A stereoselective synthesis of sugar-derived chiral β-lactams

Article abstract of DOI:10.1002/ejoc.201100953

The importance of the β-lactam substructure is exemplified by the several classes of β-lactam antibiotics. Among the synthetic routes available to obtain this interesting scaffold, the Kinugasa reaction is a convergent strategy. In this article, the synth

Full text of DOI:10.1002/ejoc.201100953

FULL PAPER
DOI: 10.1002/ejoc.201100953
A Stereoselective Synthesis of Sugar-Derived Chiral β-Lactams
Rama Kanwar Khangarot[a] and Krishna P. Kaliappan*[a]
Keywords: Asymmetric synthesis / Nitrones / Alkynes / Lactams
The importance of the β-lactam substructure is exemplified
by the several classes of β-lactam antibiotics. Among the syn-
thetic routes available to obtain this interesting scaffold, the
Kinugasa reaction is a convergent strategy. In this article, the
tion between cyclic nitrones derived from different sugars,
tartrate ester, and alkynes obtained from different sugars.
The reaction gave moderate to good yields of β-lactams with
high diastereoselectivity, mainly producing a single product.
synthesis of a variety of chiral β-lactams by the Kinugasa re- The stereochemical preferences observed in these reactions
action between terminal alkynes and nitrones is described.
are also explained.
These sugar-derived β-lactams were synthesized by the reac-
1907.[5] Since then several approaches have been reported
for their synthesis, such as (1) the rhodium-catalyzed car-
bonylation of an aziridine (kinetic resolution)[6a,6b] and in-
tramolecular insertion of an α-diazo amide into a C–H
bond,[6c] (2) the copper-catalyzed coupling of an alkyne
with a nitrone (Kinugasa reaction),[7,8] (3) the condensation
of ester enolates with imines (Gilman–Speeter reaction),[9]
(4) the alkaloid-catalyzed ketene-imine cycloaddition,[10]
(5) the copper(I)-catalyzed intramolecular coupling of
amides with vinyl bromides,[11] (6) the condensation of
metal enolates with imines,[12] (7) the palladium-catalyzed
synthesis of β-lactams from imines, acyl chlorides, and car-
bon monoxide,[13a] the intramolecular hydroamination of
difluoropropargyl amides,[13b] and the carbonylation of
vinyl aziridines,[13c] (8) the organoiron-catalyzed β-lactam
synthesis,[14] (9) the cobalt-catalyzed β-lactam synthesis,[15]
(10) the ceric ammonium nitrate catalyzed solid-phase syn-
thesis of N-unsubstituted β-lactams[16a] and the free-radical
cyclization of enamides,[16b] (11) the bifunctional Lewis
acid/nucleophile-catalyzed synthesis of β-lactams,[17]
(12) the catalytic Hunsdiecker-like reaction with unsatu-
rated aromatic amides,[18] (13) the tandem Petasis–Ugi ap-
proach and 1,3-diisopropylcarbodiimide condensation reac-
Introduction
Bacterial infection is a global problem, and it is a serious
issue in tropical countries where the death rate is very high
due to this type of infection. To counter this serious men-
ace, the first half of the 20th century witnessed active re-
search directed at the development of new classes of anti-
biotics starting with the serendipitous discovery of penicil-
lin. However, bacteria, being smarter, often developed resis-
tance to antibiotics, putting the onus on scientists to de-
velop new types of antibiotics. Moreover, the gross negli-
gence and continuous misuse of antibiotics have led to the
limited lifetime of existing antibiotics. Unfortunately, the
present situation in antibiotic research is not too encourag-
ing as only a handful of new antibiotics have come to mar-
ket in the last century. With these constraints, it is very im-
portant to design and synthesize new molecular scaffolds
and to study their activity against various bacterial
strains.[1]
As a continuation of our interest in the synthesis of anti-
biotics,[2] we became interested in synthesizing new small
molecules that are structurally similar to existing antibiotics
but with additional features. When we looked at the range
of available antibiotics, we realized that β-lactam antibiot-
ics, such as penicillins, cephalosporins, carbapenems, and
monobactams (Figure 1),[3] have been successfully used as
first-level antibiotics. In addition to their antibiotic activity,
β-lactams are also important synthetic intermediates in or-
ganic synthesis[4] and as a result they have attracted the at-
tention of the scientific community for over a century. The
first synthesis of a β-lactam was reported by Staudinger in
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
E-mail: kpk@chem.iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100953.
Figure 1. Different classes of β-lactam antibiotics.
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R. K. Khangarot, K. P. Kaliappan
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Figure 2. Different approaches to the synthesis of β-lactams.
tion,[19] (14) the Reformatsky reaction,[20] and (15) N-het- the literature,[22] but the asymmetric version started to ap-
erocyclic carbene catalyzed [2+2] cycloaddition of ketenes pear only at the beginning of this decade. Chmielewski and
to N-tosylimines[21] (Figure 2).
co-workers[23] reported the use of chiral cyclic nitrones and
Although all the other approaches to β-lactams have achiral simple alkynes in the Kinugasa reaction. Basak[24]
been studied extensively, the Kinugasa reaction[7,8] re- and Hsung[25] and their co-workers demonstrated the asym-
mained relatively unexplored until recently. In 1972, Kinu- metric version of this reaction by using chiral oxazolidone-
gasa and Hashimoto discovered a convergent route to β- derived alkynes. During the course of our investigation of
lactams through the reaction of copper acetylide with nitro- this reaction, Chmielewski and co-workers[23c] reported the
ne.[7a] Four years later, in 1976, Ding and Irwin proposed Kinugasa reaction using chiral alkynes. The first catalytic
the first mechanism for the Kinugasa reaction.[7b] The and asymmetric version of the Kinugasa reaction was re-
mechanism involves two steps, namely 1,3-dipolar cycload- ported by Miura and co-workers.[8] Later on, Fu,[26]
dition followed by protonation of the intermediate enolate Tang,[27] Guiry,[28] and Saito and Otani[29] and their co-
(Figure 3). This atom-economic reaction between acyclic workers reported the Kinugasa reaction prompted by metal
nitrones and alkynes has been documented a few times in complexes. During the last few years, our group has been
investigating the synthetic utility of sugar-derived cyclic
nitrones[30] and alkynes[31] in various synthetic transforma-
tions, and herein we disclose one more application of this
couple to the synthesis of chiral β-lactams through the
Kinugasa reaction (Scheme 1). We also believe that the
Scheme 1. Kinugasa reaction between sugar-derived cyclic nitrones
and alkynes.
Figure 3. Proposed mechanism for the Kinugasa reaction.
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A Stereoselective Synthesis of Sugar-Derived Chiral β-Lactams
addition of a sugar unit to both the templates may have a tained in good yields, but in the case of alkyne 16, the de-
significant effect in improving the bioavailability of these sired Kinugasa product 21 was accompanied by its dimer
chiral β-lactams.
41.
This optimized procedure was then applied to nitrones
ent-8–11 with alkynes 12–16. In all cases the Kinugasa
products were obtained in poor yields and, in the case of
d-mannose-derived cyclic nitrone 11, only the alkyne di-
mers 37–41 were isolated instead of the desired Kinugasa
product. This problem was subsequently overcome by
screening different bases such as triethylamine, diisopropyl-
(ethyl)amine, and dicyclohexylamine with nitrone ent-8 and
alkyne 12 (the results of the screening of bases are illus-
trated in Table 1). In the case of triethylamine, a mixture of
Kinugasa product 22 and alkyne dimer 37 was observed. In
the case of diisopropyl(ethyl)amine, only the alkyne dimer
37 was observed with no trace of the Kinugasa product 22.
Dicyclohexylamine gave much better results and afforded
the Kinugasa product 22 in 71% yield and the alkyne dimer
37 in 10% yield. Then the nitrone ent-8 was treated with
the alkynes 13–16, furnishing the Kinugasa product in good
to excellent yields. The optimized reaction conditions with
dicyclohexylamine were also found to be compatible with
other nitrones, and the β-lactams were obtained in good to
excellent yields (the results of these experiments are col-
lected in Table 2).
Results and Discussion
To accomplish our goal, we selected nitrones 8–11 and
alkynes 12–16 (Figure 4), which were synthesized from dif-
ferent carbohydrate precursors according to literature pro-
tocols.[30–32] It is also important to note that the Kinugasa
reaction occasionally suffers from some side-reactions, for
instance, Glaser coupling,[33a–33c] the nucleophilic addition
of copper acetylide,[8b] and CuI-mediated deoxygenation of
the nitrone.[33d] In our investigation of this reaction, in some
cases we observed only the Glaser coupling product of al-
kynes in addition to the major Kinugasa product.
Table 1. Screening of bases in the Kinugasa reaction.[a]
Figure 4. Sugar-derived nitrones 8–11 and alkynes 12–16.
Entry
Base
Yield of 22 [%]
Yield of 37 [%]
1.
2.
3.
Et3N
DIPEA
Cy2NH
mixture[b]
mixture[b]
Having all these nitrones and alkynes in hand, our first
task was to identify suitable reaction conditions to carry
out the Kinugasa reaction between the two carbohydrate
moieties (nitrones and alkynes). Initially, d-xylose-derived
nitrone 8 and d-glucose-derived alkyne 12 were employed
0
71
35
10
[a] The β-lactams were synthesized from the corresponding cyclic
nitrones and alkynes by using CuI and base in CH3CN at 0 °C
to room temp. [b] A mixture of β-lactam and alkyne dimer was
as model substrates to optimize the reaction conditions. To obtained.
begin with, we examined the effect of various solvents like
DMF, DMSO, and acetonitrile and finally found that ace-
The reaction worked well for most of the substrates; in
tonitrile was the most efficient solvent and provided the re- the case of d-ribose-derived nitrone 9 the desired products
quired product in excellent yield. Then the reaction was 30 and 31 were obtained in moderate yields, but compounds
standardized by employing 1 equiv. of nitrone, 1.5 equiv. of 27–29 could not be separated from the dimers of the corre-
alkyne, 3 equiv. of CuI, and 3 equiv. of triethylamine in dry sponding alkynes (37–39, respectively). The l-tartrate
acetonitrile at room temperature for 5 h. After optimization nitrone 10 also gave good results with alkynes 12, 14, and
of the reaction conditions, we then treated nitrone 8 with 16, furnishing solely the Kinugasa products 32, 34, and 36
the alkynes 13–16. In the case of alkyne 13, product 18 was in moderate to good yields; but with alkynes 13 and 15 the
obtained in excellent yield, whereas in the cases of alkynes Kinugasa products were accompanied by their dimers (38
14 and 15, the corresponding Kinugasa products were ob- and 40, respectively). Unfortunately, in the case of d-mann-
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R. K. Khangarot, K. P. Kaliappan
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Table 2. Kinugasa reaction between sugar-derived cyclic nitrones and alkynes.[a–c]
[a] The β-lactams were synthesized from the corresponding cyclic nitrones and alkynes by using CuI and Et3N or Cy2NH in CH3CN at
0 °C to room temp. [b] A mixture of the β-lactam and alkyne dimer was obtained. [c] Yields are given in parentheses.
Figure 5. Alkyne dimers 37–41.
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Figure 6. Stereochemical outcome of the Kinugasa reaction.
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A Stereoselective Synthesis of Sugar-Derived Chiral β-Lactams
Figure 7. Expanded 400 MHz COSY (top) and NOESY (bottom) spectra of compound 23.
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R. K. Khangarot, K. P. Kaliappan
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monitored by thin-layer chromatography on 0.25 mm E. Merck sil-
ica plates (60F-254) using UV light for visualization and 7% ethan-
olic phosphomolybdic acid and heat for development. Optical ro-
tations were measured with a Rudolph Autopol IV digital polari-
meter. High-resolution mass spectra were recorded with a Micro-
mass ESI TOF (time-of-flight) mass spectrometer. IR spectra were
recorded with a Perkin–Elmer Spectrum One FTIR spectrometer.
1H and 13C NMR spectra were recorded with a Varian ASM 300,
Varian AS 400, or Bruker AV 400 MHz instrument in CDCl3. The
following abbreviations were used to report the NMR spectro-
ose-derived cyclic nitrone 11, the results could not be im-
proved, and only the alkyne dimers 37–41 (Figure 5) were
isolated instead of the desired Kinugasa products. This may
presumably be due to the steric hindrance exposed by the
acetonide group on the nitrone.
The stereochemistry of the β-lactams was first tentatively
assigned on the basis of previous reports.[23] The acetylene–
copper complex approaches the nitrone anti to the substitu-
ent close to the 1,3-dipole, and the protonation of the cop-
per enolate occurs from the less hindered convex side of the scopic data: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet
of doublets; m, multiplet.
β-lactam skeleton, which leads exclusively to cis-β-lactams.
The stereogenic centers in the alkynes do not influence the
stereochemical outcome of the reaction unless the nitrones
are achiral or the chiral centre in the nitrone is not close to
the 1,3-dipole.[34] A possible stereochemical representation
of the Kinugasa reaction is shown in Figure 6.
General Procedure for the Kinugasa Reaction: Triethylamine or di-
cyclohexylamine (3 mmol) was added to a cold (0 °C) suspension
of CuI (3 mmol) in dry MeCN (15 mL). Then a solution of alkyne
(1.5 mmol) in MeCN (1 mL) was added, and the mixture obtained
was stirred for 5 min. Then a solution of nitrone (1 mmol) in
MeCN (1 mL) was added, and the mixture was kept at 0 °C for an
additional 15 min. Then the cooling bath was removed, and the
reaction mixture was stirred at room temperature for 5 h. Comple-
tion of the reaction was confirmed by TLC. Subsequently, the sol-
vent was removed in vacuo, and the residue was purified by silica
gel chromatography.
Compound 23 exhibits a particularly well-resolved 1H
NMR spectrum that allowed an extensive structural analy-
sis through COSY and NOESY experiments (Figure 7). A
distinct NOE interaction indicated strong cross-peaks be-
tween 3-H and 5-H, which confirms that the protons at C-
3 and C-5 are on the same side. The cis relationship of the
β-lactams was confirmed on the basis of coupling (J =
6 Hz) between 5-H and 6-H (Figure 8).
(2S,3S,4S)-3,4-Bis(benzyloxy)-6-[(3aR,5R,6S,6aR)-6-(benzyloxy)-
tetrahydro-2,2-dimethylfuro[2,3-d][1,3]dioxol-5-yl]-2-(benzyloxy-
methyl)-1-azabicyclo[3.2.0]heptan-7-one (17): According to the ge-
neral procedure, starting from alkyne 12 (50 mg, 0.18 mmol) and
nitrone 8 (50 mg, 0.12 mmol), β-lactam 17 was obtained as a color-
less oil (70 mg, 85 %) after purification by silica gel column
chromatography (27% ethyl acetate/hexanes). Rf = 0.6 (25% ethyl
acetate/hexanes). [α]2D0 = 22.4 (c = 1.00, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.35–7.20 (m, 20 H), 5.88 (d, J = 3.6 Hz,
1 H), 4.74 and 4.64 (ABq, J = 11.3 Hz, 2 H), 4.62–4.39 (m, 8 H),
4.30–4.21 (m, 3 H), 4.10–4.04 (m, 2 H), 3.90 (dd, J = 5.5, 2.9 Hz,
1 H), 3.47 (d, J = 6.7 Hz, 2 H), 1.24 (s, 3 H), 1.17 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 175.9, 137.9, 137.7, 137.6, 137.2,
128.4, 128.3, 128.3, 127.9, 127.7, 127.6, 127.6, 111.6, 104.7, 88.1,
83.2, 82.8, 82.2, 75.8, 73.1, 72.6, 72.5, 71.5, 68.0, 62.3, 60.2, 51.4,
Figure 8. NOE correlation in 23.
26.5, 26.3 ppm. IR (neat): ν = 3031, 2933, 2865, 1765, 1650, 1454,
˜
Conclusions
1373, 1217, 1164, 1095, 1027, 698 cm–1. HRMS (ESI): calcd. for
C42H46NO8 [M + 1]+ 692.3223; found 692.3218.
We have successfully explored the Kinugasa reaction of
sugar-derived cyclic nitrones and alkynes, obtaining a range
of chiral sugar-derived β-lactams that may act as precursors
to several potential water-soluble β-lactams. This reaction
is highly diastereoselective and in many cases mainly fur-
nished a single product. Work is in progress to use alkynes
derived from other sources to synthesize a library of
β-lactams.
(2S,3S,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-[(3aR,5R,
5aS,8aS,8bR)-tetrahydro-2,2,7,7-tetramethyl-3aH-bis[1,3]dioxolo-
[4,5-b:4Ј,5Ј-d]pyran-5-yl]-1-azabicyclo[3.2.0]heptan-7-one (18): Ac-
cording to the general procedure, starting from alkyne 13 (46 mg,
0.18 mmol) and nitrone 8 (50 mg, 0.12 mmol), β-lactam 18 was ob-
tained as a colorless oil (70 mg, 88%) after purification by silica
gel column chromatography (27% ethyl acetate/hexanes). Rf = 0.6
(25% ethyl acetate/hexanes). [α]2D0 = 31.8 (c = 1.00, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.33–7.19 (m, 15 H), 5.46 (d, J =
5.1 Hz, 1 H), 4.61–4.46 (m, 6 H), 4.40–4.23 (m, 6 H), 4.12–4.07 (m,
1 H), 4.01 (dd, J = 11.3, 5.1 Hz, 1 H), 3.84 (dd, J = 5.4, 2.2 Hz, 1
H), 3.54–3.43 (m, 2 H), 1.46 (s, 3 H), 1.37 (s, 3 H), 1.24 (s, 3 H),
1.22 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.3, 138.1,
138.0, 136.9, 128.4, 128.3, 128.2, 127.8, 127.6, 127.5, 109.1, 108.4,
96.2, 88.6, 83.3, 73.1, 72.4, 71.2, 70.6, 70.2, 67.7, 64.2, 61.5, 60.7,
Experimental Section
General: Unless otherwise noted, all the starting materials and rea-
gents were obtained from commercial suppliers and used without
further purification. Tetrahydrofuran was distilled from sodium
benzophenone ketyl and toluene from sodium. Dichloromethane,
hexane, and pyridine were freshly distilled from calcium hydride.
All solvents for the routine isolation of products and chromatog-
raphy were reagent-grade and glass-distilled. Air- and moisture-
sensitive reactions were performed under argon/UHP nitrogen.
Flash chromatography was performed by using silica gel (100–
200 mesh, Aceme) with the indicated solvents. All reactions were
52.0, 26.0, 25.3, 24.6, 24.3 ppm. IR (neat): ν = 2983, 2932, 2867,
˜
1769, 1654, 1455, 1373, 1258, 1213, 1166, 1104, 1069, 1001, 901,
699 cm–1. HRMS (ESI): calcd. for C39H46NO9 [M + 1]+ 672.3173;
found 672.3163.
(2S,3S,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-[(3aR,6R,
6aS)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl]-1-azabi-
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A Stereoselective Synthesis of Sugar-Derived Chiral β-Lactams
cyclo[3.2.0]heptan-7-one (19): According to the general procedure,
acetate/hexanes). [α]2D0 = –73.0 (c = 1.00, CHCl3). 1H NMR
starting from alkyne 14 (30 mg, 0.18 mmol) and nitrone 8 (50 mg, (400 MHz, CDCl3): δ = 7.34–7.18 (m, 20 H), 5.96 (d, J = 4.0 Hz,
0.12 mmol), β-lactam 19 was obtained as a colorless oil (50 mg,
72%) after purification by silica gel column chromatography (27%
ethyl acetate/hexanes). Rf = 0.6 (25% ethyl acetate/hexanes). [α]2D0
1 H), 4.47–4.42 (m, 7 H), 4.42–4.28 (m, 5 H), 4.05–4.04 (m, 1 H),
3.93 (dd, J = 9.1, 5.8 Hz, 1 H), 3.77–3.73 (m, 2 H) 3.49 (d, J =
6.7 Hz, 2 H), 1.27 (s, 3 H), 1.21 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 176.8, 138.0, 137.4, 137.3, 128.6, 128.4, 128.2, 127.9,
127.8, 127.5, 111.8, 105.4, 87.8, 83.5, 82.3, 81.9, 75.8, 73.3, 72.2,
1
= 30.5 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.35–
7.22 (m, 15 H), 4.67–4.63 (m, 2 H), 4.58 (dd, J = 11.7, 5.4 Hz, 1
H), 4.51–4.37 (m, 5 H), 4.30–4.27 (m, 2 H), 4.12–4.11 (m, 1 H),
4.05 (dd, J = 10.9, 5.4 Hz, 1 H), 3.93 (d, J = 10.6 Hz, 1 H), 3.90
(dd, J = 5.8, 2.9 Hz, 1 H), 3.59 (dd, J = 11.3, 1.5 Hz, 1 H), 3.48
(d, J = 6.9 Hz, 2 H), 3.90 (dd, J = 10.6, 2.9 Hz, 1 H), 1.48 (s, 3 H),
1.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.7, 137.9,
137.6, 137.4, 128.3, 128.3, 127.8, 127.7, 127.7, 127.6, 127.6, 112.3,
88.6, 82.6, 80.8, 80.4, 77.8, 73.1, 72.7, 72.0, 71.4, 68.1, 62.6, 60.2,
72.0, 71.8, 68.6, 61.8, 58.8, 51.8, 26.8, 26.5 ppm. IR (neat): ν =
˜
3031, 2926, 2853, 1775, 1655, 1455, 1374, 1215, 1166, 1098, 1076,
1027, 932, 863, 699 cm–1. HRMS (ESI): calcd. for C42H46NO8 [M
+ 1]+ 692.3223; found 692.3223.
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-[(3aR,5R,
5aS,8aS,8bR)-tetrahydro-2,2,7,7-tetramethyl-3aH-bis[1,3]dioxolo-
[4,5-b:4Ј,5Ј-d]pyran-5-yl]-1-azabicyclo[3.2.0]heptan-7-one (23): Ac-
cording to the general procedure, starting from alkyne 13 (46 mg,
0.18 mmol) and nitrone ent-8 (50 mg, 0.12 mmol), β-lactam 23 was
obtained as a colorless oil (50 mg, 63%) after purification by silica
gel column chromatography (27% ethyl acetate/hexanes). Rf = 0.6
(25% ethyl acetate/hexanes). [α]2D0 = –47.5 (c = 1.00, CHCl3). 1H
52.0, 26.0, 24.7 ppm. IR (neat): ν = 3019, 2930, 2858, 1764, 1651,
˜
1455, 1383, 1271, 1216, 1100, 1028, 928, 860, 669 cm–1. HRMS
(ESI): calcd. for C35H40NO7 [M + 1]+ 586.2805; found 586.2806.
(2S,3S,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(3aR,4R,6R,6aR)-tetrahydro-4-methoxy-2,2-dimethylfuro[3,4-
d][1,3]dioxol-6-yl]-1-azabicyclo[3.2.0]heptan-7-one (20): According NMR (400 MHz, CDCl3): δ = 7.36–7.21 (m, 15 H), 5.53 (d, J =
to the general procedure, starting from alkyne 15 (36 mg,
0.18 mmol) and nitrone 8 (50 mg, 0.12 mmol), β-lactam 20 was ob-
5.1 Hz, 1 H), 4.61 (d, J = 12.4 Hz, 1 H), 4.55–4.47 (m, 3 H), 4.41
(d, J = 12.4 Hz, 1 H), 4.38 (dd, J = 7.8, 2.6 Hz, 1 H), 4.32–4.27
tained as a colorless oil (50 mg, 70%) after purification by silica (m, 3 H), 4.25 (dd, J = 7.8, 2.6 Hz, 1 H), 4.05 (dd, J = 10.2, 1.8 Hz,
gel column chromatography (27% ethyl acetate/hexanes). Rf = 0.6
(25% ethyl acetate/hexanes). [α]2D0 = 55.4 (c = 1.00, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.35–7.24 (m, 15 H), 4.94 (d, J =
4.4 Hz, 1 H), 4.93 (s, 1 H), 4.64–4.55 (m, 5 H), 4.50–4.44 (m, 3 H),
4.32–4.30 (m, 2 H), 4.25 (t, J = 6.9 Hz, 1 H), 3.83 (dd, J = 5.5,
2.9 Hz, 1 H), 3.70 (dd, J = 12.1, 5.5 Hz, 1 H), 3.47 (d, J = 7.3 Hz,
1 H), 3.95 (dd, J = 3.1, 2.0 Hz, 1 H), 3.85 (dd, J = 10.2, 6.0 Hz, 1
H), 3.76 (dd, J = 6.0, 3.6 Hz, 1 H), 3.61 (dd, J = 7.8, 1.9 Hz, 1 H),
3.51–3.41 (m, 2 H), 1.43 (s, 3 H), 1.35 (s, 3 H), 1.29 (s, 3 H), 1.26
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.9, 138.1,
137.5, 137.4, 128.7, 128.6, 128.5, 128.5, 128.2, 127.8, 127.7, 109.8,
108.9, 96.4, 88.2, 83.1, 73.3, 71.6, 71.4, 71.0, 70.6, 65.1, 61.8, 59.3,
2 H), 3.29 (s, 3 H), 1.40 (s, 3 H), 1.30 (s, 3 H) ppm. 13C NMR 52.1, 26.1, 25.9, 25.0, 24.9 ppm. IR (neat): ν = 2929, 2868, 1777,
˜
(75 MHz, CDCl3): δ = 175.7, 138.0, 137.8, 137.3, 128.5, 128.0, 1650, 1455, 1383, 1257, 1214, 1168, 1072, 1002, 902, 700 cm–1
127.9, 127.8, 127.7, 127.7, 112.5, 109.9, 87.9, 85.4, 83.2, 83.0, 82.4,
73.2, 72.6, 71.7, 68.2, 62.4, 61.0, 55.9, 54.9, 26.4, 24.9 ppm. IR 672.3180.
.
HRMS (ESI): calcd. for C39H46NO9 [M + 1]+ 672.3173; found
(neat): ν = 2935, 2862, 1768, 1454, 1382, 1276, 1208, 1162, 1105,
˜
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-[(3aR,6R,
6aS)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl]-1-azabi-
cyclo[3.2.0]heptan-7-one (24): According to the general procedure,
starting from alkyne 14 (30 mg, 0.18 mmol) and nitrone ent-8
(50 mg, 0.12 mmol), β-lactam 24 was obtained as a colorless oil
(70 mg, 92%) after purification by silica gel column chromatog-
raphy (27% ethyl acetate/hexanes). Rf = 0.6 (25% ethyl acetate/
868, 801, 699 cm–1. HRMS (ESI): calcd. for C36H42NO8 [M + 1]+
616.2910; found 616.2892.
(2S,3S,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(3aS,4S,6R,6aS)-tetrahydro-4-methoxy-2,2-dimethylfuro[3,4-
d][1,3]dioxol-6-yl]-1-azabicyclo[3.2.0]heptan-7-one (21, Mix.): Ac-
cording to the general procedure, starting from alkyne 16 (36 mg,
0.18 mmol) and nitrone 8 (50 mg, 0.12 mmol), a mixture of β-lact- hexanes). [α]2D0 = –58.3 (c = 1.00, CHCl3). 1H NMR (400 MHz,
am 21 and alkyne dimer 41 was obtained as a colorless oil (55 mg,
78%) after purification by silica gel column chromatography (27%
ethyl acetate/hexanes). Rf = 0.6 (25% ethyl acetate/hexanes). 1H
CDCl3): δ = 7.37–7.23 (m, 15 H), 4.63–4.48 (m, 6 H), 4.37–4.30
(m, 3 H), 4.21 (dd, J = 5.8, 3.6 Hz, 1 H), 4.02–3.84 (m, 4 H), 3.63
(dd, J = 10.1, 3.6 Hz, 1 H), 3.50 (d, J = 7.4 Hz, 2 H), 3.29 (dd, J
NMR (300 MHz, CDCl3): δ = 7.33–7.23 (m, 15 H), 4.79 (s, 1 H), = 10.6, 3.6 Hz, 1 H), 1.47 (s, 3 H), 1.31 (s, 3 H) ppm. 13C NMR
4.75–4.67 (m, 2 H), 4.58–4.40 (m, 6 H), 4.35–4.18 (m, 4 H), 4.05
(dd, J = 11.4, 5.9 Hz, 1 H), 3.93 (dd, J = 5.8, 2.5 Hz, 1 H), 3.50
(d, J = 7.5 Hz, 2 H), 3.04 (s, 3 H), 1.46 (s, 3 H), 1.31 (s, 3 H) ppm.
(100 MHz, CDCl3): δ = 178.1, 138.1, 137.5, 137.5, 128.7, 128.6,
128.5, 128.2, 128.0, 127.9, 127.8, 127.8, 112.7, 88.3, 82.4, 81.2, 80.2,
78.5, 73.3, 72.9, 71.6, 71.4, 68.2, 62.3, 59.2, 52.5, 26.2, 25.2 ppm.
13C NMR (75 MHz, CDCl3): δ = 176.1, 138.0, 137.6, 137.4, 128.5, IR (neat): ν = 2930, 2856, 1773, 1634, 1454, 1371, 1272, 1208, 1171,
˜
128.4, 127.8, 127.7, 127.7, 127.4, 113.6, 112.7, 107.4, 107.2, 87.7,
84.9, 84.8, 82.6, 80.8, 79.7, 75.5, 73.2, 72.4, 71.8, 71.4, 71.2, 67.9,
1097, 1028, 986, 860, 699 cm–1. HRMS (ESI): calcd. for
C35H40NO7 [M + 1]+ 586.2805; found 586.2791.
63.3, 60.7, 55.0, 54.7, 52.1, 26.4, 26.1, 25.4, 24.8 ppm. IR (neat): ν
˜
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(3aR,4R,6R,6aR)-tetrahydo-4-methoxy-2,2-dimethylfuro[3,4-
d][1,3]dioxol-6-yl]-1-azabicyclo[3.2.0]heptan-7-one (25): According
to the general procedure, starting from alkyne 15 (36 mg,
= 2934, 2860, 1772, 1496, 1454, 1373, 1271, 1207, 1163, 1018, 963,
856, 699 cm–1. HRMS (ESI): calcd. for C36H41NO8Na [M + Na]+
638.2730; found 638.2722.
(2R,3R,4R)-3,4-Bis(benzyloxy)-6-[(3aR,5R,6S,6aR)-6-(benzyloxy)- 0.18 mmol) and nitrone ent-8 (50 mg, 0.12 mmol), β-lactam 25 was
tetrahydro-2,2-dimethylfuro[2,3-d][1,3]dioxol-5-yl)-2-(benzyloxy-
methyl]-1-azabicyclo[3.2.0]heptan-7-one (22): According to the ge-
neral procedure, starting from alkyne 12 (50 mg, 0.18 mmol) and
nitrone ent-8 (50 mg, 0.12 mmol), β-lactam 22 was obtained as a
colorless oil (58 mg, 71%) after purification by silica gel column
chromatography (27% ethyl acetate/hexanes). Rf = 0.6 (25% ethyl
obtained as a colorless oil (40 mg, 55%) after purification by silica
gel column chromatography (27% ethyl acetate/hexanes). Rf = 0.6
(25% ethyl acetate/hexanes). [α]2D0 = –26.6 (c = 0.50, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.34–7.26 (m, 15 H), 5.00 (s, 1 H),
4.61–4.44 (m, 9 H), 4.25–4.19 (m, 3 H), 3.75 (dd, J = 5.8, 3.5 Hz,
1 H), 3.67 (dd, J = 11.6, 5.8 Hz, 1 H), 3.48–3.46 (m, 2 H), 3.93 (s,
Eur. J. Org. Chem. 2011, 6117–6127
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6123

R. K. Khangarot, K. P. Kaliappan
FULL PAPER
3 H), 1.38 (s, 3 H), 1.28 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 176.5, 138.1, 137.7, 137.5, 128.6, 128.6, 128.5, 128.1,
128.0, 127.9, 127.9, 127.8, 113.2, 109.6, 88.2, 85.4, 83.7, 83.4, 82.6,
73.3, 72.7, 71.8, 68.6, 62.5, 59.5, 55.7, 54.9, 26.7, 25.7 ppm. IR
999, 897, 699 cm–1. HRMS (ESI): calcd. for C39H46NO9 [M + 1]+
672.3173; found 672.3177.
(2S,3R,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-[(3aR,6R,
6aS)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl]-1-azabi-
cyclo[3.2.0]heptan-7-one (29, Mixture): According to the general
procedure, starting from alkyne 14 (30 mg, 0.18 mmol) and nitrone
9 (50 mg, 0.12 mmol), a mixture of β-lactam 29 and alkyne dimer
39 was obtained as a colorless oil (30 mg, 43%) after purification
by silica gel column chromatography (27% ethyl acetate/hexanes).
Rf = 0.6 (25% ethyl acetate/hexanes). 1H NMR (400 MHz, CDCl3):
δ = 7.33–7.27 (m, 15 H), 4.77–4.70 (m, 3 H), 4.59–4.49 (m, 5 H),
4.18 (t, J = 4.8 Hz, 1 H), 4.07 (dd, J = 12.8, 6.4 Hz, 1 H), 4.04–
3.97 (m, 3 H), 3.93 (dd, J = 9.9, 4.7 Hz, 1 H), 3.73 (dd, J = 9.9,
6.4 Hz, 1 H), 3.64 (dd, J = 9.9, 7.6 Hz, 1 H), 3.37 (dd, J = 10.4,
3.5 Hz, 2 H), 1.48 (s, 3 H), 1.33 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 176.6, 138.3, 138.2, 138.0, 128.5, 128.0, 127.9, 127.9,
127.8, 112.6, 82.4, 80.9, 80.9, 78.3, 78.0, 73.9, 73.4, 73.1, 72.4, 67.6,
(neat): ν = 3019, 2933, 2857, 1770, 1648, 1455, 1374, 1210, 1109,
˜
1022, 669 cm–1. HRMS (ESI): calcd. for C36H42NO8 [M + 1]+
616.2904; found 616.2910.
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(3aS,4S,6R,6aS)-tetrahydro-4-methoxy-2,2-dimethylfuro[3,4-
d][1,3]dioxol-6-yl]-1-azabicyclo[3.2.0]heptan-7-one (26): According
to the general procedure, starting from alkyne 16 (36 mg,
0.18 mmol) and nitrone ent-8 (50 mg, 0.12 mmol), β-lactam 26 was
obtained as a colorless oil (50 mg, 68%) after purification by silica
gel column chromatography (27% ethyl acetate/hexanes). Rf = 0.6
(25% ethyl acetate/hexanes). [α]2D0 = –79.2 (c = 0.50, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.42–7.20 (m, 15 H), 4.89 (s, 1 H),
4.60–4.48 (m, 5 H), 4.41–4.29 (m, 5 H), 4.12 (dd, J = 9.7, 3.8 Hz,
1 H), 3.93 (s, 1 H), 3.88–3.82 (m, 2 H), 3.53–3.49 (m, 2 H), 3.13 (s,
3 H), 1.45 (s, 3 H), 1.29 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 177.7, 138.0, 137.4, 137.2, 128.5, 128.4, 128.4, 128.0,
128.0, 127.8, 127.7, 127.7, 127.6, 112.9, 106.7, 88.4, 84.8, 82.4, 79.3,
76.1, 73.2, 71.6, 71.4, 68.0, 62.4, 59.1, 54.4, 52.4, 26.0, 25.1 ppm.
59.7, 58.0, 50.2, 26.1, 24.8 ppm. IR (neat): ν = 3019, 2930, 2855,
˜
1763, 1639, 1456, 1375, 1271, 1105, 1077, 1097, 1029, 985, 861,
669 cm–1. HRMS (ESI): calcd. for C35H40NO7 [M + 1]+ 586.2805;
found 586.2798.
(2S,3R,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(3aR,4R,6R,6aR)-tetrahydro-4-methoxy-2,2-dimethylfuro[3,4-
d][1,3]dioxol-6-yl]-1-azabicyclo[3.2.0]heptan-7-one (30): According
to the general procedure, starting from alkyne 15 (36 mg,
0.18 mmol) and nitrone 9 (50 mg, 0.12 mmol), β-lactam 30 was ob-
tained as a colorless oil (50 mg, 68%) after purification by silica
gel column chromatography (27% ethyl acetate/hexanes). Rf = 0.6
(25% ethyl acetate/hexanes). [α]2D0 = 11.3 (c = 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.25 (m, 15 H), 4.97 (s, 1 H),
4.94 (d, J = 5.8 Hz, 1 H), 4.75 (s, 1 H), 4.66 (s, 2 H), 4.64 (d, J =
5.8 Hz, 1 H), 4.59 (d, J = 11.4 Hz, 1 H), 4.53, 4.50 (ABq, J =
11.8 Hz, 2 H), 4.25 (d, J = 12.4 Hz, 1 H), 4.21 (t, J = 4.6 Hz, 1 H),
4.03–3.93 (m, 3 H), 3.71 (dd, J = 9.7, 7.1 Hz, 1 H), 3.65–3.60 (m,
2 H), 3.31 (s, 3 H), 1.48 (s, 3 H), 1.31 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 176.0, 138.2, 138.1, 138.0, 128.6, 128.6,
128.0, 128.0, 127.8, 112.7, 110.0, 85.4, 83.0, 82.4, 82.3, 78.8, 74.2,
IR (neat): ν = 2932, 2859, 1774, 1654, 1455, 1373, 1272, 1210, 1163,
˜
1106, 1022, 967, 863, 699 cm–1. HRMS (ESI): calcd. for
C36H42NO8 [M + 1]+ 616.2910; found 616.2929.
(2S,3R,4S)-3,4-Bis(benzyloxy)-6-[(3aR,5R,6S,6aR)-6-(benzyloxy)-
tetrahydro-2,2-dimethylfuro[2,3-d][1,3]dioxol-5-yl]-2-(benzyloxy-
methyl)-1-azabicyclo[3.2.0]heptan-7-one (27, Mixture): According
to the general procedure, starting from alkyne 12 (50 mg,
0.18 mmol) and nitrone 9 (50 mg, 0.12 mmol), a mixture of β-lac-
tam 27 and alkyne dimer 37 was obtained as a colorless oil (60 mg,
73%) after purification by silica gel column chromatography (27%
ethyl acetate/hexanes). Rf = 0.6 (25% ethyl acetate/hexanes). 1H
NMR (400 MHz, CDCl3): δ = 7.37–7.23 (m, 20 H), 5.87 (d, J =
3.6 Hz, 1 H), 4.86–4.65 (m, 4 H), 4.59–4.48 (m, 5 H), 4.33 (dd, J
= 9.2, 2.9 Hz, 1 H), 4.19–4.00 (m, 5 H), 3.92 (dd, J = 9.2, 5.1 Hz,
1 H), 3.73–3.62 (m, 2 H), 1.43 (s, 3 H), 1.31 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 176.3, 138.3, 138.2, 138.1, 137.5,
137.2, 128.6, 128.5, 128.5, 128.4, 128.2, 128.1, 128.0, 128.0, 127.9,
127.8, 127.7, 112.3, 111.8, 104.9, 83.0, 82.7, 82.6, 78.8, 75.9, 73.7,
73.3, 72.9, 72.7, 71.5, 67.5, 59.7, 58.6, 50.0, 27.0, 26.3 ppm. IR
73.4, 72.8, 67.7, 59.5, 58.2, 55.1, 53.7, 26.5, 24.9 ppm. IR (neat): ν
˜
= 3020, 2930, 2856, 1766, 1644, 1455, 1374, 1217, 1104, 868,
699 cm–1. HRMS (ESI): calcd. for C36H42NO8 [M + 1]+ 616.2910;
found 616.2905.
(neat): ν = 3033, 2987, 2933, 2870, 1763, 1497, 1454, 1375, 1215,
˜
(2S,3R,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(3aS,4S,6R,6aS)-tetrahydro-4-methoxy-2,2-dimethylfuro[3,4-
d][1,3]dioxol-6-yl]-1-azabicyclo[3.2.0]heptan-7-one (31): According
to the general procedure, starting from alkyne 16 (36 mg,
0.18 mmol) and nitrone 9 (50 mg, 0.12 mmol), β-lactam 31 was ob-
tained as a colorless oil (40 mg, 55%) after purification by silica
gel column chromatography (27% ethyl acetate/hexanes). Rf = 0.6
(25% ethyl acetate/hexanes). [α]2D0 = 73.5 (c = 0.50, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.33–7.21 (m, 15 H), 4.82 (s, 1 H),
4.77 (dd, J = 5.8, 2.9 Hz, 1 H), 4.68–4.50 (m, 7 H), 4.19–4.10 (m,
2 H), 4.05–3.95 (m, 4 H), 3.77–3.51 (m, 2 H), 3.11 (s, 3 H), 1.46 (s,
3 H), 1.32 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.3,
138.1, 137.8, 138.7, 128.4, 128.3, 127.7, 127.6, 127.3, 112.8, 107.6,
84.7, 82.3, 80.0, 78.1, 75.5, 73.5, 73.1, 72.3, 67.2, 59.6, 58.2, 55.1,
1164, 1075, 1026, 885, 698 cm–1. HRMS (ESI): calcd. for
C42H46NO8 [M + 1]+ 692.3223; found 692.3220.
(2S,3R,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-[(3aR,5R,
5aS,8aS,8bR)-tetrahydro-2,2,7,7-tetramethyl-3aH-bis[1,3]dioxolo-
[4,5-b:4Ј,5Ј-d]pyran-5-yl]-1-azabicyclo[3.2.0]heptan-7-one (28, Mix-
ture): According to the general procedure, starting from alkyne 13
(46 mg, 0.18 mmol) and nitrone 9 (50 mg, 0.12 mmol), a mixture
of β-lactam 28 and alkyne dimer 38 was obtained as a colorless oil
(40 mg, 50%) after purification by silica gel column chromatog-
raphy (27% ethyl acetate/hexanes). Rf = 0.6 (25% ethyl acetate/
1
hexanes). H NMR (400 MHz, CDCl3): δ = 7.36–7.09 (m, 15 H),
5.49 (d, J = 4.8 Hz, 1 H), 4.70–4.50 (m, 7 H), 4.38 (dd, J = 7.9,
1.5 Hz, 1 H), 4.25–4.21 (m, 3 H), 4.10 (t, J = 5.8 Hz, 1 H), 3.99–
3.94 (m, 2 H), 3.80–3.67 (m, 3 H), 1.46 (s, 3 H), 1.41 (s, 3 H), 1.31
(s, 3 H), 1.29 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
176.7, 138.4, 138.3, 137.8, 128.5, 128.5, 128.3, 127.9, 127.9, 127.8,
127.7, 110.2, 109.5, 109.1, 108.4, 96.5, 96.4, 82.9, 73.5, 73.3, 72.9,
72.7, 71.5, 70.8, 70.7, 70.5, 70.3, 67.1, 64.5, 60.9, 59.8, 58.9, 51.1,
50.4, 26.0, 24.7 ppm. IR (neat): ν = 3020, 1762, 1650, 1430, 1286,
˜
1216, 1108, 1022, 929, 883, 669 cm–1. HRMS (ESI): calcd. for
C36H42NO8 [M + 1]+ 616.2910; found 616.2912.
(3S,4S)-3,4-Bis(benzyloxy)-6-[(3aR,5R,6S,6aR)-6-(benzyloxy)-tetra-
hydro-2,2-dimethylfuro[2,3-d][1,3]dioxol-5-yl]-1-azabicyclo-
[3.2.0]heptan-7-one (32): According to the general procedure, start-
ing from alkyne 12 (70 mg, 0.26 mmol) and nitrone 10 (50 mg,
26.3, 26.2, 26.1, 24.9, 24.7, 24.6, 24.5 ppm. IR (neat): ν = 2988,
˜
2931, 2856, 1762, 1639, 1455, 1383, 1258, 1214, 1167, 1103, 1069,
6124
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6117–6127

A Stereoselective Synthesis of Sugar-Derived Chiral β-Lactams
0.17 mmol), β-lactam 32 was obtained as a colorless oil (40 mg,
(dd, J = 5.8, 1.4 Hz, 1 H), 3.73 (dd, J = 12.0, 5.8 Hz, 1 H), 3.31 (s,
59%) after purification by silica gel column chromatography (27% 3 H), 3.03–2.99 (m, 1 H), 1.37 (s, 3 H), 1.30 (s, 3 H) ppm. 13C
ethyl acetate/hexanes). Rf = 0.6 (25% ethyl acetate/hexanes). [α]2D0
NMR (100 MHz, CDCl3): δ = 177.1, 137.7, 137.1, 128.8, 128.7,
128.6, 128.3, 128.1, 127.9, 127.8, 112.8, 110.0, 85.9, 85.6, 83.2, 82.7,
1
= 42.8 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.38–
7.18 (m, 15 H), 5.87 (d, J = 3.6 Hz, 1 H), 4.73 and 4.67 (ABq, J =
11.3 Hz, 2 H), 4.62 (d, J = 11.3 Hz, 1 H), 4.56–4.49 (m, 4 H), 4.35
(d, J = 11.3 Hz, 1 H), 4.21 (s, 1 H), 4.14 (d, J = 3.2 Hz, 1 H), 4.05
(dd, J = 11.3, 5.8 Hz, 1 H), 4.04–4.01 (m, 2 H), 3.87 (dd, J = 5.8,
1.4 Hz, 1 H), 3.01 (dd, J = 13.1, 3.2 Hz, 1 H), 1.23 (s, 3 H), 1.07
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.2, 137.8, 137.6,
137.1, 128.5, 128.1, 128.0, 127.9, 111.7, 104.7, 86.3, 83.0, 82.3, 76.2,
82.2, 72.6, 71.1, 61.1, 56.2, 55.0, 50.4, 26.4, 25.0 ppm. IR (neat): ν
˜
= 2930, 2855, 1768, 1632, 1454, 1373, 1271, 1217, 1108, 1018, 869,
699 cm–1. HRMS (ESI): calcd. for C28H34NO7 [M + 1]+ 496.2335;
found 496.2331.
(3S,4S)-3,4-Bis(benzyloxy)-6-[(3aS,4S,6R,6aS)-tetrahydro-4-
methoxy-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl]-1-azabicyclo-
[3.2.0]heptan-7-one (36): According to the general procedure, start-
ing from alkyne 16 (52 mg, 0.26 mmol) and nitrone 10 (50 mg,
0.17 mmol), β-lactam 36 was obtained as a colorless oil (50 mg,
83%) after purification by silica gel column chromatography (27%
ethyl acetate/hexanes). Rf = 0.6 (25% ethyl acetate/hexanes). [α]2D0
72.7, 72.4, 71.0, 60.3, 51.7, 50.3, 26.5, 26.4 ppm. IR (neat): ν =
˜
3020, 2930, 1761, 1455, 1375, 1216, 1164, 1092, 1020, 930,
699 cm–1. HRMS (ESI): calcd. for C34H38NO7 [M + 1]+ 572.2648;
found 572.2645.
1
= 43.0 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.36–
(3S,4S)-3,4-Bis(benzyloxy)-6-[(3aR,5R,5aS,8aS,8bR)-tetrahydro-
2,2,7,7-tetramethyl-3aH-bis[1,3]dioxolo[4,5-b:4Ј,5Ј-d]pyran-5-yl]-
1-azabicyclo[3.2.0]heptan-7-one (33, Mixture): According to the ge-
neral procedure, starting from alkyne 13 (66 mg, 0.26 mmol) and
nitrone 10 (50 mg, 0.17 mmol), a mixture of β-lactam 33 and alkyne
dimer 38 was obtained as a colorless oil (40 mg, 61%) after purifi-
cation by silica gel column chromatography (27% ethyl acetate/hex-
7.23 (m, 10 H), 4.78 (s, 1 H), 4.62 (dd, J = 5.8, 3.5 Hz, 1 H), 4.59–
4.52 (m, 4 H), 4.43 (d, J = 5.9 Hz, 1 H), 4.37 (d, J = 11.8 Hz, 1
H), 4.26 (dd, J = 11.4, 3.3 Hz, 1 H), 4.15 (s, 2 H), 4.08 (dd, J =
11.4, 5.9 Hz, 1 H), 4.03 (d, J = 13.3 Hz, 1 H), 3.91 (dd, J = 5.9,
1.0 Hz, 1 H), 3.04 (s, 3 H), 1.47 (s, 3 H), 1.30 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 177.3, 137.6, 137.3, 128.7, 128.6,
128.1, 128.0, 127.8, 127.7, 112.8, 107.4, 85.9, 85.1, 81.6, 79.8, 75.7,
1
anes). Rf = 0.6 (25% ethyl acetate/hexanes). H NMR (400 MHz,
71.8, 70.7, 60.5, 54.7, 52.2, 51.1, 26.3, 25.0 ppm. IR (neat): ν =
˜
CDCl3): δ = 7.37–7.21 (m, 10 H), 5.46 (d, J = 5.1 Hz, 1 H), 4.64–
4.57 (m, 2 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.50 (dd, J = 7.6, 2.2 Hz,
1 H), 4.33 (dd, J = 7.6, 1.8 Hz, 1 H), 4.27–4.07 (m, 6 H), 4.04 (dd,
J = 11.3, 5.8 Hz, 1 H), 3.81 (dd, J = 5.8, 1.0 Hz, 1 H), 2.93 (dd, J
= 13.1, 2.5 Hz, 1 H), 1.47 (s, 3 H), 1.38 (s, 3 H), 1.21 (s, 3 H), 1.18
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.8, 138.0,
136.8, 128.8, 128.5, 128.5, 128.1, 128.0, 127.9, 109.3, 108.6, 96.4,
86.4, 82.4, 72.5, 71.4, 70.8, 70.4, 64.5, 60.5, 52.5, 49.3, 26.2, 25.4,
2935, 1771, 1645, 1454, 1374, 1216, 1163, 1109, 1019, 967, 880,
699 cm–1. HRMS (ESI): calcd. for C28H34NO7 [M + 1]+ 496.2335;
found 496.2331.
1,4-Bis{(3aR,5R,6S,6aR)-6-(benzyloxy)-tetrahydro-2,2-dimethyl-
furo[2,3-d][1,3]dioxol-5-yl}buta-1,3-diyne (37): According to the ge-
neral procedure, starting from alkyne 12 (66 mg, 0.24 mmol) and
nitrone 11 (40 mg, 0.16 mmol), alkyne dimer 37 (50 mg, 38%) was
obtained as a pale-yellow solid after purification by silica gel col-
umn chromatography (25% ethyl acetate/hexanes). Rf = 0.65 (25%
ethyl acetate/hexanes). M.p. 102 °C. [α]2D0 = 14.1 (c = 0.50, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.37–7.21 (m, 10 H), 5.96 (d, J
= 3.7 Hz, 2 H), 4.90 (d, J = 2.9 Hz, 2 H), 4.75 and 4.70 (ABq, J =
12.0 Hz, 4 H), 4.57 (d, J = 3.7 Hz, 2 H), 4.00 (d, J = 2.9 Hz, 2 H),
1.46 (s, 6 H), 1.29 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 136.9, 128.4, 127.9, 127.8, 112.1, 104.7, 82.8, 82.5, 73.4, 72.7,
24.8, 24.6 ppm. IR (neat): ν = 2931, 1767, 1637, 1456, 1373, 1313,
˜
1259, 1216, 1166, 1115, 1069, 1000, 901, 699 cm–1. HRMS (ESI):
calcd. for C31H38NO8 [M + 1]+ 552.2597; found 552.2587.
(3S,4S)-3,4-Bis(benzyloxy)-6-[(3aR,6R,6aS)-tetrahydro-2,2-di-
methylfuro[3,4-d][1,3]dioxol-6-yl]-1-azabicyclo[3.2.0]heptan-7-one
(34): According to the general procedure, starting from alkyne 14
(44 mg, 0.26 mmol) and nitrone 10 (50 mg, 0.17 mmol), β-lactam
34 was obtained as a colorless oil (50 mg, 82%) after purification
by silica gel column chromatography (27% ethyl acetate/hexanes).
Rf = 0.6 (25% ethyl acetate/hexanes). [α]2D0 = 104.2 (c = 0.20,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.23 (m, 10 H),
4.69–4.49 (m, 5 H), 4.29 (d, J = 11.3 Hz, 1 H), 4.15 (d, J = 3.4 Hz,
1 H), 4.10 (s, 1 H), 4.08 (dd, J = 11.3, 5.8 Hz, 1 H), 4.02 (d, J =
13.2 Hz, 1 H), 3.92 (d, J = 10.6 Hz, 1 H), 3.88 (dd, J = 5.8, 1.8 Hz,
1 H), 3.61 (dd, J = 11.3, 3.3 Hz, 1 H), 3.21 (dd, J = 10.6, 3.3 Hz,
1 H), 3.03 (dd, J = 13.2, 3.4 Hz, 1 H), 1.49 (s, 3 H), 1.33 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 177.1, 137.7, 137.4, 128.6,
128.1, 128.0, 112.5, 86.5, 81.9, 81.1, 80.5, 78.1, 72.8, 72.1, 70.9,
71.9, 71.2, 26.7, 26.1 ppm. IR (neat): ν = 3020, 2989, 2934, 1555,
˜
1455, 1376, 1217, 1163, 1075, 911, 858, 698 cm–1. HRMS (ESI):
calcd. for C32H34O8Na [M + Na]+ 569.2151; found 569.2169.
1,4-Bis[(3aR,5R,5aS,8aS,8bR)-tetrahydro-2,2,7,7-tetramethyl-3aH-
bis[1,3]dioxolo[4,5-b:4Ј,5Ј-d]pyran-5-yl]buta-1,3-diyne (38): Accord-
ing to the general procedure, starting from alkyne 13 (61 mg,
0.24 mmol) and nitrone 11 (40 mg, 0.16 mmol), alkyne dimer 38
(40 mg, 50%) was obtained as a colorless solid after purification
by silica gel column chromatography (25% ethyl acetate/hexanes).
Rf = 0.65 (25% ethyl acetate/hexanes). M.p. 98 °C. [α]2D0 = –263.4
1
60.3, 52.3, 50.7, 26.2, 24.9 ppm. IR (neat): ν = 2930, 1769, 1645,
˜
(c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 5.92 (d, J =
1455, 1380, 1217, 1112, 1028, 924, 700 cm–1. HRMS (ESI): calcd.
for C27H32NO6 [M + 1]+ 466.2230; found 466.2225.
4.7 Hz, 2 H), 4.64 (d, J = 1.5 Hz, 2 H), 4.60 (dd, J = 7.6, 2.5 Hz,
2 H), 4.30 (dd, J = 4.7, 2.5 Hz, 2 H), 4.25 (dd, J = 7.6, 1.5 Hz, 2
H), 1.52 (s, 6 H), 1.50 (s, 6 H), 1.36 (s, 6 H), 1.32 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 110.0, 108.9, 96.3, 74.2, 72.6,
(3S,4S)-3,4-Bis(benzyloxy)-6-[(3aS,4R,6R,6aS)-tetrahydro-4-
methoxy-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl]-1-azabicyclo-
[3.2.0]heptan-7-one (35, Mixture): According to the general pro-
cedure, starting from alkyne 15 (52 mg, 0.26 mmol) and nitrone 10
(50 mg, 0.17 mmol), a mixture of β-lactam 35 and alkyne dimer 40
was obtained as a colorless oil (40 mg, 67%) after purification by
silica gel column chromatography (27% ethyl acetate/hexanes). Rf
70.6, 70.4, 70.1, 60.8, 26.1, 26.0, 24.7, 24.4 ppm. IR (neat): ν =
˜
2989, 2932, 1556, 1458, 1383, 1257, 1213, 1165, 1068, 998,
896 cm–1. HRMS (ESI): calcd. for C26H35O10 [M + 1]+ 507.2230;
found 507.2219.
1,4-Bis[(3aS,4R,6aR)-tetrahydro-2,2-dimethylfuro[3,4-d][1,3]dioxol-
4-yl]buta-1,3-diyne (39): According to the general procedure, start-
1
= 0.6 (25% ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ
= 7.38–7.26 (m, 10 H), 4.92–4.90 (m, 2 H), 4.68–4.54 (m, 5 H), ing from alkyne 14 (40 mg, 0.24 mmol) and nitrone 11 (40 mg,
4.38–4.30 (m, 2 H), 4.18–4.17 (m, 1 H), 4.01–3.97 (m, 1 H), 3.79 0.16 mmol), alkyne dimer 39 (15 mg, 34%) was obtained as a color-
Eur. J. Org. Chem. 2011, 6117–6127
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6125

R. K. Khangarot, K. P. Kaliappan
FULL PAPER
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less oil after purification by silica gel column chromatography (25%
ethyl acetate/hexanes). Rf = 0.65 (25 % ethyl acetate/hexanes).
1
[α]2D0 = –73.0 (c = 0.50, CHCl3). H NMR (400 MHz, CDCl3): δ =
4.78 (dd, J = 6.1, 3.7 Hz, 2 H), 4.71 (dd, J = 6.1, 3.9 Hz, 2 H), 4.23
(d, J = 3.9 Hz, 2 H), 4.05 (d, J = 10.7 Hz, 2 H), 3.49 (dd, J = 10.7,
3.7 Hz, 2 H), 1.54 (s, 6 H), 1.35 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 113.3, 81.5, 81.0, 76.2, 73.0, 72.9, 26.3, 25.3 ppm. IR
(neat): ν = 3271, 2987, 2937, 2853, 1456, 1382, 1271, 1216, 1213,
˜
1164, 1108, 984, 861 cm–1. HRMS (ESI): calcd. for C18H23O6 [M
+ 1]+ 335.1495; found 335.1484.
[2]
[3]
1,4-Bis[(3aR,4R,6R,6aR)-tetrahydro-6-methoxy-2,2-dimethylfuro-
[3,4-d][1,3]dioxol-4-yl]buta-1,3-diyne (40): According to the general
procedure, starting from alkyne 15 (48 mg, 0.24 mmol) and nitrone
11 (40 mg, 0.16 mmol), alkyne dimer 40 (15 mg, 20%) was obtained
as a colorless solid after purification by silica gel column
chromatography (25% ethyl acetate/hexanes). Rf = 0.65 (25% ethyl
acetate/hexanes). M.p. 154 °C. [α]2D0 = –69.7 (c = 1.00, CHCl3). H
1
[4]
[5]
NMR (400 MHz, CDCl3): δ = 5.03 (s, 2 H), 4.87 (d, J = 5.8 Hz, 2
H), 4.83 (s, 2 H), 4.66 (d, J = 5.8 Hz, 2 H), 3.38 (s, 6 H), 1.44 (s,
6 H), 1.29 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 113.1,
109.4, 85.3, 85.2, 75.3, 69.9, 54.7, 26.5, 25.1 ppm. IR (neat): ν =
˜
2989, 2932, 1556, 1458, 1374, 1271, 1213, 1196, 1108, 1056, 1029,
953, 868 cm–1. HRMS (ESI): calcd. for C20H26O8Na [M + Na]+
417.1525; found 417.1540.
1,4-Bis[(3aS,4R,6S,6aS)-tetrahydro-6-methoxy-2,2-dimethylfuro-
[3,4-d][1,3]dioxol-4-yl]buta-1,3-diyne (41): According to the general
procedure, starting from alkyne 16 (48 mg, 0.25 mmol) and nitrone
11 (40 mg, 0.16 mmol), alkyne dimer 41 (30 mg, 30%) was obtained
as a colorless oil after purification by silica gel column chromatog-
raphy (25% ethyl acetate/hexanes). Rf = 0.65 (25% ethyl acetate/
hexanes). [α]2D0 = –26.8 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 4.93 (s, 2 H), 4.75 (dd, J = 5.8, 4.0 Hz, 2 H), 4.68 (d,
J = 4.0 Hz, 2 H), 4.55 (d, J = 5.8 Hz, 2 H), 3.33 (s, 6 H), 1.51 (s,
6 H), 1.34 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 113.5,
107.1, 84.7, 80.7, 73.0, 72.3, 71.3, 54.9, 26.3, 25.3 ppm. IR (neat):
[6]
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˜
HRMS (ESI): calcd. for C20H27O8 [M + 1]+ 395.1706; found
395.1707.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data including 1H and 13C NMR spectra for
all the compounds.
[10]
Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi, for financial support and SAIF, IIT Bombay, for the use
of spectral facilities. K. P. K. thanks the DST for the award of a
Swarnajayanti fellowship and AstraZeneca Research Foundation
for partial financial support. R. K. K. thanks the Council of Scien-
tific and Industrial Research (CSIR), New Delhi, for a fellowship.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: June 30, 2011
Published Online: August 18, 2011
Eur. J. Org. Chem. 2011, 6117–6127
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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