/5b in place of the formyl group. The 5a/5b mixture was treated
with Boc2O to provide the corresponding derivatives 8a and 8b in 85% yield up to 10 g scale;
significantly, these two diastereoisomers could be separated conveniently by column chromatography
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(Scheme 2). Thus, starting from N-vinylformamide 2a and glyoxylate 3a, the two-step protocol provided
both 8a and 8b as single diastereoisomers in 39% combined overall yield. Each derivative was engaged
in a one-pot selective deprotection sequence employing K2CO3 in methanol to give racemic Boc-
protected (±)-oxetin 9a and (±)-epi-oxetin 9b in 97% and 96% yields, respectively (Scheme 2).
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Scheme 2
Here it became evident that we should consider an alternative pathway to 8a and 8b, using N-Boc-N-
vinylformamide 2b as a Paternò-Büchi partner; this substrate was prepared in 93% yield from N-
vinylformamide 2a upon treatment with Boc2O and was evaluated in the photochemical reaction with
3a (Table 3). The first experiment, conducted at 75 mM, gave only 13% combined yield of adducts 8a/8b
(entry 1). Further investigation (entries 2,3) revealed that a high 2b concentration was deleterious to the
efficiency of the reaction and that the best yield was obtained when the concentration of 3a was 20 mM
(entry 3). This result could be reproduced on a larger scale (1 L; entry 4). On the premise that
photochemical degradation of reagent 2b might be occurring during the reaction time,19 an experiment
was conducted in which the concentration of 2b (75 mM) represented a 5-fold excess with respect to 3a
(entry 5); in this case, the reaction was indeed more efficient and 8a/8b was obtained in 53% yield. In
the course of these investigations, the cis/trans ratio remained close to 1:1. The best result, obtained at
20 mM on large scale (1 L), gave both 8a and 8b as single diastereoisomers in 45% yield. This approach
represents a valid alternative for access to 8a and 8b; starting from N-vinylformamide 2a, the two-step
protocol is slightly more efficient than the first route (42% combined overall yield) but requires higher
dilution for the photochemical step.
Table 3 Scaling the reaction between 2b and 3a
Entry
Conc.
75 mM
40 mM
20 mM
20 mM
75 mM
Scale
200 mL
200 mL
200 mL
1000 mL
200 mL
Ratio 8a/8ba
48:52
Yield (%)b
1
2
13
18
45
45
53
44:56
3
43:57
4
48:52
5c
50:50
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The Journal of Organic Chemistry
1
b
c
aRatio determined from crude H NMR spectra. Combined yield of isolated diastereoisomers. Reaction performed using 5
1
2
equiv. of 2b.
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8
For completeness, we examined a third enamine substrate, N-vinyl tert-butyl carbamate 2c, obtained in
98% yield by selective deformylation of 2b using NaOH in THF. The Paternò-Büchi reaction of 2c in
acetonitrile (75 mM, 200 mL scale) with two equivalents of 3a gave 10a and 10b in 41% yield as an
inseparable 1:1 diastereoisomeric mixture (Scheme 3). Since this route offered no advantage with
respect to the previous series, it was not pursued.
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Scheme 3
We turned our attention to the matter of resolution. Noting previous successes with chiral non-racemic
oxazolidinones as resolving agents for cyclic β-aminoacids,20 we screened three such auxiliaries for the
chiral derivatization of 9a and 9b (Table 4). Standard peptide coupling reagents were unproductive so
we applied more stringent conditions: the acid function of 9a or 9b was activated using pivaloyl chloride
and then treated with the lithium salt of the oxazolidinone 11a-c; highest yields were obtained using an
excess of both of these reagents.
After optimization, (±)-N-Boc-oxetin 9a and oxazolidinone 11a gave diastereoisomers 12aa1 and 12aa2
in 45% combined yield, which equated to 52% yield taking recovered starting material 9a into account
(entry 1). The modest yield was compounded by the impracticality of the separation of the two
diastereoisomers and unreacted 11a. With oxazolidinone 11b, the yield and ease of separation
improved slightly (entry 2). Oxazolidinone 11c gave better results: diastereoisomers 12ac1 and 12ac2
were obtained in 69% combined yield (81% based on recovered 9a) and were easily separated by
chromatography (entry 3).
With (±)-N-Boc-epi-oxetin 9b, oxazolidinone 11a provided diastereoisomers 12ba1 and 12ba2 in 66%
combined yield (86% yield based on recovered 9b) and separation by chromatography was satisfactory
(entry 4). This turned out to be the most practical system, for the corresponding derivatizations using
oxazolidinones 11b and 11c gave lower yields and poorer separations (entries 5,6).
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Table 4 Chiral resolution
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O
O
2
3
(a), (b)
Ox∗
Ox∗
BocHN
BocHN
(±)-9a
O
O
4
12aa1 12ab1 12ac1
12aa2 12ab2 12ac2
5
O
O
6
Ox∗
Ox∗
(a), (b)
BocHN
BocHN
(±)-9b
7
8
9
O
O
12ba1 12bb1 12bc1
12ba2 12bb2 12bc2
Conditions:
OBn
Me
Ph
(a) PivCl (1.5 eq),
NEt3 (1.2 eq), THF, 0 °C;
(b) LiOx∗ (1.6 eq),
THF, -78 °C
Ph
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LiN
O
LiN
O
LiN
O
LiOx∗
=
O
O
O
11c
11a
11b
Entry Sub. 9
LiOx▪ 11
11a
Product
12aa1/2
12ab1/2
12ac1/2
12ba1/2
12bb1/2
12bc1/2
Separationa
Yield (%)b
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4
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6
9a
Poor
Good
Excellent
Good
Fair
45 (52)
51c (57)
69 (81)
66 (86)
34 (44)
48 (55)
11b
11c
9b
11a
11b
11c
Poor
aEase of preparative chromatographic separation of diastereoisomers 12 and unreacted 11. bCombined yield of
diastereoisomers; in parentheses, yields based on recovered 9.
An important spin-off from the above endeavors was the isolation of crystals of derivatives 12ab2 and
12bb2 which were suitable for X-ray diffraction analysis, thus confirming the molecular structures and
revealing the absolute configurations of the oxetane stereogenic centers (Figure 2).
Me
Ph
O
N
O
BocHN
O
O
12ab2
Me
N
Ph
O
O
BocHN
O
O
12bb2
Figure 2 X-ray structures of 12ab2 and 12bb2.
Enantiomerically pure N-Boc-oxetins (2R,3S)-9a and (2S,3R)-9a were obtained in high yields by
LiOH/H2O2 hydrolysis of derivatives 12ac1 and 12ac2, respectively, in a procedure which allowed
recovery and recycling of oxazolidinone 11c. Similarly, derivatives 12ba1 and 12ba2 provided N-Boc-epi-
oxetins (2R,3R)-9b and (2S,3S)-9b as well as recovered oxazolidinone 11a. The absolute configurations of
these compounds were deduced by conducting analogous hydrolyses on 12ab2, which gave (+)-(2S,3R)-
9a, and 12bb2, which gave (_)-(2S,3S)-9b. Each N-Boc-β-aminoacid was deprotected in excellent yield
using TFA to complete the stated objectives and provide all four oxetin and epi-oxetin stereoisomers:
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The Journal of Organic Chemistry
(+)-1a, (_)-1a, (+)-1b and (_)-1b (Scheme 4). Spectroscopic and optical rotation data were in full
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agreement with the literature.2,4
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Scheme 4
Chiral derivatization may not always be a favored option so we considered an alternative access to
single oxetin stereoisomers using chiral HPLC. Racemates (±)-9a and (±)-9b (Scheme 2) were extensively
degraded regardless of the nature of the stationary phase. Pleasingly, however, each racemate (±)-8a
and (±)-8b (Table 3) was separated on a lux cellulose column with good selectivity (α = 1.63 for 8a and α
= 1.25 for 8b) providing ∼1 g of each enantiomer (ee >99% by chiral HPLC analysis) in 12 h using an
automatic injection sequence. We verified that the one-pot selective deprotection protocol proceeded
without incident, and obtained the expected single enantiomers of N-Boc-oxetin 9a and N-Boc-epi-
oxetin 9b in high yields on gram-scale (Scheme 5).
Scheme 5
In summary, an expedient access to all stereoisomers of oxetin on gram-scale has thus been established
via a Paternò-Büchi synthetic strategy starting from 2b and 3a. For any individual oxetin target, the
protocol requires 5 synthetic steps and 2 chromatographic separations if a resolving agent is employed,
or just 3 steps plus one chromatographic separation and one chiral HPLC operation if this latter
technique is preferred. The overall yield for a single isomer is ∼8% in the former case and ∼11% in the
latter.
Experimental Section
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General Experimental: All reagents and solvents were of commercial grade and were used without
further purification, with the exception of MeCN which was distilled from P2O5, n-BuOH which was
distilled from MgSO4, CH2Cl2 which was dried over activated alumina, and THF which was distilled from
sodium/benzophenone. Flash chromatography was performed on columns of silica gel (35–70 μm).
Analytical thin-layer chromatography was carried out on commercial 0.25 mm silica gel plates which
were visualized by UV fluorescence at 254 nm then revealed using a phosphomolybdic acid solution
(10% in EtOH) or a ninhydrin solution (0.3% in n-BuOH). Retention factors (Rf) are given for such TLC
analyses. Melting points were obtained in open capillary tubes and are uncorrected. Optical rotations
were measured using a 10 cm quartz cell; values for [α]DT were obtained with the D-line of sodium at the
indicated temperature T, using solutions of concentration (c) in units of g·100 mL-1. Fourier-transform
Infrared (IR) spectra were recorded for neat samples using an ATR diamond accessory; maximum
absorbances (ν) are given in cm-1. Nuclear magnetic resonance (NMR) data were acquired on a
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1
spectrometer operating at 400/360/300/250 MHz for H, and at 90/75/63 MHz for 13C. Chemical shifts
(δ) are reported in ppm with respect to tetramethylsilane (δ = 0 ppm). Splitting patterns for 1H NMR and
13C NMR signals are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintuplet),
broad singlet (br. s) or m (multiplet). Coupling constants (J) are reported in Hz. High-resolution mass
spectrometry (HRMS) data were recorded using on a spectrometer equipped with an electrospray
ionization source either in positive or negative mode as appropriate, with a tandem Q-TOF analyzer.
Preparative HPLC purification of the two enantiomers of the compounds 8a and 8b was carried out on a
commercial apparatus equipped with semi-preparative auto-sampler and collector accessories. All
solvents were HPLC grade and were filtered through a 0.45 μm PTFE membrane. Injected solutions were
filtered through a 0.22 μm PTFE membrane. Methyl glyoxylate 3b,14 tert-butyl glyoxylate 3c,14
oxazolidin-2-one 11a21a and oxazolidin-2-one 11b21b were prepared according to literature procedures.
General Procedure A for the Paternò-Büchi reaction
A solution of glyoxylate 3 (1 equiv.) and enamine derivative 2 (2 equiv.) in MeCN was placed in a
cylindrical immersion photochemical reactor and degassed with an argon stream for 30 min. The
solution was irradiated for 24 h with a 400 W medium-pressure Hg lamp fitted with a Pyrex® filter and a
water-cooling jacket. The solution was then evaporated under reduced pressure to give the crude
product which was purified by flash chromatography to afford the requisite product.
General Procedure B for the deformylation/saponification sequence
To an ice-cold solution of compound 8 (1 equiv.) in MeOH (13 mL/mmol) was added K2CO3 (3 equiv.).
The reaction mixture was stirred at 0 °C for 10 min then at room temperature for 2 h. Water (6
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mL/mmol) was added and the reaction was further stirred at room temperature for 1 h. MeOH was
evaporated under reduced pressure and the remaining aqueous solution was washed with EtOAc (3 × 6
mL/mmol). The aqueous phase was then acidified with KHSO4 and extracted with EtOAc (4 × 6
mL/mmol). The combined organic phases were dried over Na2SO4, filtrated and concentrated under
reduced pressure to give product 9.
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General procedure C for oxazolidinone coupling
To a cold (–78 °C) solution of racemic compound 9 (1 equiv.) and triethylamine (1.2 equiv.) in THF (10
mL/mmol) was added pivaloyl chloride (1.5 equiv.) dropwise. The mixture was stirred at 0 °C for 1 h to
form the mixed anhydride, and then cooled to –78 °C. In a separate flask, a cold (–40 °C) solution of
oxazolidinone 11 (1.6 equiv.) in THF (5 mL/mmol) was treated with a hexane solution of n-BuLi (1.6
equiv.) and stirred for 25 min. The resulting solution was cooled to –78 °C and added by rapid
cannulation to the cooled (–78 °C) solution of the mixed anhydride. Residual metalated oxazolidinone
was taken up by rinsing with dry THF and added to the cooled reaction mixture. After 2 h, the reaction
mixture was quenched at –78 °C by addition of a saturated aqueous solution of NaHCO3 then allowed to
warm to room temperature. THF was removed under reduced pressure and the remaining aqueous
solution was extracted with CH2Cl2 (3 × 15 mL/mmol). The combined organic phases were washed with a
saturated aqueous solution of NaHCO3 (15 mL/mmol) then brine (15 mL/mmol), dried over Na2SO4,
filtered and evaporated under reduced pressure. The residue was purified by flash chromatography to
afford the two diastereoisomers 12. Unreacted 9 was recovered from the basic aqueous phase by
acidification then extraction with CH2Cl2.
General procedure D for oxazolidinone cleavage
To an ice-cold solution of the indicated compound 12 (1 equiv.) in a 1:4 mixture of water and THF (25
mL/mmol) was added a 35% w/w solution of H2O2 (2 equiv.). The resulting mixture was stirred at 0 °C
for 5 min then a solution of LiOH·H2O (2 equiv.) in water (6 mL/mmol) was added. The mixture was
stirred at 0 °C for 2 h then a saturated aqueous solution of Na2SO3 (14 mL/mmol) and a saturated
aqueous solution of NaHCO3 (14 mL/mmol) were added successively. THF was removed under reduced
pressure and the residual aqueous solution was washed with CH2Cl2 to remove and recycled the chiral
auxiliary. The aqueous solution was then acidified to pH 1 with an aqueous solution of KHSO4 (1 M) and
extracted with CH2Cl2 (3 × 10 ml/mmol). The combined organic extracts were dried over Na2SO4, filtrated
and evaporated under reduced pressure to give non-racemic product 9.
General procedure E for Boc group removal
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To a solution of the indicated compound 9 (1 equiv.) in CH2Cl2 (15 mL/mmol) under argon was added
trifluoroacetic acid (15 equiv.). The solution was stirred for 3 h then reaction mixture was concentrated
under reduced pressure. The residue was applied to a column of Dowex® 50W-X8 cation exchange resin
(200 mesh) and eluted using 1 M NH4OH to give the target amino acid.
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Di-n-butyl tartrate
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To a mixture of tartaric acid (118 g, 0.78 mol, 1 equiv.) and n-BuOH (350 mL, 3.93 mol, 5 equiv.) was
added TMSCl (200 mL, 1.56 mol, 2 equiv.). The reaction mixture was refluxed for 6 h and then cooled to
room temperature. Excess n-BuOH and TMSCl were removed under reduced pressure and the oily
o
residue was distilled under reduced pressure (0.45 mm Hg) at 130 C to give the expected product as a
colorless oil (121 g, 59%). Rf (25:75 EtOAc/Petroleum ether): 0.60; IR ν 3487, 2961, 2935, 2875, 1738,
1243, 1124, 1086; 1H NMR (250 MHz, CDCl3) δ 4.48 (s, 2H), 4.18 (t, J = 6.6 Hz, 4H), 3.53 (s, 2H), 1.67-1.53
(m, 4H), 1.41-1.25 (m, 4H), 0.87 (t, J = 7.3 Hz, 6H), (lit.14a); 13C NMR (63 MHz, CDCl3) δ 171.6 (2C), 72.2
(2CH), 66.0 (2CH2), 30.5 (2CH2), 18.9 (2CH2), 13.5 (2CH3), (lit.14a); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C12H22O6Na 285.1314; Found 285.1302.
n
-Butyl glyoxylate 3a
o
To a solution of di-n-butyl tartrate (31.5 g, 120 mmol, 1 equiv.) in Et2O (1 L) at 0 C under argon was
added periodic acid dihydrate (27.3 g, 120 mmol, 1 equiv.) in portions (3 × 9.1 g) over a period of 1 h.
The reaction mixture was stirred further for 5 h at room temperature. The resulting mixture was then
filtered through a pad of Celite®/Na2SO4 and the filtrate was concentrated under reduced pressure. The
o
residue was distilled from P2O5 under reduced pressure (18 mm Hg) at 70 C to give product 3a as a
1
colorless oil (27 g, 86%). H NMR (250 MHz, CDCl3) δ 9.40 (s, 1H), 4.32 (t, J = 6.7 Hz, 2H), 1.81-1.63 (m,
2H), 1.51-1.34 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H), (lit.14d); 13C NMR (63 MHz, CDCl3) δ 184.0 (CH), 159.6 (C),
66.4 (CH2), 30.3 (CH2), 18.9 (CH2), 13.5 (CH3); HRMS (ESI-TOF) not stable.
tert-Butyl formyl(vinyl)carbamate 2b
To a solution of N-vinylformamide 2a (4.18 mL, 60 mmol, 1 equiv.) in THF (200 mL) were added Boc2O
(15.7 g, 72 mmol, 1.2 equiv.) and 4-dimethylaminopyridine (73 mg, 0.6 mmol, 0.01 equiv.). The reaction
mixture was stirred for 22 h under argon at room temperature then the solvent was removed under
reduced pressure. The residue was purified by flash chromatography (20:80 EtOAc/Petroleum ether) to
give product 2b as a colorless liquid (9.55 g, 93%). Rf (5:95 EtOAc/Petroleum ether): 0.46; IR ν 2982,
1
1740, 1709, 1349, 1297, 1249, 1140, 1053; H NMR (250 MHz, CDCl3) δ 9.23 (s, 1H), 6.57 (dd, J = 16.2,
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9.7 Hz, 1H), 5.65 (dd, J = 16.2, 1.2 Hz, 1H), 5.01 (d, J = 9.7 Hz, 1H), 1.54 (s, 9H), (lit.22); 13C NMR (63 MHz,
CDCl3) δ 162.1 (CH), 151.3 (C), 126.1 (CH), 107.8 (CH2), 84.8 (C), 27.8 (3CH3); HRMS (ESI-TOF) not stable.
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tert-Butyl vinylcarbamate 2c
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To a solution of tert-butyl formyl(vinyl)carbamate 2b (7.16 g, 41.9 mmol, 1 equiv.) in THF (25 mL) at 0 °C
was added carefully over a 20 min period a 2 M aqueous solution of NaOH (25 ml, 50 mmol, 1.2 equiv.).
The reaction mixture was left at 0 °C for a further 10 min, then stirred at room temperature for 2.5 h.
The reaction mixture was diluted with water (20 mL) and extracted with tBuOMe (4 × 20 mL). The
combined organic phases were then washed with water then brine. The resulting organic solution was
dried over Na2SO4 and concentrated under reduced pressure. The crude product was then recrystallized
at –20 °C overnight in pentane to give product 2c as a white solid (5.87 g, 98%). Rf (50:50
EtOAc/Petroleum ether): 0.33; Mp: 65-67 °C (lit.22 Mp: 67-68 °C); IR ν 3324, 2986, 2974, 1690, 1646,
1369, 1250, 1152, 1083, 977; 1H NMR (360 MHz, CDCl3) δ 6.75-6.58 (m, 1H), 6.29 (br. s, 1H), 4.40 (d, J =
15.7 Hz, 1H), 4.21 (d, J = 8.2 Hz, 1H), 1.47 (s, 9H), (lit.22); 13C NMR (90 MHz, CDCl3) δ 152.9 (C), 130.2 (CH),
92.0 (CH2), 80.4 (C), 28.3 (3CH3); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C7H14NO2 144.1019; Found
144.1021.
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n
-Butyl 3-formamidooxetane-2-carboxylate 5a/b
General procedure A was applied for the photochemical reaction between n-butyl glyoxylate 3a (13.0 g,
100 mmol) and N-vinylformamide 2a (14.2 g, 13.9 mL, 200 mmol) in MeCN (1 L). Flash chromatography
(70:30 EtOAc/Petroleum ether) gave a mixture of two inseparable diastereoisomers 5a and 5b (d.r.
50/50) as a colorless oil (9.17 g, 46%). Rf (70:30 EtOAc/Petroleum ether): 0.32; IR ν 3675, 3309, 2964,
2901, 1735, 1669, 1394, 1212, 1042; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H15NO4Na 224.0899;
Found 224.0891. From the mixture, the following NMR data was deduced. 5a: 1H NMR (300 MHz, CDCl3)
δ 8.13 (s, 1H), 6.83-6.73 (m, 1H), 5.56-5.41 (m, 1H), 5.29 (d, J = 7.8 Hz, 1H), 4.97 (dd, J = 7.6, 6.9 Hz, 1H),
4.66 (t, J = 6.6 Hz, 1H), 4.21 (t, J = 6.7 Hz, 2H), 1.71-1.55 (m, 2H), 1.44-1.29 (m, 2H), 0.93 (t, J = 7.3 Hz,
3H); 13C NMR (90 MHz, CDCl3) δ 170.1 (C), 161.0 (CH), 83.2 (CH), 76.7 (CH2), 65.4 (CH2), 44.1 (CH), 30.5
1
(CH2), 18.9 (CH2), 13.5 (CH3); 5b: H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 6.71-6.62 (m, 1H), 5.14- 5.01
(m, 2H), 4.84 (t, J = 6.9 Hz, 1H), 4.56 (t, J = 6.3 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2H), 1.69-1.55 (m, 2H), 1.42-
1.28 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 170.3 (C), 161.2 (CH), 83.9 (CH), 75.6
(CH2), 65.5 (CH2), 46.5 (CH), 30.4 (CH2), 18.9 (CH2), 13.6 (CH3).
Methyl 3-formamidooxetane-2-carboxylate 6a/b
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General procedure A was applied for the photochemical reaction between methyl glyoxylate 3b (924
mg, 10.5 mmol) and N-vinylformamide 2a (1.49 g, 1.46 mL, 21 mmol) in MeCN (200 mL). Flash
chromatography (90:10 EtOAc/Petroleum ether) gave a mixture of two inseparable diastereoisomers 6
(d.r. 50/50) as a white solid (622 mg, 37%). Rf (90:10 EtOAc/Petroleum ether): 0.21; IR ν 3676, 3299,
2987, 2971, 2961, 2901, 1735, 1670, 1522, 1388, 1230, 1178, 1042, 993; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C6H9NO4Na 182.0424; Found 182.042. From the mixture, the following NMR data was
deduced. 6a: 1H NMR (360 MHz, CDCl3) δ 7.99 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 5.36-5.25 (m, 1H), 5.21 (d,
J = 7.8 Hz, 1H), 4.81 (t, J = 7.2 Hz, 1H), 4.55 (t, J = 6.6 Hz, 1H), 3.64 (s, 3H); 13C NMR (90 MHz, CDCl3) δ
170.1 (C), 161.3 (CH), 83.1 (CH), 76.2 (CH2), 52.0 (CH3), 44.0 (CH). 6b: 1H NMR (360 MHz, CDCl3) δ 8.04 (s,
1H), 7.95 (d, J = 9.0 Hz, 1H), 5.02-4.93 (m, 2H), 4.69 (t, J = 6.8 Hz, 1H), 4.48 (t, J = 6.2 Hz, 1H), 3.66 (s, 3H);
13C NMR (90 MHz, CDCl3) δ 170.6 (C), 161.4 (CH), 83.5 (CH), 75.4 (CH2), 52.3 (CH3), 46.2 (CH).
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tert-Butyl 3-formamidooxetane-2-carboxylate 7a/b
General procedure A was applied for the photochemical reaction between tert-butyl glyoxylate 3c (1.06
g, 8.18 mmol) and N-vinylformamide 2a (1.16 g, 1.14 mL, 16.4 mmol) in MeCN (200 mL). Flash
chromatography (85:15 EtOAc/Petroleum ether) gave
a mixture of two inseparable and
indistinguishable diastereoisomers (d.r. 54/46) as a colorless oil (557 mg, 34%). Rf (90:10
EtOAc/Petroleum ether): 0.31; IR ν 3311, 2977, 2932, 2899, 2854, 1731, 1684, 1369, 1248, 1154, 1027;
1H NMR (360 MHz, CDCl3) δ 8.12 (s, 1H), 8.11 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H),
5.41-5.30 (m, 1H), 5.15 (d, J = 7.6 Hz, 1H), 5.07-4.95 (m, 1H), 4.93-4.85 (m, 2H), 4.75 (t, J = 7.0 Hz, 1H),
4.58 (t, J = 6.4 Hz, 1H), 4.49 (t, J = 6.5 Hz, 1H), 1.43 (s, 9H), 1.41 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 169.5
(C), 169.2 (C), 161.1 (CH), 161.0 (CH), 84.3 (CH), 83.2 (CH), 83.0 (C), 82.7 (C), 76.4 (CH2), 75.4 (CH2), 46.5
(CH), 44.3 (CH), 28.1 (3CH3), 27.9 (3CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H15NO4Na
224.0893; Found 224.0889.
Butyl 3-(N-(tert-butoxycarbonyl)formamido)oxetane-2-carboxylate 8a and 8b
General procedure A was applied for the photochemical reaction between n-butyl glyoxylate 3a (2.44 g,
18.8 mmol) and enecarbamate 2b (6.42 g, 37.5 mmol) in MeCN (1 L). Flash chromatography (70:20:10
Petroleum ether/CH2Cl2/EtOAc) of the crude mixture of diastereoisomers 8 (d.r. 48/52 by NMR analysis)
gave cis diastereoisomer 8a (1.00 g, 18%) and trans diastereoisomer 8b (1.53 g, 27%) as colorless oils
(2.53 g, 45%). 8a: Rf (70:20:10 Petroleum ether/CH2Cl2/EtOAc): 0.22; IR ν 2963, 2936, 1739, 1696, 1348,
1299, 1147, 1078, 1024; 1H NMR (360 MHz, CDCl3) δ 9.06 (s, 1H), 5.46 (dd, J = 16.3, 8.3 Hz, 1H), 5.22 (dd,
J = 7.7, 6.2 Hz, 1H), 5.17 (d, J = 8.6 Hz, 1H), 4.81 (dd, J = 8.4, 6.2 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 1.66-1.57
(m, 2H), 1.52 (s, 9H), 1.40-1.29 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 169.3(C),
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163.0 (CH), 151.5 (C), 85.6 (C), 81.4 (CH), 74.3 (CH2), 65.2 (CH2), 47.1 (CH), 30.5 (CH2), 28.0 (3CH3), 19.1
(CH2), 13.7 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H23NO6Na 324.1418; Found 324.1433. 8b:
Rf (70:20:10 Petroleum ether/CH2Cl2/EtOAc): 0.35; IR ν 2963, 2936, 1740, 1698, 1369, 1248, 1218, 1148,
1049; 1H NMR (250 MHz, CDCl3) δ 9.13 (s, 1H), 5.43 (d, J = 7.1 Hz, 1H), 5.34 (dd, J = 15.2, 7.2 Hz, 1H), 4.93
(t, J = 6.7 Hz, 1H), 4.73 (dd, J = 8.1, 6.2 Hz, 1H), 4.21 (q, J = 6.6 Hz, 2H), 1.72-1.59 (m, 2H), 1.57 (s, 9H),
1.47-1.31 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 170.0 (C), 162.9 (CH), 151.4 (C),
85.7 (C), 81.5 (CH), 73.0 (CH2), 65.4 (CH2), 48.4 (CH), 30.6 (CH2), 28.1 (3CH3), 19.0 (CH2), 13.7 (CH3);
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H23NO6Na 324.1418; Found 324.1423.
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To a solution of Boc2O (17.1 g, 78.5 mmol, 1.5 equiv.) and n-butyl 3-formamidooxetane-2-carboxylate
5a/b (d.r. 50/50; 10.5 g, 52.3 mmol, 1 equiv.) in THF (400 mL) was added the 4-dimethylaminopyridine
(64 mg, 0.52 mmol, 0.01 equiv.). The reaction mixture was stirred under argon at room temperature for
24 h. The solvent was removed under reduced pressure. Flash chromatography of the residue (70:20:10
Petroleum ether/CH2Cl2/EtOAc) gave cis diastereoisomer 8a (5.75 g, 37%) and trans diastereoisomer 8b
(7.61 g, 48%) as colorless oils. Spectral data of 8a and 8b were identical to those described above.
Butyl 3-(tert-butoxycarbonylamino)oxetane-2-carboxylate 10a/b
General procedure A was applied for the photochemical reaction between n-butyl glyoxylate 3a (2.10 g,
16.1 mmol) and enecarbamate 2c (4.61 g, 32.3 mmol) in MeCN (200 mL). Flash chromatography (20:80
EtOAc/Petroleum ether) gave the mixture of two inseparable and indistinguishable diastereoisomers 10
(d.r. 50/50) as a colorless oil (1.79 g, 41%). Rf (50:50 EtOAc/Petroleum ether): 0.33; IR ν 3350, 2965,
1
1696, 1367, 1249, 1161, 1062; H NMR (360 MHz, CDCl3) δ 5.58-5.05 (m, 4H), 4.99-4.45 (m, 6H), 4.22-
4.04 (m, 4H), 1.66-1.50 (m, 4H), 1.44-1.27 (m, 22H), 0.92-0.83 (m, 6H); 13C NMR (90 MHz, CDCl3) δ 170.3
(C), 170.3 (C), 154.5 (2C), 84.9 (CH), 84.2 (CH), 80.3 (2C), 78.3 (CH2), 76.5 (CH2), 65.3 (CH2), 65.1 (CH2),
49.4 (CH), 46.7 (CH), 30.7 (CH2), 30.6 (CH2), 28.4 (3CH3), 28.3 (3CH3), 19.1 (CH2), 19.0 (CH2), 13.7 (2CH3);
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H23NO5Na 296.1468; Found 296.1462.
cis-3-(tert-Butoxycarbonylamino)oxetane-2-carboxylic acid 9a
General procedure B was applied on compound 8a (1.01 g, 3.36 mmol) using K2CO3 (1.39 g, 10.1 mmol)
in MeOH (45 mL) to give product 9a as a white solid (703 mg, 97%). Mp: 153-155 °C; IR ν 3285, 2977,
1749, 1654, 1568, 1288, 1202, 1165, 1066; 1H NMR (250 MHz, CD3OD) δ 5.17 (d, J = 7.8 Hz, 1H), 5.06-
4.94 (m, 1H), 4.83-4.77 (m, 1H), 4.58 (t, J = 6.6 Hz, 1H), 1.39 (s, 9H); 13C NMR (63 MHz, CD3OD) δ 173.1
(C), 157.2 (C), 85.5 (CH), 80.7 (C), 77.0 (CH2), 48.3 (CH), 28.6 (3CH3); HRMS (ESI-TOF) m/z: [M – H]– Calcd
for C9H14NO5 216.0877; Found 216.0882.
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trans-3-(tert-Butoxycarbonylamino)oxetane-2-carboxylic acid 9b
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General procedure B was applied on compound 8b (1.00 g, 3.33 mmol) using K2CO3 (1.38 g, 10.0 mmol)
in MeOH (45 mL) to give product 9b as a white solid (687 mg, 96%). Mp: 124-125 °C; IR ν 3363, 2981,
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1724, 1693, 1533, 1169, 1055; H NMR (300 MHz, CD3OD) δ 4.96 (d, J = 4.8 Hz, 1H), 4.72-4.60 (m, 2H),
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8
9
4.53-4.46 (m, 1H), 1.41 (s, 9H); 13C NMR (90 MHz, CD3OD) δ 173.9 (C), 157.0 (C), 85.6 (CH), 80.9 (C), 76.9
(CH2), 50.7 (CH), 28.6 (3CH3); HRMS (ESI-TOF) m/z: [M – H]– Calcd for C9H14NO5 216.0877; Found
216.0872.
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tert-Butyl (2
R
,3
S
)-2-[(
R)-2-oxo-4-phenyloxazolidine-3-carbonyl]oxetan-3-yl carbamate 12ac1 and tert-
butyl (2 ,3 )-2-[(R
S
R
)-2-oxo-4-phenyloxazolidine-3-carbonyl]oxetan-3-yl carbamate 12ac2
General procedure C was applied using racemic Boc-oxetin 9a (1.30 g, 5.99 mmol) and triethylamine (1.0
mL, 7.19 mmol) in THF (60 mL), pivaloyl chloride (1.10 mL, 8.98 mmol), (R)-4-phenyloxazolidin-2-one 11c
(1.56 g, 9.58 mmol) in THF (29 mL) and n-BuLi (1.51 M solution in hexane; 6.35 mL, 9.58 mmol). Flash
chromatography (80:20 Et2O/Petroleum ether then 75:25 Et2O/EtOAc) gave diastereoisomer 12ac1 as
white powder (764 mg, 35%) and diastereoisomer 12ac2 as a white powder (731 mg, 34%). In addition,
unreacted 9a was recovered (190 mg, 15%). 12ac1: Rf (80:20, Et2O/Petroleum ether): 0.20; Mp: 84-85
27
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°C; [α]D –76 (c 0.5, CHCl3); IR ν 3316, 2977, 1777, 1704, 1383, 1251, 1161, 989; H NMR (360 MHz,
CDCl3) δ 7.44-7.27 (m, 5H), 6.22 (d, J = 7.0 Hz, 1H), 5.47 (dd, J = 8.6, 3.5 Hz, 1H), 5.34-5.13 (m, 2H), 4.90
(t, J = 7.0 Hz, 1H), 4.69 (t, J = 8.8 Hz, 1H), 4.47 (t, J = 5.7 Hz, 1H), 4.35 (dd, J = 8.8, 3.5 Hz, 1H), 1.44 (s, 9H);
13C NMR (90 MHz, CDCl3) δ 169.4 (C), 154.3 (C), 153.0 (C), 138.3 (C), 129.3 (2CH), 129.1 (CH), 126.3
(2CH), 85.0 (CH), 80.4 (C), 77.4 (CH2), 71.1 (CH2), 57.3 (CH), 48.6 (CH), 28.3 (3CH3); HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C18H22N2O6Na 385.1370; Found 385.1354. 12ac2: Rf (80:20, Et2O/Petroleum ether):
0.09; Mp: 146-148 °C; [α]D27 +11 (c 0.5, CHCl3); IR ν 3308, 2976, 1793, 1697, 1383, 1206, 1160, 1001; 1H
NMR (360 MHz, CDCl3) δ 7.46-7.28 (m, 5H), 6.03 (d, J = 7.7 Hz, 1H), 5.40 (dd, J = 8.7, 3.5 Hz, 1H), 5.36 (br.
s, 1H), 4.85-4.71 (m, 3H), 4.37 (t, J = 6.8 Hz, 1H), 4.30 (dd, J = 8.9, 3.5 Hz, 1H), 1.46 (s, 9H); 13C NMR (63
MHz, CDCl3) δ 169.6 (C), 154.0 (C), 153.1 (C), 139.0 (C), 129.5 (2CH), 129.0 (CH), 126.2 (2CH), 84.8 (CH),
80.5 (C), 78.1 (CH2), 71.4 (CH2), 57.6 (CH), 48.2 (CH), 28.4 (3CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C18H22N2O6Na 385.1370; Found 385.1352.
tert-Butyl (2
R
,3
S
)-2-[(4
S
,5
R
)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl]oxetan-3-yl carbamate
12ab1 and tert-butyl (2
S
,3 )-2-[(4 ,5 )-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl]oxetan-3-yl
R
S R
carbamate 12ab2
General procedure C was applied using racemic Boc-oxetin 9a (400 mg, 1.84 mmol) and triethylamine
(0.31 mL, 2.21 mmol) in THF (18 mL), pivaloyl chloride (0.34 mL, 2.76 mmol), (4S,5R)-4-methyl-5-
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phenyloxazolidin-2-one 11b (523 mg, 2.95 mmol) in THF (9 mL) and n-BuLi (1.37 M solution in hexane;
2.15 mL, 2.95 mmol). Flash chromatography (80:20 Et2O/Petroleum ether) gave diastereoisomer 12ab1
as a white powder (170 mg, 25%) and diastereoisomer 12ab2 as white powder (182 mg, 26%). Each
compound was purified by precipitation from Et2O solution by slow addition of petroleum ether. In
addition, unreacted 9a was recovered (45 mg, 11%). 12ab1: Rf (90:10 Et2O/Petroleum ether): 0.16; Mp:
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9
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190-192 °C; [α]D –30 (c 0.5, CHCl3); IR ν 3349, 2981, 1770, 1706, 1356, 1206, 1151, 978; H NMR (250
MHz, CDCl3) δ 7.48-7.27 (m, 5H), 6.23 (d, J = 7.6 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 5.44-5.24 (m, 1H), 5.20-
5.05 (m, 1H), 4.98 (t, J = 7.2 Hz, 1H), 4.90-4.77 (m, 1H), 4.58 (t, J = 6.6 Hz, 1H), 1.41 (s, 9H), 0.96 (d, J =
6.6 Hz, 3H); 13C NMR (250 MHz, CDCl3) δ 169.8 (C), 153.9 (C), 152.2 (C), 133.0 (C), 129.0 (CH), 128.8
(2CH), 125.6 (2CH), 84.9 (CH), 80.8 (C), 80.1 (CH), 77.6 (CH2), 54.5 (CH), 48.5 (CH), 28.3 (3CH3), 14.5
(CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H24N2O6Na 399.1527; Found 399.1510. 12ab2: Rf
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(90:10, Et2O/Petroleum ether): 0.22; Mp: 183-184 °C; [α]D +15 (c 0.25, CHCl3); IR ν 3356, 2984, 2973,
1770, 1711, 1364, 1249, 1216, 1147, 979; 1H NMR (250 MHz, CDCl3) δ 7.48-7.27 (m, 5H), 6.28 (d, J = 7.5
Hz, 1H), 5.68 (d, J = 7.1 Hz, 1H), 5.49 (br. s, 1H), 5.32-5.14 (m, 1H), 4.95 (t, J = 7.1 Hz, 1H), 4.90-4.75 (m,
1H), 4.55 (t, J = 6.6 Hz, 1H), 1.42 (s, 9H), 0.92 (d, J = 6.6 Hz, 3H); 13C NMR (250 MHz, CDCl3) δ 169.5 (C),
154.4 (C), 152.4 (C), 133.0 (C), 129.0 (CH), 128.8 (2CH), 125.7 (2CH), 85.2 (CH), 80.5 (C), 80.3 (CH), 77.2
(CH2), 54.7 (CH), 48.8 (CH), 28.3 (3CH3), 14.7 (CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C19H24N2O6Na 399.1527; Found 399.1533.
tert-Butyl
(2
R
,3
R
)-2-[(
S
)-4-benzyloxymethyl-2-oxooxazolidine-3-carbonyl]oxetan-3-yl
carbamate
12ba1 and tert-butyl (2S,3S)-2-[(S)-4-benzyloxymethyl-2-oxooxazolidine-3-carbonyl]oxetan-3-yl
carbamate 12ba2
General procedure C was applied using racemic Boc-epi-oxetin 9b (250 mg, 1.15 mmol) and
triethylamine (0.19 mL, 1.38 mmol) in THF (12 mL), pivaloyl chloride (0.21 mL, 1.73 mmol), (S)-4-
(benzyloxymethyl)oxazolidin-2-one 11a (382 mg, 1.84 mmol) in THF (6 mL) and n-BuLi (1.55 M solution
in hexane; 1.19 mL, 1.84 mmol). Flash chromatography (50:50 then 60:40 EtOAc/Petroleum ether) gave
the diastereoisomer 12ba1 as a colorless oil (130 mg, 28%) and diastereoisomer 12ba2 as a white solid
(177 mg, 38%). The latter compound was purified by precipitation from Et2O solution by slow addition of
petroleum ether. In addition, unreacted 9b was recovered (60 mg, 24 %). 12ba1: Rf (55:45
26
EtOAc/Petroleum ether): 0.42; [α]D +46 (c 0.5, CHCl3); IR ν 3349, 2967, 1779, 1702, 1365, 1260, 1160,
1092, 1014; 1H NMR (360 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 5.84 (d, J = 5.5 Hz, 1H), 5.67 (br. s, 1H), 4.86-
4.75 (m, 1H), 4.67-4.51 (m, 5H), 4.49-4.43 (m, 2H), 3.83 (dd, J = 9.8, 4.9 Hz, 1H), 3.64 (dd, J = 9.8, 1.8 Hz,
1H), 1.43 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 169.6 (C), 155.2 (C), 153.9 (C), 137.3 (C), 128.7 (2CH), 128.2
(CH), 127.9 (2CH), 83.2 (CH), 80.2 (C), 76.1 (CH2), 73.6 (CH2), 67.5 (CH2), 67.0 (CH2), 53.6 (CH), 50.3 (CH),
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28.4 (3CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H26N2O7Na 429.1632; Found 429.1631. 12ba2:
Rf (55:45, EtOAc/Petroleum ether): 0.35; Mp: 124-126 °C; [α]D26 +41 (c 0.5, CHCl3); IR ν 3351, 2980, 2884,
1775, 1710, 1691, 1384, 1247, 1204, 1165, 986; 1H NMR (360 MHz, CDCl3) δ 7.39-7.22 (m, 5H), 5.97 (d, J
= 5.8 Hz, 1H), 5.75 (br. s, 1H), 4.84-4.66 (m, 2H), 4.62-4.36 (m, 6H), 3.79 (dd, J = 9.9, 4.6 Hz, 1H), 3.59 (d,
J = 9.9 Hz, 1H), 1.44 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 169.7 (C), 155.1 (C), 153.7 (C), 137.3 (C), 128.5
(2CH), 128.0 (CH), 127.6 (2CH), 84.2 (CH), 80.2 (C), 75.4 (CH2), 73.3 (CH2), 67.5 (CH2), 66.5 (CH2), 53.7
(CH), 50.1 (CH), 28.3 (3CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H26N2O7Na 429.1632; Found
429.1611.
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tert-Butyl (2
R
,3
R
)-2-[(4
S
,5
R
)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl]oxetan-3-yl carbamate
12bb1 and tert-butyl (2
S
,3 )-2-[(4 ,5 )-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl]oxetan-3-yl
S
S R
carbamate 12bb2
General procedure C was applied using racemic Boc-epi-oxetin 9b (150 mg, 0.69 mmol) and
triethylamine (0.12 mL, 0.83 mmol) in THF (7 mL), pivaloyl chloride (0.13 mL, 1.04 mmol), (4S,5R)-4-
methyl-5-phenyloxazolidin-2-one 11b (196 mg, 1.11 mmol) in THF (3.5 mL) and n-BuLi (1.52 M solution
in hexane; 0.73 mL, 1.11 mmol). Flash chromatography (80:20, Et2O/Petroleum ether) gave the single
diastereoisomer 12bb2 as a white solid (45 mg, 17%) and a mixture of diasteroisomers 12bb1 and 12bb2
as a white solid (44 mg, 17%). In addition, unreacted 9b was recovered (34 mg, 23%). 12bb2: Rf (80:20
27
Et2O/Petroleum ether): 0.26; Mp: 147-148 °C; [α]D –50 (c 0.38, CHCl3); IR ν 3380, 2990, 2886, 1795,
1
1713, 1346, 1256, 1247, 1197, 1161, 989; H NMR (360 MHz, CDCl3) δ 7.46-7.28 (m, 5H), 6.10 (d, J = 3.8
Hz, 1H), 5.81 (d, J = 7.1 Hz, 1H), 5.66 (d, J = 5.8 Hz, 1H), 4.89-4.74 (m, 3H), 4.64-4.55 (m, 1H), 1.44 (s, 9H),
0.94 (d, J = 6.6 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 169.6 (C), 155.3 (C), 153.1 (C), 133.0 (C), 129.0 (CH),
128.8 (2CH), 125.7 (2CH), 84.8 (CH), 80.5 (C), 80.2 (CH), 75.3 (CH2), 55.0 (CH), 50.3 (CH), 28.3 (3CH3), 14.6
(CH3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H24N2O6Na 399.1527; Found 399.1511. From the
1
diastereoisomeric mixture, the following NMR data was deduced. 12bb1: H NMR (400 MHz, CDCl3) δ
7.46-7.28 (m, 5H), 5.94 (d, J = 5.4 Hz, 1H), 5.76 (d, J = 7.5 Hz, 1H), 5.63 (d, J = 3.5 Hz, 1H), 4.89-4.75 (m,
2H), 4.73-4.64 (m, 1H), 4.64-4.55 (m, 1H), 1.47 (s, 9H), 0.98 (d, J = 6.6 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ
169.3 (C), 154.9 (C), 152.5 (C), 132.8 (C), 128.4 (CH), 128.3 (2CH), 125.4 (2CH), 84.1 (CH), 79.7 (CH), 79.4
(C), 74.9 (CH2), 54.0 (CH), 49.7 (CH), 27.9 (3CH3), 14.0 (s, CH3).
(2R,3S)-3-(tert-Butoxycarbonylamino)oxetane-2-carboxylic acid (–)-9a
General procedure D was applied on compound 12ac1 (78 mg, 0.22 mmol) in a 1:4 mixture of water and
THF (5 mL) with a 35% w/w solution of H2O2 (0.037 mL, 0.43 mmol) and LiOH·H2O (18 mg, 0.43 mmol) in
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water (0.8 mL), to give (–)-9a (38 mg, 82%). [α]D –31 (c 0.5, CHCl3). Spectral data were identical to
1
2
3
those obtained for racemic material described above.
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5
6
General procedure B was applied on compound (2
R
,3
S
)-8a (1.51 g, 5.0 mmol) using K2CO3 (2.07 g, 15.0
26
mmol) in MeOH (65 mL) to give (–)-9a (1.08 g, 99%). [α]D –32 (c 0.5, CHCl3). Spectral data were
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identical to those described above.
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(2S,3R)-3-(tert-Butoxycarbonylamino)oxetane-2-carboxylic acid (+)-9a
General procedure D was applied on compound 12ac2 (62 mg, 0.17 mmol) in a 1:4 mixture of water and
THF (4 mL) with a 35% w/w solution of H2O2 (0.030 mL, 0.34 mmol) and LiOH·H2O (14 mg, 0.34 mmol) in
27
water (0.5 mL), to give (+)-9a (29 mg, 78%). [α]D +32 (c 0.5, CHCl3). Spectral data were identical to
those described for racemic material above.
General procedure D was applied on compound 12ab2 (39 mg, 0.10 mmol) in a 1:4 mixture of water and
THF (2.5 mL) with a 35% w/w solution of H2O2 (0.018 mL, 0.21 mmol) and LiOH·H2O (9 mg, 0.21 mmol) in
27
water (0.4 mL), to give (+)-9a (20 mg, 89%). [α]D +30 (c 0.5, CHCl3). Spectral data were identical to
those described above.
General procedure B was applied on compound (2
S
,3
R
)-8a (1.01 g, 3.35 mmol) using K2CO3 (1.39 g, 10.1
25
mmol) in MeOH (45 mL), to give (+)-9a (698 mg, 96%). [α]D +33 (c 0.5, CHCl3). Spectral data were
identical to those described above.
(2R,3R)-3-(tert-Butoxycarbonylamino)oxetane-2-carboxylic acid (+)-9b
General procedure D was applied on compound 12ba1 (140 mg, 0.35 mmol) in a 1:4 mixture of water
and THF (10 mL) with a 35% w/w solution of H2O2 (0.060 mL, 0.69 mmol) and LiOH·H2O (29 mg, 0.69
mmol) in water (2 mL), to give (+)-9b (75 mg, 99%). [α]D24 +35 (c 0.5, CHCl3). Spectral data were identical
to those described for racemic material above.
General procedure B was applied on compound (2
R,3
R)-8b (1.28 g, 4.25 mmol) using K2CO3 (1.76 g, 12.8
26
mmol) in MeOH (55 mL) to give (+)-9b (890 mg, 97%). [α]D +31 (c 0.5, CHCl3). Spectral data were
identical to those described above.
(2S,3S)-3-(tert-Butoxycarbonylamino)oxetane-2-carboxylic acid (–)-9b
General procedure D was applied on compound 12ba2 (59 mg, 0.15 mmol) in a 1:4 mixture of water and
THF (3 mL) with a 35% w/w solution of H2O2 (0.025 mL, 0.29 mmol) and LiOH·H2O (12 mg, 0.29 mmol) in
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25
water (0.5 mL), to give (–)-9b (31 mg, 97%). [α]D –36 (c 0.5, CHCl3) {lit.4 [α]D –61.2 (c 0.5, CDCl3)}.
Spectral data were identical to those described for racemic material above, and in the literature.4
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General procedure D was applied on compound 12bb2 (76 mg, 0.20 mmol) in a 1:4 mixture of water and
THF (5 mL) with a 35% w/w solution of H2O2 (0.035 mL, 0.40 mmol) and LiOH·H2O (17 mg, 0.40 mmol) in
water (1 mL), to give (–)-9b (38 mg, 87%). [α]D22 –33 (c 0.5, CHCl3). Spectral data were identical to those
described above.
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General procedure B was applied on compound (2
S
,3S
)-8b (1.02 g, 3.40 mmol) and K2CO3 (1.41 g, 10.2
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mmol) in MeOH (45 mL), to give (–)-9b (710 mg, 96%). [α]D –32 (c 0.5, CHCl3). Spectral data were
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identical to those described above.
(2R,3S)-3-aminooxetane-2-carboxylic acid (+)-1a
General procedure E was applied on (2R,3S)-Boc-oxetin (87 mg, 0.40 mmol) in CH2Cl2 (6 mL) with
trifluoroacetic acid (0.460 mL, 6.02 mmol) to give (2R,3S)-oxetin (+)-1a (45 mg, 96%). Mp: 199-201 °C
(lit.2 Mp: 185-190 °C); [α]D26 +54 (c 0.18, H2O) {lit.2 [α]D25 +56.4 (c 1.0, H2O)}; IR ν 3117, 2986, 2895, 1636,
1
1618, 1555, 1410, 1378 1297, 1007, 952; H NMR (360 MHz, D2O) δ 5.13 (d, J = 6.9 Hz, 1H), 4.88-4.81
(m, 1H), 4.46-4.35 (m, 2H), (lit.2); 13C NMR (90 MHz, D2O) δ 175.2 (C), 81.1 (CH), 72.9 (CH2), 47.4 (CH),
(lit.2); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C4H8NO3 118.0499; Found 118.0501.
(2S,3R)-3-aminooxetane-2-carboxylic acid (–)-1a
General procedure E was applied on (2S,3R)-Boc-oxetin (+)-9a (128 mg, 0.59 mmol) in CH2Cl2 (9 mL)
with trifluoroacetic acid (0.677 mL, 8.85 mmol) to give (2S,3R)-oxetin (–)-1a (67 mg, 97%). Mp: 199-201
°C (lit.2 Mp: 185-190 °C); [α]D27 –54 (c 0.2, H2O) {lit.2 [α]D21 –56.0 (c 1, H2O)}; IR ν 3117, 2986, 2895, 1636,
1618, 1555, 1410, 1378 1297, 1007, 952; 1H NMR (360 MHz, D2O) δ 5.13 (d, J = 6.9 Hz, 1H), 4.88-4.81 (m,
1H), 4.46-4.35 (m, 2H), (lit.2); 13C NMR (90 MHz, D2O) δ 174.9 (C), 80.3 (CH), 72.2 (CH2), 47.3 (CH), (lit.2);
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C4H8NO3 118.0499; Found 118.0498.
(2R,3R)-3-aminooxetane-2-carboxylic acid (+)-1b
General procedure E was applied on (2R,3R)-Boc-epi-oxetin (+)-9b (130 mg, 0.60 mmol) in CH2Cl2 (9 mL)
with trifluoroacetic acid (0.688 mL, 8.99 mmol) to give (2R,3R)-epi-oxetin (+)-1b (68 mg, 97%). Mp: 182-
183 °C; [α]D27 +13 (c 0.5, H2O) {lit.2 [α]D21 +13.7 (c 1, H2O)}; IR ν 3663, 2971, 2903, 1565, 1392, 1297, 946,
1
928; H NMR (250 MHz, D2O) δ 4.91 (t, J = 5.2 Hz, 1H), 4.72-4.60 (m, 1H), 4.56-4.45 (m, 1H), 4.26-4.14
(m, 1H), (lit.2); 13C NMR (90 MHz, D2O) δ 176.8 (C), 83.1 (CH), 72.0 (CH2), 49.7 (CH), (lit.2); HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C4H7NO3Na 140.0318; Found 140.0321.
(2S,3S)-3-aminooxetane-2-carboxylic acid (–)-1b
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General procedure E was applied on (2S,3S)-Boc-epi-oxetin (–)-9b (108 mg, 0.5 mmol in CH2Cl2 (7.5 mL)
with trifluoroacetic acid (0.57 mL, 7.46 mmol) to give (2S,3S)-epi-oxetin (–)-1b (58 mg, 99%). Mp: 182-
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5
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15
25
183 °C; [α]D –12 (c 0.5, H2O) {lit.2 [α]D –12 (c 1, H2O); lit.4 [α]D –13.6 (c 1, H2O)}; IR v 3663, 2971,
1
2903, 1565, 1392, 1297, 946, 928; H NMR (250 MHz, D2O) δ 4.91 (virt.t, J = 5.2 Hz, 1H), 4.72-4.60 (m,
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8
1H), 4.56-4.45 (m, 1H), 4.26-4.14 (m, 1H), (lit.2,4); 13C NMR (90 MHz, D2O) δ 176.8 (C), 83.1 (CH), 72.0
9
(CH2), 49.7 (CH), (lit.2,4); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C4H7NO3Na 140.0318; Found 140.0320.
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Enantiomeric separation of 8a
Separation was performed using a Lux Cellulose-1 column (250 mm × 10 mm; particle size 5 μm). The
HPLC system was operated with 80:20 hexane/iso-propanol as mobile phase flowing at a rate of 5
mL·min–1. The mobile phase and the column were thermostated at 20 ± 2 °C. Detection was performed
at 210 nm with a 15 min run time. Sample solutions were in iso-propanol (500 mg·mL–1), injection
26
volume 100 μL. (2
R,3S)-8a: retention time: 10.0 min; [α]D –20 (c 0.5, CHCl3); spectral data were
identical to those reported above. (2
S,3R
)-8a: retention time: 7.0 min; [α]D26 +21 (c 0.5, CHCl3). Spectral
data were identical to those reported for racemic material above.
Enantiomeric separation of 8b
Separation was performed using a Lux Cellulose-2 column (250 mm × 10 mm; particle size 5 μm). The
HPLC system was operated with 80:20 hexane/ethanol as mobile phase flowing at a rate of 5 mL·min–1.
The mobile phase and the column were thermostated at 20 ± 2 °C. Detection was performed at 210 nm
with a 15 min run time. Sample solutions were in ethanol (500 mg·mL–1), injection volume 75 μL.
25
(2
R,3
R)-8b: retention time: 11.9 min; [α]D –3 (c 1.5, CHCl3); spectral data were identical to those
25
reported above. (2S,3S)-8b: retention time: 10.0 min; [α]D +3 (c 1.5, CHCl3). Spectral data were
identical to those reported for racemic material above.
Associated content
Supporting Information
Copies of 1H and 13C NMR spectra, crystallographic data for the compounds 12ab2 and 12bb2
(respectively CCDC 1491706 and CCDC 1491705) and chiral HPLC chromatograms are presented in the
Electronic Supporting Information. The ESI and crystallographic data in CIF are available free of charge
on the ACS Publications website at http://pubs.acs.org/.
Author information
Corresponding Authors
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* E-mail: david.aitken@u-psud.fr
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Notes
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The authors declare no competing financial interest.
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Acknowledgments
A. F. K. is grateful to the Municipality of Dair Kanoun Al-Nahr, Lebanon, for the award of a doctoral
research scholarship, and warmly thanks Dr O. Yazbeck of the Lebanese University for help and
professional council. S. S. R. acknowledges the award of a Fellowship by the Institut Français d’Egypte
and the Science and Technology Development Fund in Egypt. For financial support allowing equipment
acquisition, we thank the French ANR (project 2011-INTB-1003-01) and Université Paris Sud (AAP-
Attractivité 2013).
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References
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2
Ōmura, S.; Murata, M.; Imamura, N.; Iwai, Y.; Tanaka, H. J. Antibiot. 1984, 37, 1324-1332.
Kawahata, Y.; Takatsuto, S.; Ikekawa, N.; Murata, M.; Ōmura, S. Chem. Pharm. Bull. 1986, 34,
3102-3110.
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5
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12 For Paternò-Büchi reactions implicating N-acyl enamines, see ref. 3 and (a) Vogt, F.; Jödicke, K.;
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13 With the exception of ref. 3, Paternò-Büchi reactions implicating glyoxylate esters have been
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19 Lenz, G. R. Synthesis 1978, 489-518.
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21 Based on procedures described in the following publications: (a) Tussetschläger, S.; Baro, A.;
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