Synthesis of β-lactams: Via diastereoselective, intramolecular Kinugasa reactions

Article abstract of DOI:10.1039/d0ob00228c

Intramolecular Kinugasa reactions on in situ generated carbohydrate-derived alkynylnitrones are described. The effects of the length of chains, their mutual configuration, influence of experimental conditions on product distribution and feasibility of the

Full text of DOI:10.1039/d0ob00228c

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OrPgleanasice&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/D0OB00228C
ARTICLE
Synthesis of β-lactams via diastereoselective, intramolecular
Kinugasa reactions
Oskar Popik, Barbara Grzeszczyk, Olga Staszewska-Krajewska, Bartłomiej Furman and Marek
Chmielewski*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Intramolecular Kinugasa reactions on in situ generated carbohydrate-derived alkynylnitrones are described. The effects of
chains length, their mutual configuration, and influence of experimental conditions on products distribution and feasibility
of the β-lactam ring construction were studied. Intramolecular reactions proceeds with high stereoselectivity to provide in
each case one product only. The cycloadducts from tartaric acid were converted into corresponding non-racemic 4-acetoxy
azetidinones in a good yield.
[2+2] cycloaddition, and not on the 1,3-dipolar cycloaddition of
Introduction
a nitrone and terminal Cu(I) acetylide.
Intramolecular reactions usually offer distinct advantages over
their intermolecular counterparts by providing a tethering unit
which connects reacting functionalities. The proximity of the
reacting functionalities, combined with some reduction of
degrees of freedom of the system, render the intramolecular
transformation more entropically and kinetically favourable.
These factors lead to a more stereo-, regio- and chemoselective
process which is often reflected in an increased yield of the
desired product.
Over the past few years it has been demonstrated that the
reaction between nitrones and the in situ generated Cu(I)–
acetylide species, known as the Kinugasa reaction, has been a
robust and versatile route for the synthesis of non-racemic β-
lactam derivatives.1-10 However, probably due to the
simultaneous presence of a nitrone and a terminal acetylide
group on a chiral scaffold and the high probability of a
spontaneous reaction between those reactive groups, the
Kinugasa reaction has been realized predominately as an
intermolecular process and only a few communications on the
catalytic enantioselective intramolecular version of that
reaction have been reported.11-13
Results and discussion
Due to their easy transformation into many different structural
forms, monosaccharides offer scaffolds that allow to place both
reacting functions in a variety of spatial arrangements. In the
present paper we selected diacetone-D-glucose and diethyl L-
tartrate for that purpose. The starting substrates, enantiopure
alkynylaldehydes 1–4 and 5–6 were conveniently synthesised
following standard transformations that allow to arrange
nitrone and terminal acetylene groups at varying distances from
one another (Figure 1). Compounds 1, 2, 5, and 6 were obtained
from their alcoholic precursors via standard Dess-Martin
periodinane oxidation.18 It should be emphasized that the
presence in the same molecule of nitrone and a triple bond
might lead to the intramolecular 1,3-dipolar cycloaddition and
formation an isoxazoline ring without participation of Cu(I) ion.
Therefore, the proper selection of reaction conditions was
essential for the successful formation of β-lactam fragment.
Initially, we investigated reactions of alkynylaldehyde 1 with N-
benzylhydroxylamine (1.5 equiv.) (Scheme 1). After several
attempts, we found out that regardless of chosen reaction
The 1,3-dipolar cycloaddition between a nitrone and acetylide
(the first step of the β-lactam ring formation) with the dipole
and dipolarophile linked by several atoms, should induce a
highly ordered transition state providing the configuration
control at C-4 of the azetidinone ring,14-16 which is crucial for
biological activity of the target compound. Recently, Hein and
co-workers17 proposed a new mechanism of Kinugasa reaction
which postulated a cascade involving (3+2) cycloaddition, (3+2)
cycloreversion to ketene and imine and, finally, [2+2]
cycloaddition. If this mechanism is correct, then the
configuration of the stereogenic center at C-4 of the four
membered β-lactam ring should depend on the Staudinger
conditions, the isoxazoline
although the expected nitrone
reaction mixture. The product
characterized with the help of IR, NMR (1D, 2D, NOE)
spectroscopy, and ESI-HRMS analysis.
8
was the only isolated product,
was observed in the crude
was unambiguously
7
8
O
O
BnO
RO
RO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
H
H
O
O
O
O
BnO
BnO
O
O
5: R=Bn
6: R=Me
1
2
3
4
Fig. 1 Substrates for the Kinugasa reaction used in this work.
Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland. E-mail: marek.chmielewski@icho.edu.pl
Electronic Supplementary Information (ESI) available: CCDC 1975296. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x
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ARTICLE
Journal Name
O-
OBn
O
BnO
H
View Article Online
DOI: 10.1039/D0OB00228C
H
1) N-BnNHOH (1 equiv.)
Na CH
N+
O
H
O
O
2SO 3CN
0 °C, 24h,
N
O
H
O
N
H
H
O
N-BnNHOH·HCl,
Et
SO4,
O
O
O
H
O
O
3N, Na2
O
H
O
O
O
H
O
O
2) CuBr (cat.),
Et
H
N (1 equiv.)
Et3
DCM, RT
O
O
O
O
O
O
3N·HCl (10 equiv.)
-30 °C to 0 °C
2
11
49%*
20 h
1
7
8
72%
Scheme 3 Synthesis of β-lactam 11.
Scheme 1 Synthesis of isoxazoline 8.
O
N-BnNHOH (1 equiv.)
2SO4,
0 °C, 2h
1)
Na
CH
3CN
H
H
O
N
H
OH
O
+
TrO
O
H
OH
HN
O
H
TrO
O
O
O
H
HO
O
O
O
O
CHCCH2Br
O
O
H
TrCl/Py
72.3%
H
p-TsOH
85.7%
2) CuBr (5 mol%),
Et
O
O
O
O
O
H
O
N (1 equiv.)
Et3
O
O
H
TBAB
PTC
O
3N·HCl (10 equiv.)
O
O
-30 °C to 0 °C, 20h
O
O
O
9
10
17%
15%
57.9%
1
12
14
13
-O
N+
Cu
O
O
H
O
O
O
OEt
O
HO
O
O
7
O
O
H
O
O
Ethyl
DIBAL-H
DCM
O
O
O
bromoacetate
H
O
O
H
H
O
94%
Scheme 2 An attempt to the synthesis of β-lactam 9.
O
BuLi/THF
44.9%
O
O
O
O
15
3
16
Following the observation of unwanted side reactions, we
decided to perform the intramolecular reaction as a one-pot
process with the in situ generated nitrone. We found that the
Bn
O
Et
O
N·HCl (10 equiv.)
3Et
N
N
H
BnNHOH (1equiv.)
(10 equiv.)
3N (1 equiv.)
CuBr (0.1 equiv.)
-30 °C to 0 °C
20 h
most effective conditions for the nitrone
7
formation consisted
O
Na2SO4
H
O
CH3CN (anhyd.)
O
O
0 o
O
C, 20 h
of treatment of substrate at 0 °C with N-benzylhydroxylamine
1
O
O
H
O
O
two steps
55.4%
O
H
in the presence of anhydrous Na2SO4 as a water scavenging
agent. After 2 h, the temperature was lowered to -30 °C and
triethylamine hydrochloride, triethylamine and CuBr were
added. The addition of triethylamine hydrochloride as a proton
donor to the reaction mixture was found to be essential for the
β-lactam ring formation. The mixture was then stirred for 20 h,
while the temperature was slowly increased to 0 °C to complete
the intramolecular Kinugasa reaction. After purification by
O
RO
17
18 R = Bn
19 R = H
Scheme 4 Synthesis of β-lactam 18
.
The alternative option located both substituents in opposite
places; propargyl at C-6 of the sugar chain and the nitrone at C-
5 carbon atoms. The alkyne-ester 21 was obtained in two steps
from 12. Reduction of 21 with DIBAL to the aldehyde
Kinugasa reaction in 22 performed under the general
procedure provided β-lactam 23 in 51.1 % yield. The product 23
was accompanied by a minute amount of the α,β-unsaturated
amide 24 (6.1%) (Scheme 5).
Structure and configuration of compound 18 was proven easily
by the H NMR (NOEs and coupling constant between four-
4 and the
chromatography, the expected β-lactam
yield (Scheme 2). The compound was accompanied by the
product of the four-membered ring opening 10
Introduction of the nitrone function to the end of the sugar
chain ( ) increased the distance between reacting groups to
allow for their more convenient mutual approach (Scheme 3).
Under reaction conditions applied previously for , β-lactam 11
9 was obtained in 17%
,
9
.
2
1
9
membered ring protons) of 3-O-debenzylated compound 19
and CD spectroscopy (absolute configuration of the β-lactam
fragment).19-26 Compound 18 exhibited a positive sign of the
Cotton effect (CE) signal of the n→π* β-lactam amide transition
was obtained as a single diastereomer in 49% yield. The
presence of the stereogenic center at C-5 of the sugar chain and
a rigid transition state of the intramolecular reaction, controlled
configuration of the final product 11. The structures and
configurations of β-lactams 9 and 11 were fully corroborated by
their respective IR and NMR (NOEs) data.
(R configuration at C-4 of the azetidinone ring). Due to the
1
overlapping of protons in H NMR spectrum of compound 23
,
the absolute configuration of the β-lactam fragment could not
be verified unambiguously by NOEs. On the other hand, the
absolute configuration of 23 was established by the CD
spectroscopy showing the ECD signal negative (S configuration
at C-4).19,25
Extension of the distance between nitrone and alkyne groups
could be easily achieved by placement of both substituents in
the side chain of 1,2-isopropylidene-gluco-furanose via
introduction of O-propargyl and O-carbonylmethyl substituents
in two variants (Scheme 4). The first one located the O-
propargyl residue at C-5 of the sugar chain (15), whereas the
nitrone was formed by a three step procedure: (i) alkylation of
the terminal hydroxyl with ethyl bromoacetate (16), (ii)
reduction of ethoxycarbonyl to the aldehyde group (
formation of the nitrone (17) which in situ reacted with the
alkyne under conditions used for and 11 formation to afford
3) and (iii)
9
β-lactam 18 in 55.4% yield as a single isomer.
2 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
ether of diethyl tartrate was easily transformed into the
O
O
H
OEt
View Article Online
5
by the standarDdOIr:e10a.c1t0i3o9n/D0sOeqBu00e2n2c8eC.
propargyl aldehyde
OH
O
O
O
O
O
Ethyl
bromoacetate
O
O
O
Intramolecular Kinugasa reaction via the in situ formation of the
nitrone group (25) led to the bicyclic product 27 with the β-
lactam fragment fused to the seven-membered ring in 54% yield
(Scheme 7).
DIBAL-H
DCM
CHCCH2Br
O
O
O
H
H
H
12
Bu2SnO
BuLi/THF
61.3%
96%
O
O
O
O
O
O
4A,toluene
57.1%
21
4
20
Bn
R
H
R
H
O
O
N
O
Et
O
N
O
NH
N·HCl (10 equiv.)
3Et
H
H
H
N
H
H
BnNHOH (1 equiv.)
(10 equiv.)
H
3N (1 equiv.)
CuBr (0.1 equiv.)
-30 °C to 0 °C
20 h
Na2SO4
H
O
CH3CN (anhyd.)
0 °C, 20 h
O
+
O
O
O
O
O
C
O
N
O
O
O
O
O
Bn
Bn
O
O
O
O
H
18
H
O
O
O
O
O
O
R
R
O
H
H
H
24
6.1%
H
22
23
51.1%
O
H
H
O
R=
H
O
O
N
O
C
BnO
N
Scheme 5 Synthesis of β-lactam 23.
Bn
O
Bn
O
23
Scheme 6 Stereochemical pathway of the [2+2]cycloaddition step of the intramolecular
Kinugasa reaction in compounds 18 and 23 following Hein et al.17 mechanistic
proposition.
In accordance with the alternative regiochemistry, the inductive
stereogenic center (C-5 of the sugar chain) was closer to the
triple bond (Scheme 4), or to the nitrone (Scheme 5). In both
cases the cis substituted β-lactam ring was fused to the 1,4-
dioxa-cyclooctane ring and located anti to the carbohydrate
substituent. Consequently, the opposite absolute configuration
of the four membered ring carbon atoms were induced.
The presence of other stereoisomers was not observed. The
only isolated side product 31 was likely formed by opening of β-
lactam ring. Formation of the seven-membered ring in 1,3-
dipolar cycloaddition in the first step of the Kinugasa reaction
caused location of the five-membered ring anti to the next
stereogenic center. The alternatively proposed mechanism
involving intramolecular Staudinger [2+2] cycloaddition of the
ketene to imine located both substituents of the β-lactam ring
cis, anti to the next benzyloxy group. The same reaction
In the case of β-lactams
9 and 11 the influence of geometry of
the sugar skeleton upon configuration of new stereogenic
centers of the four-membered ring is rather obvious. On the
other hand, the effect of the sugar chain stereogenic center (C-
5) configuration upon intramolecular 1,3-dipolar cycloaddition
of the nitrones 17 and 22 to the terminal copper acetylide and
formation of the eight-membered ring fused to the metalated
isoxazolidine ring (suggested the first step of the Kinugasa
reaction) is not straightforward. It looks that a rigid transition
state of the cycloaddition and formation of the eight-membered
ring placed the five-membered ring anti to the sugar substituent
in both cases. Subsequent rearrangement and exclusive
formation of only cis-substituted β-lactam rings are obvious.
Consequently, in both cases [propargyl at C-5 (17), or propargyl
at C-6 (22) of the sugar chain] the terminal sugar stereogenic
center affects the configuration of the β-lactam ring in the same
direction to provide in the case of 18 - (R) configuration at the
carbon atom next to the nitrogen atom (C-4 of the azetidinone
ring), whereas in the case of 23 - (S) configuration.25
Formation of cis substituted β-lactam can be explain by the
generally accepted mechanism of Kinugasa reaction involving
formation of isoxazoline, rearrangement to the enol form of
azetidinone, and the final protonation. The mechanism
proposed by Hein and co-workers17 involving Staudinger’s [2+2]
cycloaddition could also explain the stereochemical pathway of
the intramolecular Kinugasa reaction (Scheme 6). That
mechanism, however, does not provide an universal
explanation for the observed general stereochemical outcome
of Kinugasa reactions.3 The plausible formation of β-lactam
enolate as a secondary process27 does not explain well the ratio
of cis–trans isomeric products (kinetic versus thermodynamic
product) usually observed in the intermolecular Kinugasa
reactions.3
sequence was performed for dimethyl ether
6 to afford β-
lactam 28. The side product 32 was not isolated. Structures and
configurations of β-lactams 27 and 28 were established easily
by the 1H NMR spectroscopy (NOEs).
Benzyl groups in 27 were removed by hydrogenation to give the
diol 29. The X-ray of the acetate 30 fully corroborated the NMR
spectral assignments. Glycolic cleavage in 29 opened the seven
membered ring to afford unstable dialdehyde 33 (Scheme 7).
Reduction of the crude dialdehyde 33 leads to the mixture of
products of β-lactam ring openings. Oxidative opening of the
diol 29 with NaJO4 and RuCl3 provided a dicarboxylic acid 34
which was esterified with trimethylsilyl diazomethane to afford
dimethyl ester 35. The acid 34 treated with lead tetraacetate
afforded an exchange of both carboxylic groups into acetoxy
substituents 36. The product 36 was accompanied by a minute
amount of the formyloxy derivative 37 which probably
originated from participation of the solvent (DMF). The acetoxy
group at C-4 of the azetidinone ring in 36 could offer a possible
pathway to introduction of a variety of substituents located anti
to the substituent at C-3, thus providing the absolute
configuration at C-4 carbon atom representative for biologically
active β-lactams.
Tartaric acid derivatives 5 and 6 provided a simplified model for
the intramolecular Kinugasa reaction (Scheme 7). Dibenzyl
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
BnNHOH (1 equiv.)
Na (10 equiv.)
charring with Pancaldi reagent ((NH4)6MoO4, Ce(VSiOew4)A2r,ticHle2OSnOlin4e,
H2O). NMR spectra were recorded using Varian VNMRS 500
1. LiAlH
O
4, Et2
R1
O
R1
O
O
R1
O
O
2SO4
2. popargyl bromide
CO2Et
CO2Et
CH
THF,
DOI: 10.1039/D0OB00228C
tBuOK
O
O
3CN (anhyd.)
0 °C
3. DMP, NaHCO3, DCM
R1
R1
R1
O
MHz and 600 MHz and Bruker 400 MHz spectrometers.
Chemical shifts are calibrated using residual solvent signals
(CDCl3: δ (1H)= 7.26, δ (13C)= 77), or TMS and are reported in
ppm using 1D, 2D, NOE measurements. Infrared spectra (IR)
were recorded on FT-IR-1600-Perkin Elmer spectrophotometer
and are reported in frequency of absorption (cm-1). HRMS
spectra were recorded on ESI-TOF Mariner spectrometer
(Perspective Biosystem) and are given in m/z. ECD spectra were
recorded using Jasco J-815 spectropolarimeter. Optical rotation
measurements were carried out using Jasco P-2000
polarimeter. Melting points were measured on Melting Point
Meter MPMH2 apparatus and are uncorrected.
N
O
O
5, R1=Bn, 50%
6, R1=Me
Bn
25, R1=Bn
26, R1=Me
R1
O
O
N.HCl (10 equiv.)
Et
Et3
R1
O
O
O
O
3N (1 equiv.)
CuBr (0.1 equiv.)
R1
R1
+
H
O
-30 °C to 0 °C
20 h
H
HN
N
O
= Bn
= Me
31, R1
32, R1
X-ray crystal structure of 30
27, R1=Bn
28, R1=Me
O
O
Pb(OAc)4
Na2CO3
DCM, 90%
1=H
Ac2O
29, R
30, R1=Ac
O
Py, 89%
H
O
H
N
33
O
OCHO
AcO
Enantiopure alkynylaldehydes 1–4 and 5–6 were synthesised
O
HO
HO
OAc
H
O
RO2C
RO2C
OAc
H
NaIO
Pb(OAc)4
AcOH
DMF
4, RuCl3
acetone/H2O
10 : 1, 100%
H
following standard carbohydrate transformations.
H
H
O
N
+
N
H
O
H
O
O
N
H
N
1,2-O-Isopropylidene-3-O-propargyl-1,5-dialdo-α-D-xylo-
pentofuranose (1)
TMSCHN
2
34, R=H
35, R=Me
29
DCM : MeOH (1:1), 27%
36, 29.4%
37, 15.9%
(79%), colorless oil; [α]D = - 89.9 (c 1.44, C6H6); IR (film, DCM)
ν
Scheme 7 Synthesis and transformations of β-lactams 27 and 28.
max: 3461, 3280, 2987, 2938, 2865, 1738, 1453, 1378 cm-1; 1H
NMR (500 MHz, C6D6) δ: 9.61 (d, J = 1.6 Hz, 1H), 5.85 (d, J = 3.6
Hz, 1H), 4.42 (dd, J = 3.8, 1.6 Hz, 1H), 4.23 (d, J = 3.6 Hz, 1H),
4.18 (d, J = 3.8 Hz, 1H), 3.60 (dd, J = 16.0, 2.4 Hz, 1H), 3.55 (dd, J
= 16.0, 2.4 Hz, 1H), 1.93 (t, J = 2.4 Hz, 1H), 1.28 (s, 3H), 1.05 (s,
3H); 13C NMR (125 MHz, C6D6) δ: 198.9, 112.4, 106.6, 84.8, 83.9,
82.6, 78.8, 75.6, 57.7, 27.1, 26.4; HRMS (ESI) m/z: [M + Na]+
calcd for C11H14O5Na 249.0739; found 249.0732;
Conclusion
As was anticipated, the facility of intramolecular Kinugasa
reaction depends mainly on the size of the ring which is fused
to the four-membered one. In the case of a six-membered ring
(Scheme 2), under typical Kinugasa reaction condition, the 1,3-
dipolar cycloaddition occurred. Addition of a proton donor
allowed to obtain β-lactam product, albeit in a low yield.
5-O-Benzyl-1,2-O-isopropylidene-3-O-propargyl-1,5-dialdo-α-D-
gluco-hexofuranose (2)
Transformation of the intermediary form
7 into products 8 and
9
depends on the relatively inflexible bicyclic sugar skeleton. An
(80%), colorless oil; [α]D = _ 3.9 (c 1.8, C6H6); IR (film, DCM) νmax
:
approach of reacting groups (a nitrone and a triple bond) is easy
if a seven (Schemes 3 and 7), or eight membered ring (Schemes
4 and 5) is formed. The experiments showed that even a three
bond distance between the cycloaddition place and the
stereogenic center located in the ring fused to the four-
membered one decides on configuration of the β-lactam
stereogenic centers, causing anti location of the β-lactam ring
to the R sugar substituent. No formation of a trans substituted
four-membered ring was observed, although the α,β-
unsaturated amide 24 as the by-product might suggests primary
formation of the trans substituted β-lactam followed by the
opening of the ring.
3280, 2987, 2930, 2856, 1736, 1454, 1377 cm-1; H NMR (600
MHz, C6D6) δ: 9.76 (d, J = 1.8 Hz, 1H), 7.29 – 7.26 (m, 2H), 7.16 –
7.10 (m, 2H), 7.10 – 7.06 (m, 1H), 5.76 (d, J = 3.7 Hz, 1H), 4.57
(d, J = 11.3 Hz, 1H), 4.52 (dd, J = 8.4, 3.4 Hz, 1H), 4.29 – 4.24 (m,
2H), 4.17 (dd, J = 8.4, 1.8 Hz, 1H), 4.07 (d, J = 3.4 Hz, 1H), 3.71
(dd, J = 15.8, 2.4 Hz, 1H), 3.65 (dd, J = 15.8, 2.4 Hz, 1H), 1.92 (t,
J = 2.4 Hz, 1H), 1.28 (s, 3H), 1.05 (s, 3H); 13C NMR (150 MHz,
C6D6) δ: 199.7, 138.1, 128.6, 128.4, 128.3, 112.1, 106.0, 81.9,
81.9, 80.3, 79.7, 79.2, 75.4, 72.9, 57.5, 27.0, 26.4; HRMS (ESI)
m/z: [M + Na]+ calcd for C19H22O6Na 369.1314, found 369.1309;
1
(2R,3S)-2,3-Dibenzyloxy-4-propargyloxybutanal (5)
(81.7%), colorless oil; [
max: 3444, 3286, 2925, 2871, 2116, 1730, 1454, 1096, 698 cm-
1; 1H NMR (600 MHz, CDCl3)
: 9.68 (s, 1H), 7.34 -7.24 (m, 10H),
α]D = + 37.9 (c 1.13, DCM); IR (film, DCM)
Experimental
General remarks:
ν
δ
4.76 (d, J = 11.9 Hz 1H), 4.63 (d, J = 11.9 Hz, 1H), 4.58 (d, J = 11.9
Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 4.07 (d, J = 2.3 Hz, 2H), 3.97 -
3.93 (m, 2H), 3.75 - 3.71 (m, 1H), 3.69 - 3.65 (m, 1H), 2.41 (t, J =
All reagents were purchased from Sigma Aldrich, Alfa Aesar, or
TCI Chemicals and used without further purification. All
reactions involving air- and moisture-sensitive materials were
carried out under argon atmosphere in oven-dried glassware
with magnetic stirring. THF was distilled from Na and
benzophenone. CH2Cl2 was distilled from CaH2. Column
chromatography was performed with silica gel 60 (240−400
mesh). Analytical TLC was performed with Silica gel 60 F254
aluminum plates (Merck) with visualization by UV light and
2.4 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ: 202.4, 137.5, 137.1,
128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 82.6, 79.2, 77.6, 74.8,
73.4, 73.0, 67.7, 58.5; HRMS (ESI) m/z: [M + Na]+ calcd for
C21H22O4Na 361.1416; found 361.1413;
(2R,3S)-2,3-Dimethoxy-4-propargyloxybutanal (6)
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
(
ν
59%), colorless oil; [α]D = + 59.8 (c 1.4, DCM); IR (film, DCM) added and the mixture was allowed to warm to RTV.iTewheArtmicleixOtnulirnee
1
max: 3447, 3279, 2935, 2833, 2116, 1732, 1462, 1360 cm-1; H was diluted with Et2O, filtered through CDeOlitI:e10a.n10d39c/oDn0cOeBn0t0ra22te8Cd
NMR (400 MHz, CDCl3) δ: 9.78 (d, J = 1.1 Hz, 1H), 4.16 (dd, J = to dryness. The crude aldehyde
2.4, 1.8 Hz, 2H), 3.77 – 3.72 (m, 3H), 3.70 – 3.66 (m, 1H), 3.52 (s, next step without purification; [
3H), 3.42 (s, 3H), 2.44 (t, J = 2.4 Hz, 1H); 13C NMR (100 MHz, DCM) νmax: 3279, 2985, 2931, 2118, 1736, 1377, 1216, 1077,
CDCl3) δ: 203.0, 85.2, 80.1, 79.3, 75.0, 67.3, 59.7, 59.1, 58.7; 1027 cm-1; 1H NMR (600 MHz, CDCl3)
: 9.75 (t, J = 0.8 Hz, 1H),
HRMS (ESI) m/z: [M + Na]+ calcd for C9H14O4Na 209.0790; found 7.37 – 7.28 (m, 5H), 5.89 (d, J = 3.9 Hz, 1H), 4.69 (d, J = 11.4 Hz,
3
(64 mg 94%) was used in the
α]D = - 37.2 (c 0.8, DCM); IR (film,
δ
209.0780;
1H), 4.63 (d, J = 11.4 Hz, 1H), 4.60 (d, J = 3.7 Hz, 1H), 4.36 (dd, J
= 15.6, 2.4 Hz, 1H), 4.26 (dd, J = 9.0, 3.2 Hz, 1H), 4.25 (dd, J =
15.6, 2.4 Hz, 1H), 4.12 (bs, 2H), 4.11 (d, J = 3.2 Hz, 1H), 4.07 –
4.0 (m, 2H), 3.72 (dd, J = 10.8, 5.3 Hz, 1H), 2.36 (t, J = 2.4 Hz, 1H),
3-O-Benzyl-6-O-ethoxycarbonylmethyl-5-O-propargyl-1,2-O-
isopropylidene-α-D-glucofuranose (16)
1.47 (s, 3H), 1.31 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ: 201.1,
To a solution of 15 (0.180 g, 0.517 mmol) in anhydrous THF (11
mL) cooled to -78 °C the BuLi (0.246 ml 2.2 M solution) was
added dropwise and the reaction was stirred for 2 h. Ethyl
bromoacetate (0.177 g, 1.034 mmol) was added to the mixture.
The reaction was allowed to warm to RT and was monitored by
TLC. After the reaction was completed, the mixture was
quenched with sat. NH4Cl (2 mL) and diluted with Et2O. Organic
137.5, 128.5, 127.9, 127.7, 111.9, 105.1, 81.9, 81.5, 79.9, 78.4,
76.9, 74.8, 74.5, 72.2, 72.2, 57.8, 26.8, 26.3; HRMS (ESI) m/z: [M
+ Na]+calcd for C21H26O7Na 413.1576; found 413.1573.
3-O-Benzyl-5-O-carbonylmethyl-6-O-propargyl-1,2-O-
isopropylidene-α-D-glucofuranose (4)
phase was separated, dried and concentrated to dryness. The Aldehyde
residue (0.271 g) was purified by chromatography with hexane- above for
4
3
was obtained following the procedure described
(96%); [
α
]D =
−
30.5 (c 1.08, DCM); IR (film, DCM)
1
AcOEt (4 : 1) to yield 16 (0.101 g 44.9%) as colorless oil; [
37.0 (c 1.1, DCM); IR (film, DCM) νmax: 3276, 2985, 2936, 2117, (500 MHz, CDCl3)
1752, 1374, 1211 cm-1; 1H NMR (600 MHz, CDCl3)
: 7.36 – 7.26 3.6 Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 3.7 Hz, 1H), 4.49
α]D = -
ν
max: 3279, 2934, 2116, 1735, 1377, 1076, 1026 cm-1; H NMR
δ
: 9.54 (s, 1H), 7.36 – 7.27 (m, 5H), 5.90 (d, J =
δ
(m, 5H), 5.87 (d, J = 3.7 Hz, 1H), 4.67, 4.63 (ABq, J = 11.5 Hz, 2H), (d, J = 11.6 Hz, 1H), 4.28 (dd, J = 17.9, 1.0 Hz, 1H), 4.21 – 4.09
4.57 (d, 3.7 Hz, 1H), 4.45 (dd, J = 15.5, 2.4 Hz, 1H), 4.29 (dd, J = (m, 4H), 3.98 (dd, J = 17.9, 1.0 Hz, 1H), 3.95 – 3.91 (m, 2H), 3.68
15.5, 2.4 Hz, 1H), 4.22 (dd, J = 8.8, 3.0 Hz, 1H), 4.19 (ddd, J = (dd, J = 10.4, 7.2 Hz, 1H), 2.41 (t, J = 2.4 Hz, 1H), 1.49 (s, 3H),
14.2, 7.1, 1.0 Hz, 2H), 4.15 (d, J = 16.5 Hz, 1H), 4.08 (d, J = 16.5 1.32 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ: 200.9, 137.3, 128.6,
Hz, 1H), 4.09 (d, J = 3.1 Hz, 1H), 4.06 – 4.00 (m, 2H), 3.67 (dd, J 128.1, 127.8, 111.9, 105.2, 81.7, 81.5, 79.4, 78.8, 76.9, 76.8,
= 10.1, 5.5 Hz, 1H), 2.32 (t, J = 2.4 Hz, 1H), 1.46 (s, 3H), 1.27 (t, J 74.7, 72.0, 71.7, 58.6, 26.8, 26.3; HRMS (ESI) m/z: [M + MeOH +
δ
= 7.1 Hz, 3H), 1.29 (s, 3H); 13C NMR, (150 MHz, CDCl3) : 170.4, Na]+ calcd for C22H30O8Na 455.1838; found 455.1841.
137.6, 128.4, 127.8, 127.7, 111.8, 105.1, 82.1, 81.6, 80.0, 78.6,
74.5, 74.3, 72.3, 72.0, 68.9, 60.8, 57.5, 26.8, 26.3, 14.2; HRMS (5aS,5bR,8aR,9aR,9bR)-1-Benzyl-7,7-dimethyl-1,5a,5b,8a,9a,9b-
(ESI) m/z: [M + Na]+ calcd for C23H30O8Na 457.1838; found hexahydro-4H-[1,3]dioxolo[4'',5'':4',5']furo[3',2':2,3]pyrano[4,5-
457.1829.
c][1,2]oxazole (8)
Reaction was performed under argon atmosphere. A mixture of
N-benzylhydroxylamine hydrochloride (0.120 g, 0.75 mmol, 1.5
equiv.) and trimethylamine (0.139 mL, 1 mmol, 2 equiv.) in
anhydrous DCM (3.5 mL) was stirred at RT for 1 h. Next, the
anhydrous sodium sulfate (0.710 g, 5 mmol, 10 equiv.) was
3-O-Benzyl-5-O-ethoxycarbonylmethyl-6-O-propargyl-1,2-O-
isopropylidene-α-D-glucofuranose (21)
Compound 21 was obtained following procedure described for
16 (61.3%); [
2985, 2936, 2116, 1754, 1375, 1210, 1144, 1075, 1029 cm-1; 1H
NMR (600 MHz, CDCl3) : 7.36 – 7.26 (m, 5H), 5.88 (d, J = 3.8 Hz,
α]D = - 31.2 (c 1.1, DCM); IR (film, DCM) νmax: 3276,
added to the mixture followed by the solution of aldehyde
1
(0.113 g, 0.5 mmol) in anhydrous DCM (1.5 mL). The resulted
mixture was vigorously stirred at RT for 2 h and monitored by
TLC. When the starting aldehyde was no longer present, the
mixture was filtered, and the filtrate evaporated under reduced
pressure. The residue was adsorbed on silica gel and purified by
flash column chromatography (hexane/ethyl acetate, 9:1) to
δ
1H), 4.66 (d, J = 11.5 Hz, 1H), 4.58 (d, J = 3.8 Hz, 1H), 4.54 (d, J =
11.5 Hz, 1H), 4.33 (d, J = 16.1 Hz, 1H), 4.21 (dd, J = 9.2, 3.1 Hz,
1H), 4.18 – 4.09 (m, 5H), 4.06 (d, J = 16.2 Hz, 1H), 3.97 – 3.92 (m,
2H), 3.68 (dd, J = 10.4, 7.3 Hz, 1H), 2.38 (t, J = 2.3 Hz, 1H), 1.48
(s, 3H), 1.30 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz,
give compound
8 (0.119 g, 72%) as a white foam; [α]D = - 269.2
CDCl3) δ: 170.3, 137.6, 128.4, 127.8, 127.6, 111.8, 105.2, 81.8,
(c 1.19, DCM); IR (film, DCM) νmax: 3097, 3028, 2989, 2927, 2900,
2868, 1678, 1495, 1454, 1377 cm-1; 1H NMR (600 MHz, CDCl3) δ:
7.44 – 7.39 (m, 2H), 7.37 – 7.31 (m, 2H), 7.32 – 7.26 (m, 1H),
6.25 (dd, J = 2.3, 1.2 Hz, 1H), 5.94 (d, J = 3.8 Hz, 1H), 4.61 (t, J =
3.4 Hz, 1H), 4.56 – 4.52 (m, 2H), 4.50 – 4.44 (m, 1H), 4.17 (d, J =
13.8 Hz, 1H), 4.14 (d, J = 13.8 Hz, 1H), 4.12 – 4.10 (m, 1H), 3.99
(d, J = 3.4 Hz, 1H), 1.49 (s, 3H), 1.31 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ: 136.5, 135.9, 129.2, 128.5, 127.7, 112.0, 105.8, 105.1,
86.2, 83.4, 80.4, 71.6, 64.7, 62.5, 27.1, 26.6; HRMS (ESI) m/z: [M
+ Na]+ calcd for C18H21NO5Na 354.1317; found 354.1310.
81.7, 79.6, 78.9, 77.0, 74.4, 72.1, 72.07, 69.0, 60.6, 58.6, 26.8,
26.3, 14.1; HRMS (ESI) m/z: [M + Na]+ calcd for C23H30O8Na
457.1838; found 457.1820.
3-O-Benzyl-6-O-carbonylmethyl-5-O-propargyl-1,2-O-
isopropylidene-α-D-glucofuranose (3)
To a solution of compound 16 (76 mg, 0.175 mmol) in
anhydrous DCM (7 mL) the DIBAL (0.210 ml, 1 M solution in
hexane) was added at -78 °C. After 1 h sat. Na2SO4 (2 mL) was
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
HRMS (ESI) m/z: calcd for C18H21NO5Na [M + Na]+ 354.1317;
View Article Online
DOI: 10.1039/D0OB00228C
General procedure for the intramolecular Kinugasa reaction (GP):
found 354.1305.
Reaction was performed under argon atmosphere. In a flame-
dried Schlenk flask aldehyde (0.5 mmol, 1 equiv.) was dissolved
in anhydrous acetonitrile (10 mL) and the mixture was cooled to
(3aR,4aR,5R,5aS,7aR,9aS,9bR)-6-Benzyl-5-(benzyloxy)-2,2-
dimethyloctahydro[1,3] dioxolo[4'',5'':4',5']furo[2',3':6,7]
oxepino[4,3-b]azet-7-(3aH)-one (11)
0
°
C. Next, anh. sodium sulfate (5 mmol, 10 equiv.) and N-
benzylhydroxylamine (0.5 mmol, 1 equiv.) were added. The
mixture was stirred at 0 C and was monitored by TLC. After full
consumption of the starting aldehyde, the mixture was cooled
to -30 C and triethylamine hydrochloride (5 mmol, 10 equiv.),
triethylamine (0.5 mmol, 1 equiv.) and copper(I) bromide (0.05
mmol, 10 mol%) were added. Reaction was continued at 0
Product 11 was obtained according to GP starting from the
aldehyde 2 (83 mg, 0.24 mmol) and N-benzylhydroxylamine (30
°
mg, 0.24 mmol) in the presence of sodium sulfate (0.341 g, 2.40
mmol, 10 equiv.), triethylamine hydrochloride (0.330 g, 2.40
mmol, 10 equiv.), triethylamine (0.033 mL, 0.24 mmol, 1 equiv.)
and copper(I) bromide (3 mg, 0.024 mmol, 10 mol%) in
anhydrous acetonitrile (4.8 mL). The mixture was stirred for 2 h
during in situ formation of the nitrone, and for the
intramolecular Kinugasa reaction the process was continued for
20 h. Crude product was adsorbed on silica gel and purified by
flash column chromatography (hexane/ethyl acetate 4:1) to
give compound 11 (56 mg, 49%) as a slightly yellow oil; [α]D = +
30.2 (c 1.4, DCM); IR (film, DCM) νmax: 3062, 3031, 2985, 2935,
°
°
C
and was monitored by TLC. Upon completion, the reaction
mixture was filtered through a pad of Florisil, pad was
thoroughly washed with ethyl acetate and combined filtrates
were concentrated in vacuo. The residue was submitted for
purification by flash column chromatography.
(2aS,4aS,4bR,7aR,8aR,8bR)-1-Benzyl-6,6-dimethyloctahydro-2H-
[1,3]dioxolo [4'',5'':4',5']furo[3',2':2,3]pyrano[4,5-b]azetidin-2-one
(9) and (3aR,3bS,7aR,8aR)-N-Benzyl-2,2-dimethyl-3a,5,7a,8a-
tetrahydro-3bH-[1,3]dioxolo[4',5':4,5]furo[3,2-b]pyran-6-
carboxamide (10)
1
2882, 1750, 1496, 1454, 1404, 1383, 1351 cm-1; H NMR (500
MHz, CDCl3) δ: 7.38 – 7.33 (m, 2H), 7.32 – 7.28 (m, 3H), 7.27 –
7.22 (m, 3H), 7.15 (dd, J = 7.5, 2.0 Hz, 2H), 5.83 (d, J = 3.6 Hz,
1H), 4.60 – 4.54 (m, 2H), 4.42 – 4.38 (m, 2H), 4.31 (d, J = 11.5 Hz,
1H), 4.22 (d, J = 14.9 Hz, 1H), 4.14 (dd, J = 12.5, 5.2 Hz, 1H), 4.05
– 3.98 (m, 2H), 3.95 (d, J = 2.0 Hz, 1H), 3.56 (t, J = 12.5 Hz, 1H),
3.48 (dt, J = 12.5, 5.2 Hz, 1H), 1.39 (s, 3H), 1.28 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ: 166.1, 137.5, 136.5, 128.7, 128.6, 128.3,
128.1, 127.9, 127.5, 111.9, 104.8, 83.1, 82.6, 79.8, 77.6, 71.3,
64.6, 53.7, 51.2, 45.4, 26.8, 26.2; HRMS (ESI) m/z: [M + Na]+
calcd for C26H29NO6Na 474.1893; found 474.1882.
Products
aldehyde
9
1
and 10 were obtained according to GP starting from
(0.170 g, 0.75 mmol) and N-benzylhydroxylamine
(0.092 g, 0.75 mmol) in the presence of sodium sulfate (1.065 g,
7.50 mmol, 10 equiv.), triethylamine hydrochloride (1.032 g,
7.50 mmol, 10 equiv.), triethylamine (0.105 mL, 0.75 mmol, 1
equiv.) and copper(I) bromide (11 mg, 0.075 mmol, 10 mol%) in
anhydrous acetonitrile (15 mL). The mixture was stirred for 2 h
during the in situ formation of the nitrone, and for the
intramolecular Kinugasa reaction the process was continued for
3(S), 6(R), 10(R)-3,10-cis-6-(1’,2’-Isopropylidene-3’-O-benzyl- α-D-
20 h. Crude product was adsorbed on silica gel and purified by xylo-pentofuranos-4’-yl)-1-benzylamino-5,8-dioxa-2-one-
flash column chromatography (hexane/ethyl acetate from 4:1
to 2:3) to give compound
(42 mg, 17%) as a slightly yellow
foam and compound 10 (37 mg, 15%) as a colorless oil:
bicyclo[2.0.6]decane (18)
9
Product 18 was obtained according to GP starting from
aldehyde
3 (51 mg, 0.131 mmol) and N-benzylhydroxylamine
Compound
9
; [α]D = + 3.5 (c 2.56, DCM); IR (film, DCM) νmax
:
(16 mg, 0.131 mmol) in the presence of sodium sulfate (0.186 g,
1.31 mmol, 10 equiv.), triethylamine hydrochloride (0.180 g,
1.31 mmol, 10 equiv.), triethylamine (0.018 mL, 0.131 mmol, 1
equiv.) and copper(I) bromide (2 mg, 0.013 mmol, 10 mol%) in
anhydrous acetonitrile (3 mL). The mixture was stirred for 20 h
during in situ formation of the nitrone, and for the
intramolecular Kinugasa reaction the process was continued for
20 h. Crude product was purified by flash column
chromatography (hexane/ethyl acetate 3 : 2) to give compound
18 (36 mg, 55.4%) as a colorless oil.
2985, 2930, 2876, 1755, 1455, 1402, 1378 cm-1; H NMR (600
MHz, CDCl3) δ: 7.38 – 7.33 (m, 2H), 7.34 – 7.28 (m, 3H), 5.81 (d,
J = 3.9 Hz, 1H), 4.52 (d, J = 15.0 Hz, 1H), 4.48 (d, J = 3.9 Hz, 1H),
4.32 (d, J = 15.0 Hz, 1H), 4.07 (dd, J = 4.1, 2.3 Hz, 1H), 3.93 (dd, J
= 12.2, 3.1 Hz, 1H), 3.88 (dd, J = 5.5, 2.3 Hz, 1H), 3.82 (d, J = 4.1
Hz, 1H), 3.75 (dd, J = 12.2, 4.1 Hz, 1H), 3.28 (ddd, J = 5.5, 4.1, 3.1
Hz, 1H), 1.33 (s, 3H), 1.25 (s, 3H); 13C NMR (150 MHz, CDCl3) δ:
167.7, 135.8, 129.1, 128.6, 128.3, 111.8, 104.7, 86.1, 77.4, 72.4,
60.1, 48.4, 47.4, 45.8, 26.9, 26.3; HRMS (ESI) m/z: calcd for
C18H21NO5Na [M + Na]+ 354.1317; found 354.1310;
1
[
α
]D =
IR (film, DCM) νmax: 2930, 1750, 1376, 1075, 1024, 700 cm-1; 1H
NMR (600 MHz, CDCl3) : 7.40 - 7.20 (m, 10H), 5.85 (d, J = 3.8
− 18.3 (c 1.14, DCM); Mol. CD (MeCN): + 2.29 (228 nm);
Compound 10; [α]D = - 27.2 (c 1.38, CHCl3); IR (film, DCM) νmax
:
3333, 3062, 3031, 2986, 2934, 2847, 1735, 1670, 1631, 1536,
δ
1
1453, 1378 cm-1; H NMR (500 MHz, CDCl3) δ: 7.38 – 7.30 (m,
Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.59 (d, J = 15.4 Hz, 1H), 4.56
(d, J = 3.8, 1H), 4.56 (d, J = 11.6 Hz, 1H), 4.18 - 4.15 (m, 2H), 4.11
(d, J = 15.4 Hz, 1H), 4.00 (d, J = 3.1 Hz, 1H), 3.99 – 3.91 (m, 4H),
3.69 (dd, J = 13.3, 2.8 Hz, 1H), 3.64 (ddd, J = 7.4, 4.9, 2.8 Hz, 1H),
3.55 – 3.50 (m, 2H), 1.44 (s, 3H), 1.28 (s, 3H); 13C NMR (150 MHz,
2H), 7.32 – 7.24 (m, 3H), 6.50 – 6.46 (m, 1H), 6.21 (t, J = 5.8 Hz,
1H), 5.91 (d, J = 3.8 Hz, 1H), 4.61 (d, J = 3.8 Hz, 1H), 4.56 (dd, J =
16.8, 1.4 Hz, 1H), 4.51 – 4.42 (m, 3H), 4.25 (dt, J = 16.8, 2.2 Hz,
1H), 3.94 (d, J = 2.7 Hz, 1H), 1.50 (s, 3H), 1.32 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ: 165.6, 139.1, 137.8, 128.9, 128.0, 127.9,
123.4, 111.9, 105.3, 84.2, 79.0, 70.8, 64.6, 43.7, 27.0, 26.3;
CDCl3) δ: 167.4, 137.3, 135.5, 128.9, 128.6, 128.2, 128.1, 127.9,
127.8, 111.7, 105.1, 82.0, 81.2, 80.2, 76.8, 74.2, 72.3, 66.8, 66.5,
6 | J. Name., 2012, 00, 1-3
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Journal Name
53.7, 53.4, 44.5, 26.7, 26.2; HRMS (ESI) m/z: [M + Na]+ calcd for Compound 24
ARTICLE
View Article Online
DOI: 10.1039/D0OB00228C
C28H33NO7Na 518.2155; found 518.2144.
[α] = − 20.0 (c 1.47, DCM); IR (film) ν : 3340, 2931, 1752,
D max
1666, 1631, 1527, 1454, 1376, 1075, 1024 cm-1; 1H NMR (500
MHz, C6D6) : 7.11 – 7.04 (m, 10H), 6.13 (dd, J = 3.7, 3.7 Hz, 1H),
3(S), 6(R), 10(R)-3,10-cis-6-(1’,2’-Isopropylidene-3’-O-hydroxyl-α-
D-xylo-pentofuranos-4’-yl)-1-benzylamino-5,8-dioxa-2-one-
bicyclo[2.0.6]decane (19)
δ
5.75 (d, J = 3.6 Hz, 1H), 5.64 (bt, J = 3.6 Hz, 1H), 4.63 (d, J = 13.9
Hz, 1H), 4.46 (d, J = 13.9 Hz, 1H), 4.29 – 4.02 (m, 9H), 4.01 (d, J
= 2.9 Hz, 1H), 3.98 – 3.90 (m, 1H), 3.56 -3.50 (m, 1H), 1.39 (s,
Compound 18 (33 mg; 0.066 mmol) in AcOEt (2 mL) and Pd (50
mg, 10% on activated carbon) was stirred under hydrogen for
18 h. Subsequently the mixture was filtered through Celite and
3H), 1.08 (s, 3H); 13C NMR (125 MHz, C6D6)
δ: 167.7, 139.1,
137.8, 135.2, 135.0, 128.4 (2C), 127.2, 127.0, 111.3, 105.4, 81.9,
81.6, 79.7, 79.3, 77.7, 71.3, 70.8, 67.9, 66.2, 43.3, 29.7, 26.6,
26.0; HRMS (ESI) m/z: [M + Na]+ calcd for C28H33NO7Na
518.2155; found 518.2157.
evaporated to afford 19 (18 mg, 66.6%) as a colorless oil; [
+ 4.08 (c 1.4, DCM); IR (film) νmax: 3409, 2925, 1732, 1375, 1073,
1015 cm-1 ;1H NMR (600 MHz, CDCl3)
: 7.35 – 7.21 (m, 5H), 5.89
α]D =
δ
(d, J = 3.7 Hz, 1H), 4.60 (d, J = 15.2 Hz, 1H), 4.48 (d, J = 3.7 Hz,
1H), 4.27 (dd, J = 13.2, 5.5 Hz, 1H), 4.22 (d, J = 2.6 Hz, 1H), 4.11
(d, J = 15.2 Hz, 1H), 4.07 (dd, J = 13.4, 2.6 Hz, 1H), 4.05 (dd, J =
13.2, 9.6 Hz, 1H), 4.00 (dd, J = 7.6, 2.7 Hz, 1H), 3.96 (dd, J = 13.4,
3(S), 7(S), 8(S), 9(S)-3,9-cis-7,8-Dibenzyloxy-1-N-benzyl-5-oxa-2-
one-bicyclo[2.0.5]nonane (27) and 5(S), 6(S)-7,8-dibenzyloxy-3-
benzyloxycarbonylo-1-oxa-cyclohept-3-ene (31)
6.5 Hz, 1H), 3.89 (dd, J = 7.3, 2.6 Hz, 1H), 3.77 (dd, J = 13.4, 2.6 Products 27 and 31 were obtained according to GP from
Hz, 1H), 3.68 (ddd, J = 6.7, 5.1, 2.6 Hz, 1H), 3.58 (dd, J = 13.2, 7.7 aldehyde (0.261 g, 0.772 mmol) and N-benzylhydroxylamine
Hz, 1H), 3.51 (dt, J = 9.5, 5.3 Hz, 1H), 1.44 (s, 3H), 1.28 (s, 3H); (0.095 g, 0.772 mmol) in the presence of sodium sulfate (1.097
13C NMR (150 MHz, CDCl3)
: 167.7, 135.4, 128.9, 128.2, 127.9, g, 7.72 mmol, 10 equiv.), triethylamine hydrochloride (1.062 g,
5
δ
111.6, 104.8, 85.0, 79.5, 78.2, 74.8, 73.3, 67.2, 66.0, 54.0, 52.9, mmol, 10 equiv.), triethylamine (0.107 mL, 0.772 mmol, 1
44.7, 26.7, 26.1; HRMS (ESI) m/z: [M + Na]+ calcd for C21H27O7Na equiv.) and copper(I) bromide (11 mg, 0.077 mmol, 10 mol%) in
428.1685; found 428.1682.
anhydrous acetonitrile (15 mL). The mixture was stirred for 20
h during in situ formation of the nitrone, and for the
intramolecular Kinugasa reaction the process was continued for
20 h. Crude product was purified by flash column
chromatography (hexane/ethyl acetate 7:3) to give compounds
27 (0.184 g, 54%) and 31 (0.028 g, 8%) as a colorless oils;
3(R), 7(R), 10(S)-3,10-cis-7-(1’,2’-Isopropylidene-3’-O-benzyl-α-D-
xylo-pentofuranos-4’-yl)-1-N-benzyl-5,8-dioxa-2-one-
bicyclo[2.0.6]decane (23) and 3-(1’,2’-Isopropylidene-3’-O-benzyl-
α-D-xylo-pentofuranos-4’-yl)-7-N-benzyl carboxamino-1,4-dioxa-
cyclooctan-6-ene (24)
Compound 27
]D = – 5.7 (c 1.1, DCM); IR (film, DCM) νmax: 2866, 1751, 1112,
1074, 699 cm-1; 1H NMR (600 MHz, toluene 80 °C)
: 7.15 - 6.94
:
[
α
Products 23 and 24 were obtained according to GP from
δ
aldehyde
4 (79 mg, 0.202 mmol) and N-benzylhydroxylamine
(m, 15H), 4.72 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 15.1 Hz, 1H), 4.33,
4.29 (ABq, J = 11.6 Hz, 2H), 4.15 (d, J = 11.5 Hz, 1H), 3.88 (d, J =
15.1 Hz, 1H), 3.82 (dd, J = 12.8, 4.9 Hz 1H), 3.67 (dd, J = 12.8, 3.0
Hz, 1H), 3.59 (dd, J = 7.8, 7.8 Hz, 1H), 3.52 (dd, J = 12.5, 9.9 Hz,
1H), 3.39 (dd, J = 7.4, 5.6 Hz, 1H), 3.34 (dd, J = 12.8, 7.4 Hz, 1H),
3.20 (ddd, J = 7.7, 7.7, 2.8 Hz, 1H), 3.02 (ddd, J = 9.9, 5.4, 4.9 Hz,
(25 mg, 0.202 mmol) in the presence of sodium sulfate (0.287 g,
2.02 mmol, 10 equiv.), triethylamine hydrochloride (0.277g,
2.02 mmol, 10 equiv.), triethylamine (0.028 mL, 0.202 mmol, 1
equiv.) and copper(I) bromide (3 mg, 0.020 mmol, 10 mol%) in
anhydrous acetonitrile (5 mL). The mixture was stirred for 20 h
during in situ formation of the nitrone, and for the
intramolecular Kinugasa reaction the process was continued for
20 h. Crude product was purified by flash column
chromatography (hexane/ethyl acetate 1:2) to give compounds
23 (51 mg, 51.1%) and 24 (6.1 mg, 6.1%) as a colorless oils;
Compound 23
1H); 13C NMR, (150 MHz, toluene 80 °C)
δ: 165.1, 138.6, 138.2,
128.6, 128.2, 128.1, 128.0 (2C), 127.7, 127.5, 127.3, 126.9,
124.9, 82.9, 80.4, 73.6, 72.6, 70.7, 67.4, 55.5, 53.3, 44.9; HRMS
(ESI) m/z: [M + Na] + calcd for C28H29 NO4Na 466.1994; found.
466.1998.
Compound 31
[
α
]D =
−
48.5 (c 1.1, DCM); Mol. CD (MeCN): _ 3.59 (220 nm); IR
[
α
]D = + 35.9 (c 0.9, DCM); IR (film, DCM) νmax: 3322, 3030, 2866,
1
(film, DCM) νmax: 2931, 1751, 1374, 1116, 1075, 1023 cm-1 ; H
1739, 1662, 1624, 1533, 1453 cm-1; 1H NMR (500 MHz, CDCl3)
δ
:
NMR (600 MHz, CDCl3 + C6D6) δ: 7.17 – 7.00 (m, 10H), 5.72 (d, J
7.38 – 7.22 (m, 15H), 6.21 - 6.18 (m, 1H), 5.87 – 5.80 (m, 1H),
4.77 (d, J = 11.8 Hz, 1H), 4.74 (d, J = 11.8 Hz, 1H), 4.71 – 4.61 (m,
3H), 4.58 – 4.51 (m, 1H), 4.46 - 4.38 (m, 3H), 3.93 (dd, J = 13.1,
4.1 Hz 1H), 3.83 (dd, J = 13.1, 4.8 Hz, 1H), 3.75 (ddd, J = 8.7, 8.7,
= 3.7 Hz, 1H), 4.45 (d, J = 11.8 Hz, 1H), 4.37 (d, J = 3.8 Hz, 1H),
4.26 (d, J = 11.8 Hz, 1H), 4.23 (d, J = 15.1 Hz, 1H), 4.08 (dd, J =
13.4, 1.8 Hz, 1H), 3.98 (dd, J = 9.6, 3.3 Hz, 1H), 3.92 - 3.87 (m,
1H), 3.89 (d, J = 15.1 Hz, 1H), 3.84 – 3.77 (m, 3H), 3.60 (dd, J =
4.0, 3.6 Hz, 1H), 3.46 (ddd, J = 10.0, 4.9, 4.0 Hz, 1H), 3.35 (dd, J
= 13.7, 5.7 Hz, 1H), 3.31 (dd, J = 12.7, 10.1 Hz, 1H), 3.24 (ddd, J
= 9.5, 4.9, 3.8 Hz, 1H), 1.31 (s, 3H), 1.13 (s, 3H); 13C NMR (150
4.4 Hz 1H); 13C NMR, (125 MHz, CDCl3)
δ: 166.7, 138.3, 138.1,
137.8, 136.5, 134.8, 128.8, 128.4 (2C), 128.0 (2C), 127.8, 127.7
(3C), 81.2, 78.8, 73.6, 72.9, 72.2, 70.71, 43.75; HRMS (ESI) m/z:
[M + Na]+ calcd for C28H29NO4Na 466.1994; found. 466.1991.
MHz, CDCl3 + C6D6) δ: 166.7, 137.4, 135.6, 128.7, 128.3, 128.2,
128.0, 127.9, 127.6, 111.5, 105.0, 81.9, 81.1, 79.7, 77.0, 72.5,
71.9, 67.3, 63.1, 54.0, 52.9, 44.7, 26.0, 25.6; HRMS (ESI) m/z: [M
+ Na]+ calcd for C28H33NO7Na 518.2155; found 518.2147.
(5S,6S)-8-Benzyl-5,6-dimethoxy-3-oxa-8-azabicyclo[5.2.0]nonan-9-
one (28)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 10
ARTICLE
Journal Name
3(S), 4(R)-N-Benzyl-3-carbonylmethoxymethyl-4-carbVoienwyAl-raticzleetOidnliinne-
Product 28 was obtained according to GP from aldehyde
6
DOI: 10.1039/D0OB00228C
2-one (33)
(0.112 g, 0.60 mmol) and N-benzylhydroxylamine (0.074 g, 0.60
mmol) in the presence of sodium sulfate (0.852 g, 6.00 mmol,
10 equiv.), triethylamine hydrochloride (0.826 g, 6.00 mmol, 10
equiv.), triethylamine (0.084 mL, 0.60 mmol, 1 equiv.) and
copper(I) bromide (3 mg, 0.024 mmol, 10 mol%) in anhydrous
acetonitrile (12 mL). The mixture was stirred for 2 h during in
situ formation of the nitrone, and for the intramolecular
Kinugasa reaction the process was continued for 20 h. Crude
product was adsorbed on silica gel and purified by flash column
chromatography (hexane/ethyl acetate for 9:1 to 2:3) to give
compound 27 (0.075 g, 43%) as a colorless oil; [α]D = - 14.9 (c
1.62, DCM); IR (film, DCM) νmax: 3489, 3030, 2930, 2827, 1751,
1665, 1496, 1455, 1406, 1356 cm-1; 1H NMR (600 MHz, DMSO-
To compound 29 (50 mg, 0.190 mmol) in dry DCM (3 mL) Na2CO3
(24 mg, 0.228 mmol) was added. Subsequently the mixture was
cooled to 0 °C and Pb(OAc)4 (93 mg, 0.209 mmol) was added.
The mixture was stirred for 1.5 h at 0 °C and 20 min at RT
Subsequently AcOEt (1.5 mL) was added and the mixture was
filtered through a pad of silica gel, washed with ethyl acetate
and concentrated in vacuo to give the crude dialdehyde 33 (45
mg, 90%) as a colorless oil. [
α
]D = + 2.66 (c 0.5, MeOH); IR (film,
1
DCM) νmax: 3372, 1735, 1571, 1415, 1285, 1074 cm-1; H NMR
(500 MHz, CDCl3) δ: 9.62 (d, J = 1.7 Hz, 1H), 9.60 (bs, 1H), 7.38 -
7.23 (m, 5H), 4.66 (d, J = 14.9 Hz, 1H), 4.44 (d, J = 14.9 Hz, 1H),
4.09, 4.01 (ABq, J = 17.9 Hz, 2H), 4.02 (dd, J = 5.8, 1.7 Hz, 1H),
3.87 (dd, J = 10.3, 5.2 Hz, 1H), 3.79 - 3.75 (m, 1H), 3.70 (dd, J =
d6 at 85 °C) δ: 7.38 – 7.34 (m, 2H), 7.30 – 7.26 (m, 3H), 4.54 (d,
10.3, 3.2 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ: 198.7, 198.6,
J = 15.4 Hz, 1H), 4.15 (d, J = 15.4 Hz, 1H), 3.80 – 3.72 (m, 2H),
3.69 – 3.63 (m, 3H), 3.55 (dd, J = 12.9, 6.5 Hz, 1H), 3.43 (dt, J =
8.4, 5.0 Hz, 1H), 3.36 (s, 3H), 3.32 (s, 3H), 3.26 (td, J = 6.8, 2.9
165.7, 134.8, 129.1, 128.6, 128.3, 76.2, 65.3, 59.5, 55.6, 46.2;
HRMS (ESI) m/z: [M + 2MeOH + Na]+ calcd for C16H23NO6Na
348.1423; found 348.1427.
Hz, 1H); 13C NMR (150 MHz, DMSO-d6 at 85
°C) δ: 165.6, 136.4,
128.0, 127.3, 126.7, 82.4, 81.3, 68.9, 66.2, 58.2, 57.5, 54.9, 52.2,
44.1; HRMS (ESI) m/z: [M + Na]+ calcd for C16H21NO4Na
314.1368, found 314.1358;
3(S),4(R)-N-Benzyl-3-methoxycarbonylmethoxymethyl-4-
methoxycarbonlmetyl-azetidin-2-one (35)
NaJO4 (52 mg, 0.242 mmol) was added to a solution of 29 (29
mg, 0.11 mmol) in a mixture of acetone/H2O (10 : 1 v/v, 3 mL)
RuCl3 x H2O (1.5 mg) was added to the resulting suspension, and
the obtained brown mixture was stirred for 3 h. Next, the
reaction mixture was diluted with acetone, filtered through
Celite and evaporated to afford the crude diacid 34 as a
colorless oil (32 mg ).
To stirred solution of crude carboxylic diacid 34 (32 mg, 0.11
mmol) in a mixture of dichloromethane : methanol (1 : 1, v/v, 1
mL) and 2M hexane solution of TMSCHN2 (0.165 ml, 0.331
mmol) was added dropwise until the yellow color persisted. The
mixture was stirred for 30 min at RT and one drop of CH3COOH
was added. After 10 min the mixture was concentrated. The
residue was purified on a silica gel column using hexane/ethyl
acetate 4 : 1- 1: 2 v/v as eluent to afford 35 (9.4 mg 27%) as a
3(S), 7(S), 8(S), 9(S)-3,9-cis-7,8-Dihydroxy-1-N-benzyl-5-oxa-2-one-
bicyclo[2.0.5]nonane (29)
Compound 27 (0.170 g; 0.383 mmol) in ethyl alcohol (15 mL)
and Pd (0.200 g, 10% on activated carbon) was stirred under
hydrogen for 18 h. Subsequently the mixture was filtered
through Celite and evaporated to afford colorless oil. Crude
product was adsorbed on silica gel and purified by flash column
chromatography (DCM / methanol 95 : 5) to give diol 29 (72 mg,
71.3%) as a colorless syrup; [
DCM) νmax: 3402, 2924, 1727, 1414, 1030, 701 cm-1; 1H NMR
(600 MHz, toluene 80 °C) : 7.27 - 6.96 (m, 5H), 4.46 (d, J = 14.8
α]D = – 52.1 (c 1.0, MeOH); IR (film,
δ
Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 3.86 (dd, J = 12.7, 5.5 Hz, 1H),
3.66 (dd, J = 12.1, 3.9 Hz, 1H), 3.30 (dd, J = 8.7, 8.7 Hz, 1H), 3.12
- 2.99 (m, 3H), 2.91 (ddd, J = 9.3, 9.3, 3.8 Hz, 1H), 2.82 (dd, J =
11.8, 9.8 Hz, 1H), 2.12 (bs, 1H, OH), 1.63 (bs, 1H, OH); 13C NMR
colorless oil; [
α]D = - 48.3 (c 0.7, DCM); IR (film, DCM) νmax: 2953,
1758, 1438, 1218, 1143, 703 cm-1 1H NMR (500 MHz, CDCl3)
δ
:
(150 MHz, toluene 80 °C) δ: 164.9, 137.2, 128.6, 127.7, 127.2,
76.1, 74.3, 70.5, 67.6, 56.8, 52.8, 45.2; HRMS (ESI) m/z: [M + Na]
7.37 - 7.26 (m, 3H), 7.25 - 7.20 (m, 2H), 4.87 (d, J = 14.9 Hz, 1H),
4.18 (d, J = 14.9 Hz, 1H), 4.09 – 4.00 (m, 3H), 3.92 - 3.84 (m, 2H)
+ calcd for C14H17NO4Na 286.1055; found 286.1072.
3.76 (s, 3H), 3.73 (s, 3H), 3.68 (ddd, J = 5.8, 5.8, 4.3 Hz, 1H); 13
C
3(S), 7(S), 8(S), 9(S)-3,9-cis-7,8-Diacetoxy-1-N-benzyl-5-oxa-2-one-
bicyclo[2.0.5]nonane (30)
NMR (125 MHz, CDCl3) δ: 170.1, 169.7, 165.9, 134.8, 128.9,
128.5, 127.9, 68.5, 65.9, 54.4, 52.7, 52.3, 51.8, 45.3. HRMS (ESI)
+
Acetylation of 29 under standard condition gave 30 (89%) as m/z: [M + Na] calcd for C16H19NO6Na 344.1110; found
white crystals m.p. 99 -101 °C; [
α
]D = – 4.14 (c 1.0, DCM); IR 344.1104.
1
(film, DCM) νmax: 2930, 1749, 1370, 1238, 1037 cm-1; H NMR
3(S), 4(R)-N-Benzyl-3-acetoxycarbonylmethoxymethyl-4-acetoxy-
azetidin-2-one (36) and 3(S), 4(R)-N-Benzyl-3-formyloxymethyl-4-
acetoxy-azetidin-2-one (37)
(600 MHz, toluene 80 °C) δ: 7.13 - 7.02 (m, 5H), 5.31 (dd, J = 9.0,
7.8, 1H), 4.75 (ddd, J = 9.1, 8.1, 3.5 Hz 1H), 4.58 (d, J = 15.4 Hz,
1H), 3.75 (d, J = 15.4 Hz, 1H), 3.72 (dd, J = 13.5, 5.1 Hz, 1H), 3.60
(dd, J = 12.5, 3.5 Hz, 1H), 3.37 - 3.30 (m, 2H), 3.23 (dd, J = 8.1,
2.5 Hz, 1H), 3.01 (ddd, J = 10.0, 5.3, 5.3 Hz, 1H), 1.60 (s, 3H), 1.57
The crude diacid 34 (32 mg, 0.11 mmol) in dry DMF (0.480 mL)
was treated with Pb(OAc)4 (0.193 g, 0.436 mmol) and acetic acid
(0.207 ml, 3.597 mmol). The mixture was stirred for 3 h and then
the solvents were evaporated. The residue was treated with
DCM (5 mL), filtered and evaporated. The crude product was
purified by chromatography using hexane-AcOEt (first only
(s, 3H); 13C NMR, (150 MHz, toluene 80 °C)
δ: 167.9, 167.8,
164.6, 136.2, 128.6, 128.5, 127.7, 73.7, 70.8, 70.6, 67.5, 54.3,
53.7, 44.6, 19.7, 19.5; HRMS (ESI) m/z: [M + Na]+ calcd for
C18H21NO6Na 370.1267; found 370.1248.
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
12
hexane and then 6:4 v/v as an eluent) to afford 36 (9.4 mg,
29.4%) and 37 (5.1 mg; 15.9 %), both as a colorless oils.
Compound 36
[α] = + 31.1 (c 0.36, DCM); IR (film, DCM) νmax: 3501, 2925,
D
1754, 1365, 1228, 1015 cm-1; 1H NMR (600 MHz, CDCl3)
δ: 7.34
R. Pal, A. Basak, Chem. Commun. 2006, 2992.
View Article Online
13
14
15
16
17
Worgull, G. Dickmeiss, K. L. Jensen, DPO. IT: 1.0F.1r0a3n9k/De,0ONB.0H02o2lu8Cb
and K. A. Jørgensen, Chem. Eur. J. 2011, 17, 4076.
M. Miura, M. Enna, K. Okuro and M. Nomura, J. Org. Chem.
1995, 60, 4999.
- 7.26 (m, 5H), 5.83 (d, J = 1.0 Hz, 1H), 5.22 (ABq, J = 6.3 Hz, 2H),
4.53 (d, J = 15.4 Hz, 1H), 4.27 (d, J = 15.4 Hz, 1H), 3.99 (dd, J =
10.5, 3.3 Hz, 1H), 3.94 (dd, J = 10.5, 4.0 Hz, 1H), 3.33 - 3.30 (m,
S. Santoro, R.-Z. Liao, T. Marcelli, P. Hammar and F. Himo, J.
Org. Chem., 2015, 80, 2649.
M. Darroudi, Y. Sarrafi and M. Hamzehloueian, Tetrahedron,
2017, 73, 1673.
1H), 2.07 (s, 3H), 1.92 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ:
170.6, 170.4, 165.6, 135.4, 128.7, 128.3, 127.7, 88.6, 78.8, 64.4,
58.0, 45.0, 29.7, 20.6; HRMS (ESI) m/z: [M + Na]+ calcd for
C16H19NO6Na 344.1110; found 344.1114.
T. C. Malig, D. Yu and J. E. Hein, J. Am. Chem. Soc., 2018, 140
9167.
,
18
19
B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
Compound 37
(a) R. Rehling and H. Jensen, Tetrahedron Lett., 1972, 2793;
(b) Z. Kałuża, W. Fudong, Cz. Bełżecki and M. Chmielewski,
Tetrahedron Lett., 1989, 30, 5171; (c) Ł. Mucha, K. Parda, O.
Staszewska-Krajewska, S. Stecko, A. Ulikowski, J. Frelek, A.
Suszczyńska, M. Chmielewski and B. Furman, Tetrahedron:
Asymmetry, 2016, 27, 12.
[
α
]D = + 29.3 (c 0.6, DCM); IR (film, DCM) νmax: 3531, 2925, 1773,
1729, 1228, 1170 cm-1 1H NMR (600 MHz, CDCl3)
δ
: 7.94 (dd, J =
1.8, 0.6 Hz, 1H), 7.35-7.27 (m, 5H), 5.78 (d, J = 1.1 Hz, 1H), 4.54
(d, J = 15.0 Hz, 1H), 4.47 – 4.45 (m, 2H), 4.27 (d, J = 15.0 Hz, 1H),
3.45 -3.43 (m, 1H) 1.95 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ:
20
21
22
170.5, 164.5, 160.1, 135.4, 128.7, 128.3, 127.9, 78.6, 58.4, 56.7,
45.1, 20.6; HRMS (ESI) m/z: [M + Na]+ calcd for C14H15O5Na
300.0848; found 300.0846.
M. Michalak, M. Stodulski, S. Stecko, M. Woźnica, O.
Staszewska-Krajewska, P. Kalicki, B. Furman, J. Frelek and M.
Chmielewski, Tetrahedron, 2012, 68, 10806.
J. Frelek, R. Łysek, K. Borsuk, J. Jagodziński, B. Furman, A.
Klimek and M. Chmielewski, Enantiomer A J. Sterochemistry,
Conflicts of interest
There are no conflicts of interest to declare.
2002, 7, 107.
J. Frelek, P. Kowalska, M. Masnyk, A. Kazimierski, A. Korda,
M. Woźnica, M. Chmielewski and F. Furche, Chem. - A Eur.
J., 2007, 13, 6732.
23
24
25
M. Chmielewski, M. Cierpucha, P. Kowalska, M. Kwit and J.
Frelek, Chirality, 2008, 20, 621.
M. Woźnica, M. Masnyk, S. Stecko, A. Mames, B. Furman, M.
Chmielewski and J. Frelek, J. Org. Chem., 2010, 75, 7219.
M. Woźnica, P. Kowalska, R. Łysek, M. Masnyk, M. Górecki,
Acknowledgements
Financial support of this research by the National Science
Centre (Poland), Grant OPUS 2015/17/B/ST5/01011 is gratefully
acknowledged.
M. Kwit, F. Furche and J. Frelek, Curr. Org. Chem., 2010, 14
,
1022.
References
26
27
T. Dražić, M. Roje, M. Jurin and G. Pescitelli, European J. Org.
Chem., 2016, 4189.
M.-C. Ye, J. Zhou and Y. Tang, J. Org. Chem., 2006, 71, 3576.
1
M. Kinugasa and S. Hashimoto, J. Chem. Soc. Chem.
Commun., 1972, 466.
J. Marco-Contelles, Angew. Chemie Int. Ed., 2004, 43, 2198.
S. Stecko, B. Furman and M. Chmielewski, Tetrahedron,
2
3
2014, 70, 7817.
Brandi, S. Cicchi and F. M. Cordero, Chem. Rev., 2008, 108
4
,
,
3988.
5
6
R. Pitts and T. Lectka, Chem. Rev., 2014, 114, 7930.
S. Hosseyni and A. Jarrahpour, Org. Biomol. Chem., 2018, 16
6840.
7
M. Soluch, B. Grzeszczyk, O. Staszewska-Krajewska, M.
Chmielewski and B. Furman, J. Antibiot. (Tokyo)., 2016, 69
,
164.
8
K. Kabala, B. Grzeszczyk, S. Stecko, B. Furman and M.
Chmielewski, J. Org. Chem., 2015, 80, 12038.
9
K. Kabala, B. Grzeszczyk, B. Furman, M. Chmielewski, J.
Solecka and A. Guśpiel, Synthesis (Stuttg)., 2018, 50, 1991.
M. Michalak, M. Stodulski, S. Stecko, A. Mames, I. Panfil, M.
Soluch, B. Furman and M. Chmielewski, J. Org. Chem., 2011,
76, 6931.
10
11
R. Shintani and G. C. Fu, Angew. Chemie Int. Ed., 2003, 42
,
4082.
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DOI: 10.1039/D0OB00228C
Intramolecular Kinugasa reactions on in situ generated carbohydrate-derived alkynylnitrones are
described. Subsequent transformations of cycloadducts from alkynylnitrones followed by
epimerization at the C-4 carbon atom led to the trans-substituted azetidinones with high
stereoselectivity, mimicking variety of important β-lactam structures.